Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21](I)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([C:31]4[N:32]=[C:33]([CH:36]=[O:37])[S:34][CH:35]=4)=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc2c(Nc3ccc(Oc4ccccc4)cc3)ccnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(C=O)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: O=Cc1nc(-c2ccc3c(Nc4ccc(Oc5ccccc5)cc4)ccnc3c2)cs1
Yield: 44 %

Procedure:
Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol), 4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g,4.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol%) heated at reflux overnight (18 hrs) in dioxane (50 ml). The cooled solution was filtered through a plug of Celite®, concentrated and triturated with iso-hexane (3×20 ml). The resultant solid was purified via flash column chromatography on silica gel, eluting with 5% methanol in chloroform. The purified product was isolated as a yellow solid (0.85 g, 44%). δH [2H6] DMSO 10.10(1H,s), 9.30(1,bs), 8.90(1Hs), 8.50(2H,s&d), 8.45(1H,d), 8.20(1H,d), 7.40(5H,bm), 7.10(4H,2d), 6.80(1H,d).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10](=O)[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15].[BH4-].[Na+]>C(O)(C)C>[Br:1][C:2]1[C:11]2[CH:10]=[CH:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: O=C1CCCc2ccc(NS(=O)(=O)c3ccc(F)cc3)c(Br)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=S(=O)(Nc1ccc2c(c1Br)C=CCC2)c1ccc(F)cc1
Temperature: 25 °C
Yield: 65.4 %

Procedure:
A mixture of Example 103A (150 mg, 0.38 mmol) and NaBH4 (14.3 mg, 0.38 mmol) in isopropanol (3 mL) was heated to reflux overnight and partitioned between diethyl ether and brine. The organic phase was dried (Na2SO4), filtered, concentrated, dissolved in toluene (5 mL), and treated with p-toluenesulfonic acid. The mixture was heated to reflux for 1 hour, cooled to room temperature, and passed through a silica gel plug with dichloromethane to provide the desired product (95 mg, 68% yield). MS (DCI/NH3) m/e 400 (M+NH4)+; 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.75 (m, 2H), 7.39 (m, 2H), 7.08 (d, 1H), 6.9 (d, 1H), 6.69 (m, 1H), 6.22 (m, 1H), 2.71 (t, 2H), 2.21 (m, 2H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15](OCC)=[O:16])[CH:11]=1.C([Mg]Cl)(C)C.Cl>C1COCC1>[Br:5][C:6]1[N:7]=[C:8]([NH:26][C:27]([CH3:43])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:28])[C:9](=[O:25])[N:10]([C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([F:24])[C:22]=2[CH3:23])[C:15]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[O:16])[CH:11]=1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC(C)(C)c3ccccc3OCc3ccccc3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC(C)(C)c2ccccc2OCc2ccccc2)c1=O
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Cyclopropylamine (1.86 mL) was added to 3-[5-bromo-3-[[1-methyl-1-[2-(phenylmethoxy)phenyl]ethyl]amino]-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methyl-benzoic acid, ethyl ester (Example 169e, 1.6 g) in THF (24 mL) under nitrogen at room temperature and isopropylmagnesium chloride (5.28 mL of a 2M solution in THF) was then added dropwise over 10 min. The resulting solution was stirred at 75° C. for 16 h. After cooling to room temperature, the solution was acidified with 2M HCl and extracted into dichloromethane. The organic fractions were concentrated in vacuo to give the subtitle compound (0.7 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][NH:16][CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[Cl:29][CH:30]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32].COC(C)(C)C>CN(C)C=O.ClCCl.Cl.CCOCC>[ClH:29].[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][N:16]([CH:30]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)c1ccccc1Cl
Reactant: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CNCC2
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(c1ccccc1Cl)N1CCc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 77.2 g of 3-benzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione, 63 g of ethyldiisopropylamine and 126 g of ethyl chloro(2-chlorophenyl)-acetate (89% pure according to GC) in 1700 ml of dimethylformamide was stirred for 48 h at room temperature. It was concentrated under reduced pressure and the residue was worked up by extraction with dichloromethane and water. The dichloromethane phases were combined, dried and concentrated. The residue was diluted with 50 ml of dichloromethane, 1.3 equivalents of a solution of hydrochloric acid in ether were added dropwise at room temperature, with stirring, and 700 ml of tert-butyl methyl ether were added slowly. This initially gave an oil, which solidified gradually to a white mass. This ethyl (3-benzyl-2,4-dioxo-2,3,4,5,7,8-hexahydro-1H-pyrido[4,3-d]pyrimidin-6-yl)(2-chlorophenyl)acetate hydrochloride was purified by recrystallization from dichloromethane/diethyl ether.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][CH:18]=1>>[O:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:17]([CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:18]1
Reactant: BrCc1coc2ccccc12
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Product: O=C(O)c1cc2ccccc2n1Cc1coc2ccccc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-benzofuran (Lit. 19) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 290.2 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[CH2:9][NH:8]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([N:8]1[CH2:9][C:10](=[O:14])[NH:11][C:12](=[O:13])[N:7]1[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:19])[CH3:18]
Reactant: O=C1CNN(Cc2ccc(Cl)cc2)C(=O)N1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CC(=O)NC(=O)N1Cc1ccc(Cl)cc1
Reaction time: 8 h
Yield: 60 %

