Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)#[N:17].O>C1C=CC=CC=1>[C:16]([C:18]1([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:20][C:21]2([O:4][CH2:1][CH2:2][O:3]2)[CH2:22][CH2:23]1)#[N:17]
Reactant: N#CC1(c2cccs2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: N#CC1(c2cccs2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
Ethylene glycol (9.08 g) and p-toluenesulfonic acid (0.0139 g) were added to a solution of 4-cyano-4-(thiophen-2-yl)cyclohexanone (15 g) in benzene (120 ml) and the reaction mixture was boiled under reflux for 4 hours at 110° C. on a water separator (Dean-Stark apparatus). The reaction mixture was cooled to RT and the organic phase was washed with aqueous sodium bicarbonate solution (1×150 ml), water (1×150 ml) and saturated NaCl solution (1×150 ml). After drying over Na2SO4, the solvents were removed under reduced pressure.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][OH:12])[CH2:6][CH2:5]1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>CCCCCCC.C1COCC1>[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:12][CH2:11][CH2:10][CH:7]3[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][CH2:6]3)=[O:27])[CH2:24][CH2:25]2)=[CH:18][CH:19]=1
Reactant: CN1CCC(CCO)CC1
Reactant: Cc1ccc(N2CCN(C(=O)Oc3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1ccc(N2CCN(C(=O)OCCC3CCN(C)CC3)CC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 8.6 %

Procedure:
NaH (60% dispersion in mineral-oil, 0.81 g, 42.2 mmol) was suspended in heptane (10 mL) under an argon atmosphere. The heptane was decanted off, and the flask was charged with THF (20 mL) and cooled to 0° C. A solution of 2-(1-methyl-piperidin-4-yl)-ethanol (1.01 g, 7.03 mmol) in THF (20 mL) was added drop-wise, followed by a solution of 4-nitrophenyl 4-(4-methylphenyl)piperazine-1-carboxylate (2.89 g, 8.46 mmol) in THF (20 mL). The reaction mixture was allowed to warm to room temperature and stirred for 48 hours. The reaction mixture was then cooled to 0° C. and quenched with the drop-wise addition of sat aq NaHCO3 solution and concentrated in vacuo. The residue was dissolved in EtOAc (200 mL), washed with a NaHCO3 solution (4×50 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography (eluting with DCM, followed by a 90:10 mixture of DCM:MeOH) followed by reverse phase chromatography (gradient eluting with MeOH in water, with 1% formic acid in each solvent, 0-20%). The resulting residue was dissolved in DCM (50 mL) and stirred with solid K2CO3 for 20 minutes, filtered and concentrated in vacuo to give the title compound 2-(1-methylpiperidin-4-yl)ethyl 4-(4-methylphenyl)piperazine-1-carboxylate (0.21 g, 7%) as a cream solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[H-].[Na+].[CH2:15](I)[CH2:16][CH3:17].O>CN(C=O)C>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][CH2:15][CH2:16][CH3:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CCO)c1ccccc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCN(CC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(N-ethylanilino)ethanol (17.83 g) in DMF (300 ml) was added at 0° C. sodium hydride (60%, 4.74 g), and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 30 minutes. To the mixture was added propyl iodide (11.0 ml), and the mixture was stirred at 50° C. for 19 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:19) to give colorless oil of N-ethyl-N-(2-propoxyethyl)aniline (10.18 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36].C=O.O.[C:41]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:37])[C:13]1[CH:18]=[C:17]([C:19]#[C:20][CH:21]2[CH2:26][CH2:25][N:24]([CH3:41])[CH2:23][CH2:22]2)[CH:16]=[C:15]([N:27]([CH2:34][CH3:35])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:36]
