Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH2:19]([O:26][C:27](=[O:46])[CH:28]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:29][C:30](O)=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:3]1([NH:2][C:30](=[O:31])[CH2:29][CH:28]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:38][CH:39]=2)[C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:46])[CH2:7][CH2:6][CH2:5][CH2:4]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1(CC(=O)OCc2ccccc2)CCCC1
Reactant: O=C(O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1)NC1(CC(=O)OCc2ccccc2)CCCC1
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of benzyl 2-(1-aminocyclopentyl)acetate hydrochloride (66 mg, 0.245 mmol), 4-(benzyloxy)-3-(biphenyl-4-ylmethyl)-4-oxobutanoic acid (78 mg, 0.209 mmol), WSC.HCl (60.1 mg, 0.314 mmol) and 1-hydroxy-7-azabenzotriazole (42.7 mg, 0.314 mmol) in DMF (2 ml) was added DIPEA (0.055 ml, 0.314 mmol) at room temperature. After stirred for 4 hours, the reaction was quenched with H2O. The product was extracted with EtOAc, and the organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 0:100) to give benzyl 4-(1-(2-(benzyloxy)-2-oxoethyl)cyclopentylamino)-2-(biphenyl-4-ylmethyl)-4-oxobutanoate (93 mg); Retention time=1.85 minutes (condition B); MS (m+1)=590.3; 1H NMR (400 MHz, CDCl3, mixture of rotamers) δ ppm 1.61-1.72 (m, 6H) 1.96-2.06 (m, 2H) 2.17-2.46 (m, 2H) 2.81-3.00 (m, 4H) 3.22-3.29 (m, 1H) 5.02-5.12 (m, 4H) 5.62 (br s, 1H) 7.15-7.57 (m, 19H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.[CH:18]1([CH2:21]Br)[CH2:20][CH2:19]1.[ClH:23]>>[ClH:23].[ClH:23].[CH:18]1([CH2:21][O:17][C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:11][C:2]([CH3:1])=[N:3]3)=[CH:8][CH:7]=2)[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Agent: Cl
Product: Cc1cc(N2CCCC2)c2ccc(OCC3CC3)cc2n1

Procedure:
In analogy to example 3, from 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol, product of example 2, and cyclopropylmethyl bromide—with reaction times of 19 h (0° C.) and isolation of the product as hydrochloride, via treatment of the reaction product with HCl-saturated diethyl ether—there was obtained 7-cyclopropylmethoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as a white solid. ISP mass spectrum, m/e: 283.2 (M+1 calculated for C18H22N2O: 283).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH2:7]([O:9][C:10]([CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][C:18]([O:20]CC)=O)=[O:11])[CH3:8].C(O)(=O)C>C1COCC1>[O:20]=[C:18]1[CH2:17][O:16][CH2:15][CH2:14][O:13][CH:12]1[C:10]([O:9][CH2:7][CH3:8])=[O:11]
Reactant: CCOC(=O)COCCOCC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1OCCOCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixing was carried out under a protective nitrogen gas atmosphere. 7.93 g (80.0 mmol) sodium-tert-butoxide were placed in 150 ml THF and heated to boiling point. At this temperature 8.50 g (36.3 mmol) ethyl (2-ethoxycarbonylmethoxy-ethoxy)-acetate (prepared analogously to Canadian Journal of Chemistry; 74; 8; 1996; 1437-1446) in 100 ml THF were added dropwise within 3 h. After the addition had ended the mixture was refluxed for 1 h and then stirred overnight at RT. Then the reaction mixture was adjusted to pH 5 with glacial acetic acid and concentrated by rotary evaporation. The residue was mixed with water and extracted with ethyl acetate. The organic phases were combined, dried and the solvent was eliminated under reduced pressure and with gentle heating.
Reaction SMILES: CN(C)[C:3]1[CH:4]=[C:5](CO)[CH:6]=[CH:7][CH:8]=1.[Br:12][C:13]1[C:14]([CH3:20])=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1>>[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[C:14]=1[CH3:20]
Reactant: Cc1c(O)cccc1Br
Reactant: CN(C)c1cccc(CO)c1
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1c(Br)cccc1OC1CCCCC1

