Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:32])[NH:19][NH:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24](S(C)(=O)=O)[N:23]=2)=[CH:13][CH:12]=1>C1COCC1.C([O-])(O)=O.[Na+]>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:32])[NH:19][NH:20][C:21]=2[C:22]2[CH:27]=[CH:26][N:25]=[C:24]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:23]=2)=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)c1nccc(-c2[nH][nH]c(=O)c2-c2ccc(F)cc2)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH][nH]c(-c2ccnc(Oc3ccccc3)n2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of phenol (0.66 g, 7.08 mmol) in THF (5 mL) is added NaH (0.24 g, 5.91 mmol) followed by a solution of the crude 4-(4-fluorophenyl)-5-(2-methanesulfonylpyrimidin-4-yl)-1,2-dihydro-pyrazol-3-one, 5, prepared herein above (0.22 g, 0.67 mmol) in THF (2 mL). The reaction mixture is stirred for 1.5 hours at room temperature, diluted with aqueous NaHCO3 and extracted with twice with ethyl acetate. The organic layers are combined, dried over MgSO4, and concentrated in vacuo to afford the crude product which is purified over silica (100% EtOAc, followed by 10% MeOH/EtOAc) to provide the desired product as a yellow solid.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(C1C(=O)C([Cl:31])=C(Cl)C(=O)C=1C#N)#N.Cl>O1CCOCC1.CC(C)=O>[ClH:31].[N:1]1[C:2]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCc2cc(-c3cn4ccccc4n3)ccc2N1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: O=c1ccc2cc(-c3cn4ccccc4n3)ccc2[nH]1
Temperature: 70 °C
Yield: 42.4 %

Procedure:
To a suspension of 6-(imidazo[1,2-a]pyridine-2-yl)-3,4-dihydrocarbostyril (5 g) in dioxane (50 ml) was added DDQ (6.47 g) with stirring at 70° C. The reaction mixture was heated for 5 hours with stirring. After completion of reaction, the solvent was evaporated. The residue was extracted by the addition of chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with 0.5 N sodium hydroxide, washed with water and dried. After evaporating chloroform, the residue obtained was isolated and purified using silica gel column chromatography. Oily product obtained was dissolved in acetone and the solution was adjusted to pH of about 1 with concentrated hydrochloric acid. Crystals which formed were collected by filtration. The crude crystals thus obtained were recrystallized from water to give 2.4 g of 6-(imidazo[1,2-a]pyridine-2-yl)carbostyril monohydrochloride.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:17]#[CH:18])[CH:7]=[C:8]3[C:13]=2[C:12](=[O:14])[CH2:11][CH2:10][C:9]3([CH3:16])[CH3:15])[CH2:3][CH2:2]1.[CH2:19]([O:21][C:22](=[O:32])/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:20]>[Cu]I.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.C(N(CC)CC)C>[CH2:19]([O:21][C:22](=[O:32])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([C:18]#[C:17][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:13]3[C:12](=[O:14])[CH2:11][CH2:10][C:9]([CH3:15])([CH3:16])[C:8]=3[CH:7]=2)=[CH:27][CH:26]=1)[CH3:20]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CCC2=O
Reactant: CCOC(=O)/C=C/c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CCC3=O)cc1

Procedure:
Following General Procedure B and using 8-cyclopropyl-4,4-dimethyl-6-ethynyl-1-tetralone (Intermediate 160, 0.1 g, 0.42 mmol), (E)-3 (4-iodo-phenyl) acrylic acid ethyl ester (0.13 g 0.42 mmol), triethyl amine (1 mL), copper(I)iodide (0.02 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.070 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh), the title compound was obtained (0.12 g, 69%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=1)[C:5]#[N:6].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:22]2[CH:23]=[CH:24][C:25]([C:2]3[CH:3]=[C:4]([CH:7]=[C:8]([O:10][CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=3)[C:5]#[N:6])=[CH:26][C:27]=2[O:28][CH2:20]1
Reactant: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(COc2cc(C#N)cc(-c3ccc4c(c3)OCO4)c2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 3-bromo-5-(4-methoxy-benzyloxy)-benzonitrile (1.1 g) in 1,2-dimethoxyethane (10 mL) were added 3,4-methylenedioxyphenylboronic acid (860 mg), 2 M aq. sodium carbonate solution (3.5 mL) and Pd(PPh3)4 (40 mg) and the resulting mixture was stirred at 90° C. for 4 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, filtered through a silica pad, concentrated and triturated with diethyl ether to yield 1.0 g of the title compound (89% yield). HRMS calcd for C22H17O4N M+ 359.1158, observed 359.1158.
