Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.C(O)C.C(O[CH:17]=[C:18]([C:24]([CH3:26])=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>O.Cl>[CH2:22]([O:21][C:19]([C:18]1[CH:17]=[N:9][N:8]([C:5]2[C:4]([Cl:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C:24]=1[CH3:26])=[O:20])[CH3:23]
Reactant: NNc1ncc(Br)cc1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2ncc(Br)cc2Cl)c1C
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of (5-bromo-3-chloropyridin-2-yl)hydrazine (14.78 g) in water (15 ml) and concentrated hydrochloric acid (15 ml), was added an ethanol solution (30 ml) of ethyl 2-(ethoxymethylene)acetoacetate (30 ml), prepared according to a method described in J. Chem. Soc. Perkin trans. I, 1875 (1988), and the mixture was stirred at 100° C. for 1.5 hours. The reaction solution was cooled to room temperature, water (100 ml) was added and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. n-Hexane (150 ml) was added, and ethyl acetate was further added little by little at 80° C. to completely dissolve the residue. The solution was cooled to room temperature and the precipitated solid was filtered. The filtrate was concentrated and a similar handling was repeated four times to give 1-(5-bromo-3-chloropyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (15.93 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI>C(#N)C>[C:12]1([C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH3:22])[C:19]([O:21][CH3:1])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CI
Product: COC(=O)C(C)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
37.60 g (0.247 mol) of DBU are added dropwise to a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 mL of acetonitrile at 20° C. 70.10 g (0.494 mol) of methyl iodide are added dropwise to the resulting solution within 30 minutes. Then the mixture is stirred overnight at 20° C. The solvent is evaporated down, the residue is extracted with diethylether/water, the organic phase is washed with water, dried over Na2SO4, and evaporated to dryness. Yield: 48.29 g of viscous residue 3.1. (89% of theory).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]([O:18][C:19]1[N:24]=[C:23]([NH2:25])[C:22]([F:26])=[CH:21][N:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:11]([O:18][C:19]1[N:24]=[C:23]([NH:25][CH:8]=[O:10])[C:22]([F:26])=[CH:21][N:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=CO
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNc1nc(OCc2ccccc2)ncc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
A 10 mL Schlenk-type flask was charged with acetic anhydride (4.0 mL, 42 mmol), formic acid (2.0 mL, 53 mmol), and CH2Cl2 (20 mL), and was cooled to 0° C. under nitrogen. N,N-Dimethylpyridin-4-amine (275 mg, 2.25 mmol) was added, and the resulting solution was allowed to stir at room temperature for 10 min. Solid 2-(benzyloxy)-5-fluoropyrimidin-4-amine (495 mg, 2.26 mmol) was added, and the reaction stirred for another 21 h at room temperature. The crude reaction mixture was diluted with CH2Cl2 (50 mL) and washed with water (50 mL), saturated aqueous NaHCO3 (50 mL), and water (50 mL). The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was then purified by flash column chromatography (EtOAc/hexane gradient) to afford the title compound (295.8 mg, 53%) as a white solid: mp 153-157° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.29 (bs, 1H), 9.34 (s, 1H), 8.48 (d, J=2.6 Hz, 1H), 7.29-7.46 (m, 5H), 5.32 (s, 2H); MS (ESI) m/z 248 (M+H)+, 246 (M−H)−.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:14](=O)[CH:15]([CH2:21][C:22](=O)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:41].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:41][C:22]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)=[CH:21][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:30][CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CC(=O)c1nccs1)C(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 68.8 %

Procedure:
To a solution of ethyl 4-[4-(cyclopropylsulfonyl)phenyl]-3-oxo-2-[2-oxo-2-(1,3-thiazol-2-yl)ethyl]-5-(tetrahydro-2H-pyran-4-yl)pentanoate (0.190 g) in acetic acid (5 mL) was added ammonium acetate (0.411 g) at room temperature, and the mixture was stirred at 100° C. for 15 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30, volume ratio) to give the title compound (0.126 g, yield 68%) as a colorless amorphous solid. MS: 515 (MH+). melting point 178-179° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([S:18]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (20 g, 169 mmol, (available from, for example Sigma Aldrich) in tetrahydrofuran (THF) (250 mL) was added sodium hydride (10.16 g, 254 mmol) portionwise during 5 min under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then benzenesulfonyl chloride was added dropwise under nitrogen at 0° C. then stirred for 2 h at r.t., until the starting material had been completely consumed (TLC, EtOAc:PE=1:1). The mixture was poured into H2O (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were washed with brine (3×150 mL), dried over Na2SO4 and filtered. The solvent was evaporated in vacuo to give the crude product, which was purified by recrystallization with (EtOAc and PE) to give desired product as a white solid (30 g, 69%)
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4]1)[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:25]=[CH:26][C:27]=1[NH:28][C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1)=[O:14]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: CCn1cc(C(=O)O)c2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)Nc2ccc(CC(=O)OC)cc2Cl)c2ccccc21
Temperature: 15 °C
Yield: 88.4 %