Procedure:
Into a 100 ml round bottomed flask equipped with an efficient condenser and a calcium chloride tube were placed 10 ml of acetic anhydride and 0.5 g of 2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5 dione. The mixture was refluxed for 3 hours, then was cooled and poured on ice water, and left overnight. The crystals that separated were filtered off by suction and dried. The product was recrystallized from isopropanol to give 0.3 g (60%) of 1-acetyl-2-(4'-chlorobenzyl)-hexahydro-1,2,4-triazine-3,5-dione; m.p. 100°.
Reaction SMILES: [OH:1][C:2]([CH3:42])([CH3:41])[CH:3]([CH3:40])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1.C[Si]([N:47]=[N+:48]=[N-:49])(C)C.C([Sn](=O)CCCC)CCC.C1(C)C=CC=CC=1>O.C(OCC)(=O)C>[OH:1][C:2]([CH3:41])([CH3:42])[CH:3]([CH3:40])[O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[NH:49][N:48]=[N:47][N:32]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[C:37]([CH3:39])[N:38]=[C:12]23)[CH2:7][CH2:6]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OC(C)C(C)(C)O)CC2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 4′-({4-[trans-4-(2-hydroxy-1,2-dimethylpropoxy)cyclohexyl]-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.24 g), trimethylsilylazide (1.4 g), dibutyltinoxide (0.052 g) and toluene (15 mL) was heated under reflux for 134 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). Tetrabutylammonium fluoride (1.0 mL, 1.0 M tetrahydrofuran solution) was added, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized (ethyl acetate) to give the title compound as a colorless solid (0.070 g, 26%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[NH3:11]>C(Cl)Cl>[NH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: N
Solvent: ClCCl
Product: N#Cc1c(N)cccc1F
Yield: 98.1 %

Procedure:
50 parts of 2,6-difluorobenzonitrile and 40 parts by volume of ammonia are stirred for 10 hours at 100° C. in a closed vessel. The reaction mixture is taken up in methylene chloride, the solid is filtered off, the organic phase is extracted three times by shaking with water and is dried over sodium sulfate, the solvent is stripped off and the residue is dried under reduced pressure. 48 parts (98.1% of theory) of 2-amino-6-fluoro-benzonitrile, of solidification point 125°-128° C., are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[NH:7][C:6]1=[O:16].[I-].[CH3:19][N:20]1[C:28]2[C:23](=[C:24]([CH3:29])[CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:30][N+](C)(C)C)=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][N:14]=[CH:15][C:8]=2[N:7]([CH2:30][C:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[N:20]([CH3:19])[CH:21]=2)[C:6]1=[O:16]
Reactant: COC(=O)Cn1c(=O)[nH]c2cnccc2c1=O
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1c(=O)c2ccncc2n(Cc2cn(C)c3cccc(C)c23)c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.7 %

Procedure:
To a solution of 62 mg of (2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl)-acetic acid methyl ester in N,N-dimethylformamide (2.5 mL) is added 109 mg of (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethylammonium iodide and 44 mg of potassium carbonate at room temperature. The solution is heated to 60° C. for 2.5 h. Then the reaction is cooled to room temperature and stirred for another 16 hrs. Then 50 mL of water is added and a pale yellow solid is formed. The solid is collected and rinsed with water. Purification of this solid by flash chromatography on silica gel gives 98 mg (95%) of [1-(1,4-dimethyl-1H-indol-3-ylmethyl)-2,4-dioxo-1,4-dihydro-2H-pyrido[3,4-d]pyrimidin-3-yl]-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH2:21]>>[CH3:17][O:18][C:19](=[O:22])[CH2:20][NH:21][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)CN
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared by the general method of Preparation 1 using 198 g (0.79 mole) of t-butoxycarbonyl-D-methionine (Boc-D-Met) and 99.5 g (0.79 mole) glycine methyl ester (Gly-OMe) hydrochloride. The title compound was isolated as an analytically pure solid without further purification.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24](O)=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:60][C:61]1[CH:62]=[C:63]([CH:73]=[C:74]([C:76]([F:79])([F:78])[F:77])[CH:75]=1)[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69]>CN(C=O)C.O>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([CH2:18][CH2:19][CH:20]([C:24]([NH:60][C:61]5[CH:62]=[C:63]([CH:73]=[C:74]([C:76]([F:77])([F:78])[F:79])[CH:75]=5)[CH2:64][NH:65][C:66](=[O:72])[O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:25])[CH2:21]4)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)C1CCc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cc2C1
Reactant: CC(C)(C)OC(=O)NCc1cc(N)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cc(NC(=O)C2CCc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3C2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.7 %