Reaction SMILES: [NH2:1][CH:2]1[C:16]2=[N:17][CH:18]=[C:19]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]2[CH2:14][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:11]([Cl:13])=[CH:12][C:4]=2[CH2:3]1.[O:24]=[C:25]1[NH:33][C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[C:26]21[CH2:41][C:40]1[C:35](=[CH:36][CH:37]=[C:38]([C:42](O)=[O:43])[CH:39]=1)[CH2:34]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:13][C:11]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:14][N:15]3[C:19]([C:20]([OH:23])([CH3:21])[CH3:22])=[CH:18][N:17]=[C:16]3[C@H:2]([NH:1][C:42]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[CH2:34][C:26]3([C:27]5[C:28](=[N:29][CH:30]=[CH:31][CH:32]=5)[NH:33][C:25]3=[O:24])[CH2:41]4)=[O:43])[CH2:3][C:4]=2[CH:12]=1
Reactant: CC(C)(O)c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)CC2N
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(O)c1cnc2n1Cc1c(cc(Cl)c3[nH]ncc13)C[C@H]2NC(=O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A solution of 2-[7-amino-4-chloro-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-10-yl]propan-2-ol (100 mg, 0.3 mmole) and (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridine]-5-carboxylic acid (78 mg, 0.28 mmol) [Bell et al. WO 2006/031606], HOBT (43 mg, 0.28 mmol), and EDC (54 mg, 0.28 mmol) in DMF (2 mL) was stirred at ambient temperature for 1 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and made basic with saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc (2×20 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound as an off white solid. MS: m/z=594 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)[CH2:5][N:4]([C:15]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3([CH3:28])[CH2:27][CH2:26]3)=[O:24])[CH2:19][CH2:18]2)=[O:16])[CH2:3]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Cl:14][C:9]1[CH:8]=[C:7]([C@H:6]2[C@H:2]([NH:1][CH:30]([CH3:32])[CH3:29])[CH2:3][N:4]([C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([C:25]4([CH3:28])[CH2:27][CH2:26]4)=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH2:5]2)[CH:12]=[CH:11][C:10]=1[Cl:13]
Reactant: CC1(C(=O)N2CCC(C(=O)N3CC(N)C(c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)N[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of rac-(3S,4R)-[3-Amino-4-(3,4-dichloro-phenyl)-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone (120 mg, 0.28 mmol) in dichloromethane (1 mL) were added acetone (21 uL, 0.28 mmol) and sodiumtriacetoxy-borohydride (72 mg, 0.34 mmol) and acetic acid (16 uL, 0.28 mmol) and the reaction mixture was stirred at ambient temperature for 3 h. It was diluted with dichloromethane and washed with aqueous sodiumhydrogenecarbonate (1M). The organic layer was dried over sodium sulfate and concentrated affording the title compound (95 mg, 72%) as a light yellow foam. MS m/e: 466.3 [M]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S-:14][C:15]#[N:16].[K+].BrBr.O>C(O)(=O)C>[NH2:16][C:15]1[S:14][C:12]2[CH:13]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: CCCCCCc1ccc(N)cc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCc1ccc2nc(N)sc2c1
Yield: 49.9 %

Procedure:
In a 2 liter-reaction vessel, 50.0 g(0.28M) of p-hexylaniline, 54.8 g (0.56M) of potassium thiocyanate and 400 ml of acetic acid were placed and cooled below 10° C. To the mixture, a solution f 45.0 g of bromine in 135 ml of acetic acid was added dropwise in 40 minutes below 10° C. under strong stirring, followed by reaction for 1.5 hours below 10° C. After the reaction, 500 ml of water was poured into the reaction mixture, followed by heating to dissolve the resultant precipitate. The resultant solution was filtered when hot. Ammonia water was added to the filtrate until the resultant solution became basic, followed by cooling with ice to precipitate a crystal. The crystal was recovered by filtration, followed by washing and drying to obtain a crude product. The crude product was recrystallized from a mixture solvent of n-hexane/benzene (1/1) to obtain 33.0 g of 2-amino-6-hexylbenzothiazole (Yield: 49.9%).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([F:9])[F:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=1[F:19].C(=O)([O-])[O-].[K+].[K+].Cl[N:27]1[N:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[NH:28]1>CN(C)C=O>[Cl:1][C:2]1[N:6]([CH:7]([F:8])[F:9])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([O:17][N:27]2[N:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([O:33][CH3:34])[NH:32]2)[C:14]([Cl:18])=[CH:13][C:12]=1[F:19]