Procedure:
The title compound was prepared by substituting cyclohexanol for (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE 34A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH2:20][CH2:21]2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN2CCOCC2)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](CN2CCOCC2)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{[4-(morpholinomethyl)cyclohexyl]-amino}-1,5-naphthyridin-3-yl)ethanone (85 mg, 0.21 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (91 mg, 0.31 mmol) to afford the desired product (59 mg, 53%) as an orange solid: 1H NMR (500 MHz, CDCl3) δ 11.18-11.16 (m, 1H), 8.95 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.99 (s, 2H), 7.94 (d, J=8.8 Hz, 1H), 5.51-5.42 (m, 1H), 3.71 (t, J=4.7 Hz, 4H), 2.70 (s, 3H), 2.41-2.43 (m, 4H), 2.34-2.32 (m, 2H), 2.23-2.22 (m, 2H), 2.02-1.95 (m, 2H), 1.62-1.58 (m, 1H), 1.46-1.39 (m, 2H), 1.28-1.15 (m, 2H); ESI MS m/z 529 [M+H]+; HPLC 98.2% (AUC), tR=9.93 min.
Reaction SMILES: FC(F)(F)C(O)=[O:4].FC(F)(F)C([O-])=O.[C:15]([C:18]1[CH:19]=[C:20]([CH:45]=[CH:46][CH:47]=1)[CH2:21][N:22]1[C:30]2[C:25](=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:33]([NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][N+:41](C)=[CH:40][CH:39]=1)=[O:34])(=[NH:17])[NH2:16].Cl.NO.C(N(CC)CC)C>C(O)C>[N:41]1[CH:42]=[CH:43][C:38]([CH2:37][CH2:36][NH:35][C:33]([C:23]2[N:22]([CH2:21][C:20]3[CH:45]=[CH:46][CH:47]=[C:18]([C:15](=[NH:17])[NH:16][OH:4])[CH:19]=3)[C:30]3[C:25]([CH:24]=2)=[C:26]([O:31][CH3:32])[CH:27]=[CH:28][CH:29]=3)=[O:34])=[CH:39][CH:40]=1
Reactant: COc1cccc2c1cc(C(=O)NCCc1cc[n+](C)cc1)n2Cc1cccc(C(=N)N)c1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Agent: NO
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2c1cc(C(=O)NCCc1ccncc1)n2Cc1cccc(C(=N)NO)c1
Yield: 54 %

Procedure:
The starting material 1-(3-cyano-benzyl)-4-methoxy-1H-indole-2-carboxylic acid 2-(4-pyridyl)-ethyl amide (example 41) was dissolved in ethanol, 2.4 equivalents of hydroxylamine hydrochloride and 2.4 equivalents of triethylamine were added and the mixture was refluxed for 6.5 h. The precipitate was filtered off to give 54% of the desired product. M.p. 220-222° C. MS: 444.3 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 1,1-dimethylethyl bromoacetate: MS (ES) m/z 325 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([P:8]([CH3:9])([CH3:10])=[O:11])=[CH:6][CH:7]=2)[N:14]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CP(C)(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-amino-dimethylphenylphosphine oxide (3.7 g, 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, can be stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-1,3,5-triazine (2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature, filtered and purified by prep-HPLC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[CH2:10]([N+:17](C)(C)C)[C:11]1C=CC=C[CH:12]=1>C(#N)C=C.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[N:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C=CC#N
Product: Cc1ccc(OCCC#N)cc1
Yield: 76 %