Procedure:
To a solution of 7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (3.03 g, 8.61 mmol) in DMF (75 mL), was added DIPEA (4.50 mL, 25.8 mmol) and HATU (4.91 g, 12.9 mmol). The reaction mixture was allowed to stir at rt for 30 min, and then tert-butyl [3-amino-5-(trifluoromethyl)benzyl]carbamate (2.50 g, 8.61 mmol) was added. The reaction mixture was allowed to stir for 18 h. Water was added and the precipitate was filtered, washed with water and hexane and dried under vacuum. The residue was purified by column chromatography to give tert-butyl [3-({[7-({2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalen-2-yl]carbonyl}-amino)-5-(trifluoromethyl)benzyl]carbamate (3.80 g, 70.6%) as a yellow solid. LCMS: (FA) ES+ 625.6, ES− 623.4.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][O:26][CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=3)[S:10][C:11]=2[C:12]([N:25]([O:26][CH3:27])[CH3:24])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C(O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a solution of 4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazole-5-carboxylic acid (850 mg, 2.57 mmol) in DMF (11.9 mL) was added N,O-dimethylhydroxylamine hydrochloride (852 mg, 8.74 mmol), HATU (1.95 g, 5.14 mmol) and diisopropylethylamine (2.42 mL, 13.9 mmol) and the resulting solution was stirred at room temperature overnight. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (3×30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→80/20) to give 775 mg of the title compound as a yellow solid (80% yield). LC/MS (FA) ES+ 374. 1H NMR (400 MHz, CDCl3) δ: 8.72-8.70 (m, 2H), 7.84-7.82 (m, 2H), 7.37-7.34 (m, 2H), 7.25-7.22 (m, 2H). 4.56 (s, 2H), 3.70 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[N:20](C(=O)C)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)n1cc(CC2CC(O)CN2C(=O)OCc2ccccc2)c2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC(O)CC1Cc1c[nH]c2ncccc12
Reaction time: 1 h

Procedure:
To a solution containing 71 (2.11 g, 5.36 mmol) in MeOH (30 mL) at 0° C. was added 1M NaOH (8.1 mL, 8.05 mmol) in a dropwise fashion. After 1 h, TLC analysis revealed complete consumption of 71 [EtOAc, Rf(71)=0.4; Rf(72)=0.2]. The MeOH was removed in vacuo and the residue was dissolved in EtOAc, washed with dilute aqueous HCl, water, brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 1.99 g of crude 72 which was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].Cl.[NH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[OH:21].C(N(CC)CC)C>C(#N)C>[C:10]([C@@H:9]1[N:5]([C:3](=[O:4])[CH2:2][NH:15][CH:16]2[CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:21])[C@H:6]([C:12]#[N:13])[CH2:7][CH2:8]1)#[CH:11]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCC[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.040 g, 0.20 mmol, Example 8D) in acetonitrile (1 mL) at room temperature was added trans-2-aminocyclopentanol hydrochloride (56 mg, 0.41 mmol) and triethylamine (0.14 ml, 1.02 mmol). The reaction mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure and purified by flash chromatography with 3% methanol:dichloromethane to provide the titled compound. MS (ESI) m/z 262 (M+H)+; 1H NMR (MeOH) 4.79 (m, 1H), 4.17-4.40 (m, 3H), 3.18 (m, 1H), 2.48 (m, 4H); 2.00-2.30 (m, 4H), 1.80 (m, 2H), 1.66 (2H, m).
Reaction SMILES: Cl.C([O:4][C:5](=[O:25])[CH:6]([NH:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)[CH:9]=1)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>O>[CH2:22]([O:21][C:19]([NH:18][CH:6]([CH2:7][C:8]1[O:12][N:11]=[C:10]([CH:13]2[CH2:17][CH2:16][CH2:15][N:14]2[S:40]([C:35]2[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=2)(=[O:42])=[O:41])[CH:9]=1)[C:5]([OH:4])=[O:25])=[O:20])[CH:23]=[CH2:24]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2S(=O)(=O)c2cc(Cl)cc(Cl)c2)no1)C(=O)O
Reaction time: 8 h
Yield: 38.7 %