Procedure:
To 1-ethylindole-3-carboxylic acid (160.2 mg, 0.847 mmol) were added methylene chloride (3.5 ml) and oxalyl chloride (108.9 μl, 1.270 mmol) under stirring at 15° C. The reaction mixture was stirred for 2.5 hours at room temperature. The solvent was then distilled off under reduced pressure. To the residue was added methylene chloride (3.5 ml). Under stirring at room temperature, a solution of methyl 3-chloro-4-aminophenylacetate (177.5 mg, 0.889 mmol) in methylene chloride (3.5 ml) and triethylamine (0.37 ml, 2.667 mmol) were added and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform. The resulting solution was washed with 1N HCl ad saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate (277.7 mg, 88%) as a brown amorphous substance. The resulting compound was provided for the subsequent reaction without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
Reactant: OB(O)C1=CCCCC1
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: C1COCCO1
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 2-bromo-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-yl boronic acid (70 mg, 0.542 mmol) and Pd(PPh3)4 (57 mg, 0.0493 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74 (br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H23NO2S, 306.1 (M+H), found 306.1.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH3:8])[C:3]#[C:4][CH2:5][CH2:6][OH:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:10]([O:7][CH2:6][CH2:5][C:4]#[C:3][C:2]([OH:9])([CH3:8])[CH3:1])(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C#CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCC#CC(C)(C)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
100 g (0.78 mol) of 5-methylhex-3-yne-1,5-diol were dissolved in 800 ml of dichloromethane and cooled to 0° C. 113 ml (1.11 mol) of acetic anhydride were added in one portion. 127 ml (1.25 mol) of triethylamine were cooled to 0-2° C. and added within 20 min. The reaction mixture was stirred at 0° C. for 2 h. The cooling was removed and the reaction mixture was stirred a 20° C. for 16 h. The mixture was cooled to 0° C. and 1200 ml of a 5% hydrochloric acid solution were added, in the course of which the temperature of the reaction mixture was kept below 5° C. The mixture was extracted three times with 150 ml each time of tert-butyl methyl ether (MTBE), and the combined organic phases were stirred four times with 400 ml each time of 5% aqueous sodium hydrogen carbonate solution for 1 h each time, until no further evolution of gas was observable in each case. The organic phase was washed with 1 l of demineralized water and dried over sodium sulfate, and the solvent was removed. This gave 122.21 g (yield 92%) of a clear, dark yellow liquid. The purity was determined by gas chromatography to be 99.5%.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[OH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[CH:13][C:14](=O)[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CO.C(Cl)(Cl)Cl>[CH3:3][O:2][N:4]=[C:14]([CH:13]=[CH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[OH:5])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: O=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Reactant: CON
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CON=C(C=Cc1ccccc1O)C=Cc1ccccc1O
Reaction time: 24 h
Yield: 86 %

Procedure:
Methoxyl-amine hydrochloride (30-35 wt % in H2O, 0.30 mL, 1.12 mmol) was added in one portion to a solution of 1,5-bis(2-hydroxyphenyl)penta-1,4-dien-3-one (EF1) in methanol/CHCl3 (2/3) (5 mL). The reaction proceeded at room temperature for 24 hrs, then additional methoxylamine hydrochloride (0.15 mL, 0.56 mmol) was added and the reaction stirred for an additional 24 hrs. After completion (TLC) the solvent was evaporated, the residue dissolved in methanol, stirred with silica gel and purified after concentration by chromatography on silica gel using 30% EtOAc/hexanes. The product was obtained as a pale yellow foam (86%).
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([CH3:42])([CH3:41])[C:33]1=[O:43].O>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:34]([CH3:42])([CH3:41])[C:33]3=[O:43])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: CC1(C)C(=O)N(CCCBr)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCN3C(=O)C(C)(C)c4ccccc43)c2CC1
Temperature: 25 °C