Procedure:
A solution of 4-methylphenol, (20.0 g 0.185 moles), in acrylonitrile, (150 ml), was treated with benzyltrimethylammonium hydroxide, 40% in methanol (Triton B), (6 ml) and the reaction refluxed for 10 hours, then cooled, and evaporated in vacuo. The residual oil was partitioned between diethyl ether and water and the organic phase separated and washed with water, dilute sodium hydroxide solution, dilute hydrochloric acid, brine and dried (MgSO4). Evaporation of the solvent in vacuo gave 23.44 g of crude product, which was recrystallized from petroleum ether 60°-80° C./diethyl ether to yield 22.93 g, (76%) of pure product as a white crystalline solid, mp 47°-8° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[F:8][C:9]1[C:14]([Sn](CCCC)(CCCC)CCCC)=[CH:13][CH:12]=[CH:11][N:10]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C.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>[Br:7][C:6]1[CH:5]=[CH:4][S:3][C:2]=1[C:14]1[C:9]([F:8])=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: Brc1ccsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1ncccc1-c1sccc1Br
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
A mixture of 2,3-dibromothiophene (2.86 g), 2-fluoro-3-tributylstannylpyridine (3.93 g), Pd(Ph3P)2Cl2 (0.153 g) in N-methylpyrrolidinone (25 mL) was heated at 75° C. under argon for 3.5 hours. Tetrabutylammonium fluoride (1M in tetrahydrofuran, 10 mL) was added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Chromatography of the residue over silica gel gave 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (1.07 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1[C:25]([CH:30]=O)=[N:26][CH:27]=[CH:28][CH:29]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:30][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccnc1C=O
Reactant: Cc1cccnc1CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of 4-[(3-methyl-pyridin-2-ylmethyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester, 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave 4-[bis-(3-methyl-pyridin-2-ylmethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.84-1.88 (m, 4H), 2.09 (s, 6H), 2.50-2.66 (m, 3H), 3.81 (s, 4H), 4.14-4.17 (m, 2H), 7.05-7.09 (m, 2H), 7.36 (d, 2H, J=9.0 Hz), 8.34 (d, 2H, J=3.0 Hz). Deprotection with TFA using General Procedure F gave COMPOUND 249 as a white solid. 1H NMR (CDCl3) δ 1.56-1.70 (m, 2H), 1.75 (s, 1H), 1.90 (d, 2H, J=12.0 Hz), 2.10 (s, 6H), 2.31-2.51 (m, 2H), 2.55-2.58 (m, 1H), 3.12 (d, 2H, J=12.0 Hz), 3.84 (s, 4H), 7.05-7.09 (m, 2H), 7.35 (d, J=7.5 Hz), 8.34 (d, 2H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.42, 28.86, 47.07, 55.13, 58.17, 122.64, 133.81, 138.29, 146.21, 157.93. ES-MS m/z 311 (M+H). Anal. Calcd. for C19H26N4.0.3H2O: C, 72.25; H, 8.49; N, 17.74. Found: C, 72.11; H, 8.41; N, 17.58.
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20](I)[CH:19]=3)[N:12]([CH3:27])[C:11]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31]B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([CH3:31])[CH:19]=3)[N:12]([CH3:27])[C:11]2=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1I
Reactant: CB(O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ccc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)cc1C
Temperature: 80 °C
Yield: 64.6 %

Procedure:
1-(4-tert-Butyl-benzyl)-4-[3-(3-iodo-4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.300 g, 0.580 mmole), methyl boronic acid (0.069 g, 1.16 mmole) and cesium carbonate (0.264 g, 1.74 mmole) are mixed in dioxane (6.0 mL). After bubbling with nitrogen for 15 minutes, 1,1′-bis(diphenylphosphino)ferrocence palladium (II) chloride (0.060 g, 0.015 mmole) is added. The reaction is heated at 80° C. for 4 hours. The solvent is removed on rota-vapor, and the crude product is purified by column chromatography (silica gel, gradient elution 0-20% acetone in hexane) to provide a yellow oil (0.153 g, 65%). Mass [EI+] 409 (M+H)+, 817(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[NH:6].Cl.[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]([C:22](OCC)=[O:23])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(#N)C>[CH3:13][S:14][C:15]1[N:16]=[N:17][C:18]2[C:22](=[O:23])[NH:7][C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[O:2][CH3:1])=[N:6][C:19]=2[N:20]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: COc1ccccc1C(=N)N
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1nc2nc(SC)nnc2c(=O)[nH]1
Temperature: 0 °C

Procedure:
A cooled (0° C.) solution of 2-methoxybenzamidine (from 1.97 g of the hydrochloride) in acetonitrile (17 ml) was added to a cooled solution of 3-methylthio-5-chloro-6-carboethoxy-1,2,4-triazine (prepared from 3-methylthio-5-oxo-6-carboethoxy-4,5-dihydro-1,2,4-triazine, 1.08 g, and thionyl chloride, 20 ml) in acetonitrile (17 ml). Triethylamine (0.51 g) was added and the reaction mixture was stirred with cooling (0° C.) for one hour and then at ambient temperature for 17 hours to afford a yellow solid which was washed with acetonitrile and ether to afford the crude title compound (1.39 g). A sample (0.35 g) of this was washed twice with boiling methanol to afford the title compound, 0.25 g, m.p. 267.5°-268.5° C. The remaining material (1.04 g) was similarly treated with boiling methanol to afford the title compound, 0.91 g, m.p. 266°-268° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:16]1(=[O:23])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:16]1=[O:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C1CCCCCN1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C1NCCCCC1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 3,5-dinitrobenzoyl chloride (50.00 g, 0.22 mol), freshly distilled ε-caprolactam (24.54 g, 0.22 mol) and 500 ml of benzene is added to a 1L, three-necked, round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. The solution is heated to 90°-100° C. After all the solids are dissolved, 165 ml of pyridine is added. White pyridine salts form immediately, and the reaction solution is kept at 90°-100° C. for 1 hour before removing the pyridine salts by filtration. The solvent is removed from the filtrate under reduced pressure and the residue is washed by a 5 percent NaHCO3 aqueous solution and distilled water several times before being dried. The product is recrystallized from a mixture of ethyl acetate and hexane to obtain 45 g (68 percent) of white crystals: mp 126°-126.5° .
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCCN1CCOCC1
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)C2CCCCC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCOCC3)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-cyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)-morpholine
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C@@H:8]1[C:17]1[CH:22]=[CH:21][C:20]([CH:23](N2CCCC2)[CH3:24])=[CH:19][CH:18]=1>>[O:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C@@H:8]1[C:17]1[CH:18]=[CH:19][C:20]([CH:23]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH3:24])=[CH:21][CH:22]=1
Reactant: C1COCCN1
Reactant: CC(c1ccc([C@H]2COc3ccccc3O2)cc1)N1CCCC1
Product: CC(c1ccc([C@H]2COc3ccccc3O2)cc1)N1CCOCC1