Procedure:
2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (110 mg, 0.294 mmol) and sodium carbonate (93.5 mg, 0.882 mmol) were dissolved in water (1.5 mL) and 3,5-dichlorobenzenesulfonylchloride (86.7 mg, 0.353 mmol) was added. This mixture was stirred overnight. The reaction was extracted twice with dichloromethane. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (59 mg, 37%). MS (Cl) m/z 545.7 (M+1) C. 2-Allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride
Reaction SMILES: [ClH:1].[CH2:2]([N:6]([CH2:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:7]([CH:9]1[O:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:8])[CH:3]([CH3:5])[CH3:4].[CH:27](=O)[C:28]1[C:29]([O:34][CH3:35])=[CH:30][CH:31]=[CH:32][CH:33]=1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[ClH:1].[CH2:2]([N:6]([CH2:15][C:16]1[CH:26]=[CH:25][C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:7]([CH:9]1[O:14][CH2:13][CH2:12][N:11]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH2:10]1)=[O:8])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CN(Cc1ccc2c(c1)OCCCC2)C(=O)C1CNCCO1
Reactant: COc1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccccc1CN1CCOC(C(=O)N(Cc2ccc3c(c2)OCCCC3)CC(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
A mixture of 31 mg (0.080 mmol) of (±)-N-isobutyl-N-(2,3,4,5-tetrahydro-1-benzoxepin-8-ylmethyl)morpholine-2-carboxamide hydrochloride, 0.0106 mL (0.088 mmol) of o-anisaldehyde, and 6.6 mg (0.080 mmol) of sodium acetate in 0.5 mL of 1,2-dichloroethane was stirred under nitrogen at ambient temperature for 10 minutes and 19 mg (0.088 mmol) of sodium triacetoxyborohydride was added. The mixture was stirred overnight then diluted with 5 mL of ethyl acetate and washed with 2 mL each of saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 41 mg of a colorless gum. Preparative TLC (60% ethyl acetate/hexanes) gave 25 mg (68%) of product free-base as a gum. The gum was taken up in 1 mL of methanol, treated with 5 drops of 4M HCl in dioxane, and the mixture was concentrated. The residue was triturated with ether, and dried under vacuum to give the hydrochloride salt as a solid white foam. MS (m+1)=467.3; H NMR (400 MHz, CD3OD) 7.45 (m, 2H), 7.10 (m, 3H), 6.85 (m, 2H), 4.97 (m, 1H), 4.81 (m, 1H), 4.56-4.39 (m, 3H), 4.1-3.7 (m, 8H), 3.6-3.2 (m, 3H), 3.2-2.85 (m, 2H), 2.77 (d, 2H, J 6 Hz), 2.04 (m, 1H), 1.94 (m, 2H), 1.70 (m, 2H), 0.90 (m, 6H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:14]=[CH:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:7][CH:8]=1.[H][H]>CO.[Ni]>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][C:12]3=[N:15][C:16]([CH2:18][O:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:17][N:11]3[C:10]2=[O:26])=[N:7][CH:8]=1
Reactant: [H][H]
Reactant: Cc1ccc(-n2ccc3nc(COc4ccccc4)cn3c2=O)nc1
Agent: [Ni]
Agent: Cl
Solvent: CO
Product: Cc1ccc(N2CCc3nc(COc4ccccc4)cn3C2=O)nc1
Yield: 5 %

Procedure:
A 1.25 M solution of HCl in MeOH (3 mL) was added to a stirred solution of 6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-6H-imidazo[1,2-c]pyrimidin-5-one (0.1 g, 0.3 mmol) in MeOH (10 mL) was hydrogenated in a H-cube reactor (1 mL/min, 30 mm Raney nickel cartridge, 30° C., full hydrogen mode, 4 cycles) and then (1 mL/min, 30 mm Raney nickel cartridge, RT, full hydrogen mode, 1 cycle). The solvents were evaporated in vacuo and the crude product was purified by flash column chromatography (silica; AcOEt in DCM with a gradient of 0/100 to 100/0 and then 7 M solution of ammonia in MeOH in DCM with a gradient of 0/100 to 2/98). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by RP HPLC (C18 XBridge 19×100 5 um, gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% CH3CN to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% ACN) to yield 6-(5-methyl-pyridin-2-yl)-2-phenoxymethyl-7,8-dihydro-6H-imidazo[1,2-c]pyrimidin-5-one (5 mg, 5% yield). 1H NMR (500 MHz, CDCl3) δ ppm 2.35 (s, 3H), 3.24 (t, J=6.6 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 5.03 (s, 2H), 6.97 (br. t, J=7.4, 7.4 Hz, 1H), 6.99-7.05 (m, 2H), 7.27-7.33 (m, 2H), 7.57 (dd, J=8.5, 2.2 Hz, 1H), 7.59 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 8.25 (dd, J=1.6, 0.7 Hz, 1H).