Procedure:
Add potassium hydroxide (170 mg, 3.03 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 mg, 0.49 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen overnight. Then add further portion of KOH (867 mg, 15.45 mmol) and heat at reflux for 3 h. Then cool to room temperature and add 1-(3-bromo-propyl)-1,3-dihydro-3,3-dimethyl-indol-2-one (274 mg, 0.97 mmol, prepared by following the procedure described in Perkin 1 2000, 769-774). Stir the reaction at room temperature overnight. Remove solvents in vacuo, add water and extract with diethyl ether (2×50 mL). Combine the organic extracts, wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(3,3-dimethyl-2-oxo-2,3-dihydro-indol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colourless oil (330 mg), 50% contaminated with 1-(3-methoxypropyl)-1,3-dihydro-3,3-dimethyl-indol-2-one. MS (ES+) m/z: 537 (M+Na)+.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[C:43](Cl)(=[O:47])[CH:44]([CH3:46])[CH3:45]>O1CCCC1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:43](=[O:47])[CH:44]([CH3:46])[CH3:45])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)C(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (1.3 mL, 8.9 mmol) in tetrahydrofuran (25 mL) at 78° C. was added n-BuLi (2.2M in hexanes, 4.1 mL, 8.9 mmol). The reaction mixture was warmed to 0° C. and after 10 min was re-cooled to 78° C. and aripiprazole (2.0 g, 4.5 mmol) added. The reaction mixture was stirred for 30 min and then isobutyryl chloride (0.7 mL, 6.7 mmol) added. After 2 h the reaction mixture was warmed to room temperature and stirred for 1 h. A second reaction was carried out under exactly the same conditions and the two reactions were combined. This mixture was washed with water, dried over MgSO4, filtered and evaporated. The residue was dissolved in diethyl ether and 4M HCl in diethyl ether added to form a precipitate. The mother liquor was decanted and the residual gum was washed with diethyl ether. The gum was then partitioned between ethyl acetate and saturated sodium bicarbonate, and the organic layer separated. After drying over MgSO4 and evaporation, the residue was further purified on silica eluting with 1:1:0.1 dichloromethane/ethyl acetate/methanol to give Compound-16 (1.3 g) as a yellow solid. 1H-NMR (300 MHz, CDCl3) δ 7.16-7.13 (m, 2H), 7.08 (d, 1H), 6.98-6.92 (m, 1H), 6.65-6.59 (m, 2H), 3.93 (t, 2H), 3.48 (dt, 1H), 3.12-3.01 (m, 4H), 2.86 (dd, 1H), 2.72-2.59 (m, 6H), 2.47 (t, 2H), 1.84-1.64 (m, 4H), 1.25 (d, 6H). [M+H]+=518.2.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH2:11])[CH:2]=1.[F:12][C:13]([F:31])([F:30])[C:14]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][C@H:22]([C:27](O)=[O:28])[CH2:21][CH2:20][C:19]=2[N:18]=1)([CH3:16])[CH3:15].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1C=NC2N(O)N=NC=2C=1>CN1CCCC1=O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:27]([C@@H:22]2[CH2:21][CH2:20][C:19]3[N:18]=[C:17]([C:14]([CH3:16])([CH3:15])[C:13]([F:31])([F:30])[F:12])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[O:28])[CH:2]=1
Reactant: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)O)C2)C(F)(F)F
Reactant: Nc1cnc2ccccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc2c(n1)CC[C@@H](C(=O)Nc1cnc3ccccc3c1)C2)C(F)(F)F
Temperature: 60 °C
Reaction time: 0.03 h
Yield: 74.7 %

Procedure:
To a mixture of 3-quinolinamine (26 mg, 0.18 mmol), (R)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (40 mg, 0.14) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (79 mg, 0.21 mmol) in N-methylpyrrolidinone (0.7 mL), followed by N,N-diisopropylethylamine (73 μL, 0.42 mmol) was added. Aliquot after 2 min: LCMS showed formation of the HOAt and Me ester, and some amide. After 1.3 h, the reaction was heated at 60° C. Aliquot after 25 h: LCMS showed the reaction was complete—all HOAt ester had been consumed. The material was filtered and purified by reverse-phase HPLC (20-80% ACN in 10 mM Et2NH/H2O; 3 injections of 400 μL, each) to afford the amide (43 mg, 75%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.76 (d, J=2.4 Hz, 1H), 7.96 (d, J=8.4 Hz, 1H), 7.92 (dd, J=1.1, 8.0 Hz, 1H), 7.68-7.54 (m, 3H), 7.40 (d, J=8.0 Hz, 1H), 3.08-3.00 (m, 2H), 2.99-2.87 (m, 3H), 2.29-2.20 (m, 1H), 2.03-1.91 (m, 1H), 1.56 (s, 6H); m/z=414.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@H:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C)C(C)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCO
Product: CC(C)[C@H](C)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 47.5 %