Procedure:
Compound 226 is prepared from intermediate J and morpholine according to the procedure described for the synthesis of compound 225.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([N:12]3[CH:17]([OH:18])[CH2:16][CH2:15][N:14]([CH3:19])[C:13]3=[O:20])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[CH:1]1([C:7]2[S:11][C:10]([N:12]3[CH:17]([O:18][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:16][CH2:15][N:14]([CH3:19])[C:13]3=[O:20])=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCC(O)N(c2nnc(C3CCCCC3)s2)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)c2ccccc2)N(c2nnc(C3CCCCC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Benzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=1.C(OC([N:26]1[CH2:31][CH2:30][C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.Cl>C(#N)C>[CH2:30]1[C:29]2([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:28][CH2:27][N:26]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=3)=[C:6]([CH2:17][CH3:18])[N:5]=[CH:4][N:3]=2)[CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Reactant: CCc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCc1ncnc(N2CCC3(CCNCC3)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 1.0 g (3.87 mmol) 4-chloro-6-ethyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 1.18 g (4.6 mmol) 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester using 1.97 mL (11.6 mmoL) DIPEA in 20 mL acetonitrile. The reaction mixture is stirred at 80° C. over night. 1.6 ml conc. HCl is added the reaction is stirred for 4 hours at 80° C. The solvent is removed under reduced pressure. The residue is taken up to in acetonitrile and K2CO3 is added. The mixture is stirred at 80° C. over night. The solvent is removed and the residue is taken up in DCM/water. After phase separation the organic phase is extracted twice with DCM. The combined organic layers are dried over Na2SO4, filtered and the solvent is removed under reduced pressure yielding 1.08 g (74%) of crude product, which is used without further purification in the next step.
Reaction SMILES: [Li+].[Cl-].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.C(N(CC)C(C)C)(C)C.[CH3:26][C:27]([S@:30]([NH:32][C@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([C:37]([F:41])([F:40])[CH:38]=O)[CH:34]([F:36])[F:35])=[O:31])([CH3:29])[CH3:28]>C(#N)C>[C:27]([S@:30]([NH:32][C@@:33]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[F:48])([CH:34]([F:35])[F:36])[C:37]([F:40])([F:41])[CH:38]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:31])([CH3:26])([CH3:28])[CH3:29]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC(C)(C)[S@@](=O)N[C@@](c1ccccc1F)(C(F)F)C(F)(F)C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C=CC(F)(F)[C@](N[S@](=O)C(C)(C)C)(c1ccccc1F)C(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
To a stirred suspension of LiCl (405 mg, 9.56 mmol) in acetonitrile (30 mL) under N2 were added ethyl 2-diethoxyphosphorylacetate (2.14 g, 9.56 mmol) and DIPEA (N,N-diisopropylethylamine) (2.06 g, 15.94 mmol) at 0° C. After 20 min, (R)-2-methyl-N—((S)-1,1,3,3-tetrafluoro-2-(2-fluorophenyl)-4-oxo-butan-2-yl)propane-2-sulfinamide (2.85 g, 7.97 mmol) in acetonitrile (10 mL) was added dropwise to the mixture at 0° C. and the mixture was stirred at 25° C. for 17.5 hours. The reaction mixture was concentrated to remove acetonitrile, water (50 ml) was added and extracted with ethyl acetate (200 ml). The organic layer was dried and evaporated. The crude product was purified by column chromatography (petrolium ether: ethyl acetate=5:1 to 4:1) to afford ethyl (S)-5-(((R)-tert-butylsulfinyl)amino)-4,4,6,6-tetrafluoro-5-(2-fluorophenyl)hex-2-enoate (1.77 g, 46.8% yield).