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: Cc1nc(-c2cc(O)c(Cl)cc2F)c(Cl)n1C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cc(-c3nc(C)n(C(F)F)c3Cl)c(F)cc2Cl)N1
Temperature: 110 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
5-Chloro-4-(4-chloro-2-fluoro-5-hydroxyphenyl)-1-difluoromethyl-2-methylimidazole (prepared according to the procedure as described in EP 590,834) (0.31 g, 1 mMol) was dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (0.17 g, 1.2 mMol) and 2-chloro-4,6-dimethoxytriazine (0.21 g, 1.2 mMol) were added and the suspension stirred at 110° C. for 2 hours under an atmosphere of nitrogen. The mixture was processed and the residue chromatographed on silica gel eluting with methylene chloride:methanol, 98:2, to give the title compound (0.25 g, 55%). 1H NMR (CDCl3, TMS): 2.61 (3H, br s), 4.00 (6H, s), 7.17 (1H, t, J=58.1 Hz), 7.29 (1H, d, J=9.3 Hz), 7.53 (1H, d, J=6.6 Hz).
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[CH2:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([F:16])[C:11]=1[NH:17]C(=O)OC(C)(C)C)[CH3:9].CCOCC>C(#N)C>[NH2:17][C:11]1[C:12]([F:16])=[N:13][CH:14]=[CH:15][C:10]=1[CH2:8][CH3:9]
Reactant: CCc1ccnc(F)c1NC(=O)OC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOCC
Product: CCc1ccnc(F)c1N
Temperature: 25 °C

Procedure:
Trimethylsilyl chloride (2.2 g, (0.18 mmol) and sodium iodide (2.7 g, 0.18 mmol) were added to a solution of 3.6 g (0.15 mmol) of t-butyl N-(4-ethyl-2-fluoro-3-pyridyl)carbamate in 50 mL of dry acetonitrile with stirring at ambient temperature. After 2 hours the mixture was poured into ether and the resulting solution was washed with dilute aqueous sodium bisulfite, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure to obtain an oil. This oil was purified by column chromatography to obtain 1.6 g (76 percent of theory) of the title compound as a gold oil.
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([C:19]([OH:21])=O)=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:35][CH2:36][CH2:37][OH:38]>CN(C)C=O>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH3:22])[C:10]([C:19]([NH:35][CH2:36][CH2:37][OH:38])=[O:21])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(-c3cncc(C)c3)c(C(=O)O)c(C)nn12
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cncc(C)c3)c(C(=O)NCCO)c(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 7-ethyl-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxylic acid (70 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (68.2 mg) and 1-hydroxybenotriazole (48 mg) in dimethylformamide (2 mL) was added 2-aminoethanol (17.4 mg) and the mixture was stirred at ambient temperature for 1 hour. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (50:1-10:1). The crude product was triturated with isopropylether to give 7-ethyl-N-(2-hydroxyethyl)-2-methyl-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carboxamide as a yellow powder (47 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.CCCCC.CON(C)[C:19](=[O:51])[C@@H:20]([NH:28][C:29]([CH2:31][N:32]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:36][N:35]([C:44](=[O:46])[CH3:45])[CH:34]([CH:47]([CH3:49])[CH3:48])[C:33]1=[O:50])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[C:44]([N:35]1[CH:36]=[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:32]([CH2:31][C:29]([NH:28][C@@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:2]2[O:1][CH2:5][CH2:4][CH:3]=2)=[O:51])=[O:30])[C:33](=[O:50])[CH:34]1[CH:47]([CH3:49])[CH3:48])(=[O:46])[CH3:45]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reactant: C1=COCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C2=CCCO2)C(=O)C1C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2,3-dihydrofuran (80 μl) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.55 N tert-butyllithium/pentane solution (660 μl) is added thereto, and the mixture is stirred for one hour. The mixture is added to a solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (295 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (3 ml) cooled at −78° C., and the whole is stirred for two hours. The temperature is raised to 0° C., and the reaction mixture is stirred for 30 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (38.4 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:17][CH2:18][O:19][CH:20]([O:22][CH2:23][CH3:24])[CH3:21])[S:7]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH:15]=O)(=[O:9])=[O:8])[CH3:2].C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:23]([O:22][CH:20]([O:19][CH2:18][CH2:17][N:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:25])=[CH:15][C:14]2[CH:13]=[CH:12][S:11][C:10]=2[S:7]1(=[O:9])=[O:8])[CH3:21])[CH3:24]