Procedure:
Racemic 3-amino-7-bromo-5-(3-methylbutan-2-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Step G of Example 13 (7.89 g) was resolved by HPLC (column: CHIRALPAK AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=600/400(v/v)) to give the title compound (3.751 g) having a shorter retention time.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[CH:6]=[N:5][C:4]=1[C:17](=[N:19]O)[NH2:18].CO.N1C=CC=CC=1.[C:29](=S)=[S:30]>>[CH:6]1[N:7]([C@@H:8]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:11]([OH:12])[C@H:9]2[OH:10])[C:3]2[C:4](=[C:17]([NH2:18])[NH:19][C:29]([N:2]=2)=[S:30])[N:5]=1
Reactant: NC(=NO)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1N
Reactant: S=C=S
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 88 %

Procedure:
To 10.0 g of 5-amino-1-β-D-ribofuranosylimidazole-4-carboxamide oxime hydrochloride were added 120 ml of methanol and 120 ml of pyridine to form a solution. 60 ml of carbon disulfide was added to the solution, and the resulting mixture was allowed to react in an autoclave at 120° C for 3 hours under autogenous pressure (about 10 kg/cm2). The reaction mixture was concentrated to dryness, and the residue was dissolved in 1N aqueous ammonia. 100 ml of n-butanol and 50 ml of glacial acetic acid were then added to the solution followed by cooling to crystallize the product to obtain 9.01 g of 2-thioadenosine having a melting point of 199° C (with decomposition) in an 88% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:12](=[O:15])(=[O:14])[NH2:13].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl>O>[ClH:1].[CH3:11][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]([S:12](=[O:15])(=[O:14])[NH2:13])=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[CH:10]=1
Reactant: Cc1cc(Cl)c(S(N)(=O)=O)cc1C(=O)O
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCN(C)CC2)c(S(N)(=O)=O)cc1C(=O)O
Reaction time: 1 h

Procedure:
125 g of 4-chloro-6-methyl-3-sulfamoylbenzoic acid (0.5 mole) were heated under reflux with 0.5 l of N-methylpiperazine for 6 hours. Subsequently the excess base was eliminated in vacuo, and the residue was dissolved in 1 l of water. After the solution had been acidified with concentrated hydrochloric acid, the final product precipitated in a crystalline form. After having stood at room temperature for 1 hour, it was suction-filtered and was dissolved and recrystallized from 50% ethanol, while activated charcoal was added.
Reaction SMILES: [CH2:1]([N:4]([C:9]1[C:10]([CH3:19])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])[C:5](=[O:8])[CH2:6]O)[C:2]#[CH:3].S([Cl:24])(C)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.O>[CH2:1]([N:4]([C:9]1[C:10]([CH3:19])=[N:11][C:12]([N:16]([CH3:18])[CH3:17])=[N:13][C:14]=1[CH3:15])[C:5](=[O:8])[CH2:6][Cl:24])[C:2]#[CH:3]
Reactant: C#CCN(C(=O)CO)c1c(C)nc(N(C)C)nc1C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C#CCN(C(=O)CCl)c1c(C)nc(N(C)C)nc1C

Procedure:
8.0 g of N-propargyl-N-(4,6-dimethyl-2-dimethylamino-pyrimidin-5-yl)-hydroxyacetamide, 3.7 g 4-dimethylaminopyridine and 100 ml dry CH2Cl2 are charged in a sulphonation flask. Thereto are added, dropwise, 3.43 g mesyl chloride in 30 ml of dry CH2Cl2. The reaction temperature rises from 22° up to 33°. The mixture is heated under reflux for 34 hours, cooled and diluted with water. The organic phase is partitioned off, dried over Na2SO4 and evaporated. The oily residue is chromatographed on silica gel with diethylether/hexane 1:1 to give the title compound, m.p. 108°-110°.