Reactant: CCOC(=O)CN(CCOC(C)OCC)S(=O)(=O)c1sccc1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCOC(C)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
To a mixture of the product from Step B (10.2 g, 25.9 mmol) and molecular sieves (10 g) in ethyl acetate (150 mL) was added DBU (1 mL). The mixture was stirred overnight at ambient temperature, poured into a sainted solution of sodium bicarbonate (150 mL), and the organic layer was separated, dried and evaporated to give an oil (8.89 g, 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23](O)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([Br:22])[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][C:32]=1[N:33]1[CH2:38][C@H:37]([C:39]([F:42])([F:41])[F:40])[CH2:36][C@H:35]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:34]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:22][C:17]1[CH:16]=[C:15]2[C:20]([CH:21]=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:13]([C:23]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][C:32]=3[N:33]3[CH2:38][C@H:37]([C:39]([F:41])([F:40])[F:42])[CH2:36][C@H:35]([NH:43][C:44]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:50])[CH2:34]3)=[O:24])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2nc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)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
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(Br)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylic acid (0.50 g, 1.2 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.45 g, 1.2 mmol) and HATU (1.2 g, 3.1 mmol) in DMF (4.9 mL), DIPEA (0.65 mL, 3.7 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 50 mL of EtOAc and 30 mL of 1 M NaOH. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organics were concentrated under reduced pressure. The residue was purified by flash chromatography on a 40 g silica gel column, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.492 g, 53%). LCMS calc. for C34H35BrF3N6O5 [M+H]+: m/z=743.2. found: 743.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1F
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl (3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([NH:7][CH:8]([C:10]2[CH:15]=[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]3[N:33]=[CH:34][CH:35]=[C:12]3[N:11]=2)[CH3:9])[CH2:3][CH2:2]1.C1C(=O)N([I:43])C(=O)C1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:43][C:35]1[CH:34]=[N:33][N:13]2[C:14]([N:16]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:22])[CH3:23])=[CH:15][C:10]([CH:8]([NH:7][CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH3:9])=[N:11][C:12]=12
Reactant: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC(NC1CCOCC1)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2ncc(I)c2n1
Reaction time: 0.17 h
Yield: 67.5 %

Procedure:
To a solution of 5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.17 g, 0.32 mmol) in acetonitrile (15 ml) at 0° C. was added NIS (78 mg, 0.35 mmol) and stirring continued for 10 minutes. LC/MS showed no starting material (M.W=521) remaining. Saturated sodium thiosulfate solution (˜0.5 ml) was added and stirring continued for 5 minutes. After the acetonitrile was rotoevaporated, the aqueous phase was extracted with DCM (25 ml), washed with water (1×5 ml), brine (1×5 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with MeOH/EtOAC (0-20%) gave desired product, 3-iodo-5-(1-(tetrahydro-2H-pyran-4-ylamino)ethyl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.14 g, 69%).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:12]>CO>[NH2:12][CH2:2][CH:3]([OH:11])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: OC(CCl)CN1CCOCC1
Reactant: N
Solvent: CO
Product: NCC(O)CN1CCOCC1
Yield: 91 %

Procedure:
1-Chloro-3-morpholin-4-yl-propan-2-ol (2.0 g, 11 mmol) was treated with the solution of NH3 in methanol (25% by weight, 20 mL) at room temperature. Nitrogen was bulbbed into the reaction mixture to remove the ammonia. Evaporation of solvent gave the hydrogen chloride salt of 1-amino-3-morpholin-4-yl-propan-2-ol (2.0 g, 91%). 1H NMR (DMSO-d6) δ 2.30 (d, J=6.0 Hz, 2H), 2.36 (m, 4H, NCH2), 2.65 (dd, J=8.4, 12.8 Hz, 1H), 2.91 (dd, J=3.6, 12.8 Hz, 1H), 3.52 (m, 4H, OCH2), 3.87 (m, 1H, CH), 5.32 (s, 1H, OH), 8.02 (brs., 3H, NH3+). MS (m/z) 161.1 (M+1).