Reactant: CCN(c1cc(C#CC2CCNCC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(c1cc(C#CC2CCN(C)CC2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methyl-5-(piperidin-4-ylethynyl)benzamide (100 mg, 0.198 mmol) in methanol (5 mL) was added 35% formaldehyde in H2O (0.155 mL, 1.98 mmol) at 0° C. After stirring at 0° C. for 10 min, sodium cyanoborohydride (24.9 mg, 0.396 mmol) was added. The resulting mixture was stirred at 0° C. for 1 h. LCMS indicated that the reaction was completed. The reaction was quenched with sat. NaHCO3/brine and extracted with EtAOc/Heptane. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (10 g column, MeOH/DCM=1:9, and then MeOH/7 M NH3 in MeOH/DCM=1:1:8) to afford the titled compound (96.0 mg, 93%). 1H-NMR (500 MHz, CD3OD) δ ppm 7.22 (brs, 1H), 7.08 (brs, 1H), 6.10 (s, 1H), 4.46 (s, 2H), 3.94-3.87 (m, 2H), 3.35-3.30 (m, 2H), 3.07 (q, J=7.0 Hz, 2H), 3.04-2.97 (m, 1H), 2.79-2.71 (m, 2H), 2.67-2.58 (m, 1H), 2.38 (s, 3H), 2.28 (s, 3H), 2.28 (s, 3H), 2.25 (s, 3H), 2.28-2.21 (m, 2H), 1.97-1.91 (m, 2H), 1.78-1.67 (m, 4H), 1.64-1.54 (m, 2H), 0.85 (t, J=7.0 Hz, 3H); MS (ESI) [M+H]+519.4.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH3:11][C:12]([CH3:14])=O>>[CH3:11][C:12]1([CH3:14])[O:4][C@@H:3]2[C@@H:5]([C@@H:7]([CH2:9][OH:10])[O:8][CH:2]2[OH:1])[O:6]1
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](CO)OC(O)[C@@H]2O1

Procedure:
D-ribose 1 of a starting material was reacted with acetone according to the method disclosed in J.Biol.Chem., 102,187-201 (1933) to form a compound 3. Physical data for the compound 3 were found to be in accord with those in literature.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH2:21]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10](/[CH:13]=[CH:14]/[C:15]([O:17][CH3:28])=[O:16])=[CH:9][C:8]=1[N+:18]([O-:20])=[O:19])[CH3:22]
Reactant: CO
Reactant: CCN(CC)CCSc1ccc(C=CC(=O)O)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CCN(CC)CCSc1ccc(/C=C/C(=O)OC)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3-(4-(2-(Diethylamino)ethylthio)-3-nitrophenyl)acrylic acid (1.74 g, 5.4 mmol) was suspended in methanol (25 mL) under stirring. To this solution, concentrated sulfuric acid (1.0 mL) was added. The resulted solution was heated to reflux for 19 hours. Cooling it to room temperature and the solvent was removed under reduced pressure. 100 ml water was added to dissolve the resulted residue. Cooling it with an ice-bath and adjusting the pH value to 9.0 using ammonia under stirring. (E)-methyl 3-(4-(2-(diethylamino)ethylthio)-3-nitrophenyl)acrylate was obtained as yellow solid. TLC: Rf=0.75 (DCM:MeOH=9:1); MP: 57.4° C.-59.1° C. HPLC: 92.0%; tR=9.74 min (LC/PDA: Diamonsil C18 5μ 150×4.6 mm, flow rate: 1.0 mL/min, grade: 10-100% B, 20 minutes: mobile phase A: water; mobile phase B: acetonitrile; UV254); IR (cm−1): 2967, 2926, 1720, 1639, 1604, 918. 1HNMR (400 MHz, CDCl3) δ: 8.36 (1H, s), 7.70 (1H, d, J=1.6 Hz), 7.69 (1H, d, J=16 Hz), 7.50 (1H, d, J=8 Hz), 7.27 (1H, s), 6.51 (1H, d, J=16 Hz), 3.83 (3H, s), 3.12 (2H, t, J=8 Hz); 2.83 (2H, t, J=8 Hz); 2.64 (4H, q, J=7.2 Hz), 1.07 (6H, t, J=7.2 Hz). MS (m/z): 339 (MH)+.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[S:13][C:14]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH2:7]1)(=O)=O.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Br:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([N:8]3[CH2:9][CH2:10][CH2:11][C@H:6]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[CH2:7]3)[S:13][C:14]=2[CH:20]=1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)O[C@@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Product: Brc1ccc2nc(N3CCC[C@H](N4CCCC4)C3)sc2c1

Procedure:
The title compound was prepared by the method of Example 34, substituting (R)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 12) in place of (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate (Reference Example 10) and substituting pyrrolidine in place of azetidine to give (S)-6-bromo-2-(3-(pyrrolidin-1-yl)piperidin-1-yl)benzo[d]thiazole. 1H NMR (300 MHz, CD3OD) δ ppm 1.47-1.75 (m, 2H), 1.77-1.95 (m, 5H), 2.11-2.20 (m, 1H), 2.28-2.39 (m, 1H), 2.67-2.76 (m, 4H), 3.06-3.25 (m, 2H), 3.87-3.96 (m, 1H), 4.25-4.32 (m, 1H), 7.33 (d, J=9 Hz, 1H), 7.39 (dd, J=2, 9 Hz, 1H), 7.79 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 366 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.C(Cl)(Cl)=O>>[NH2:21][CH2:20][C@@H:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: O=C(Cl)Cl
Product: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1

Procedure:
WO 01/47919, application disclosed the Rivaroxaban with applications for prevention and treatment of various thromboembolic diseases. Further this patent describes a method for preparation of Rivaroxaban of formula (I), wherein 4-(4-aminophenyl)morpholin-3-one is reacted with 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione, in presence of solvent to obtain 2-[(2R)-2-hydroxy-3-{[4(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1,3(2H)-dione which is further converted to 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione by phosgene equivalent. Departing of the pthalamide group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one, which is finally coupled with 5-chlorothiophene-2-carbonyl chloride to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide i.e. Rivaroxaban of formula (I) as shown in scheme-1;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:28]4[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Product: Cn1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cn1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole following a procedure analogous to that described in Example 28. LC (method 7): tR=1.11 min; Mass spectrum (ESI+): m/z=385 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C([Li])CCC.[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])[C:2]1[N:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: COc1cccc(Br)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution containing 2-bromo-6-methoxypyridine (0.65 mL, 5.3 mmol) in ether (11 mL) at −78° C. was treated with n-butyllithium (4.0 mL, 1.6 M in hexanes) dropwise, warmed to 0° C. for 10 minutes, cooled to −78° C., treated with tributyltin chloride (2.25 mL, 8.30 mmol), stirred at −78° C. for 0.5 hours, and then at 0° C. for 0.5 hours. The reaction was quenched with saturated ammonium chloride solution and partitioned between ether and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound.
Reaction SMILES: CO[C:3](=[O:38])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:37])(=[O:36])[NH:11][C@H:12]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](OC)=[O:25])=[CH:18][CH:17]=1.[NH2:39][C:40]1[NH:41][CH2:42][CH2:43][CH2:44][N:45]=1>CN(C)C=O>[C:32]([O:31][C:29](=[O:30])[C@@H:12]([NH:11][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3](=[O:38])[NH:39][C:40]1[NH:45][CH2:44][CH2:43][CH2:42][N:41]=1)(=[O:37])=[O:36])[CH2:13][NH:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=[O:25])[NH:39][C:40]2[NH:45][CH2:44][CH2:43][CH2:42][N:41]=2)=[CH:18][CH:17]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: NC1=NCCCN1
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccccc2C(=O)OC)C(=O)OC(C)(C)C)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccccc1C(=O)NC1=NCCCN1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
75 mg (0.13 mmol) of 2-((1S)-1-tert-butoxycarbonyl-2-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)-ethylsulfamoyl)-benzoic acid methyl ester was dissolved in 1 ml of dimethylformamide and 68 mg (0.69 mmol) of 2-amino-1,4,5,6-tetrahydropyrimidine was added. The reaction was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with dichloromethane/methanol (1/1), followed by dichloromethane/methanol/acetic acid/water (85/15/1.5/1.5). Yield 54 mg. MS (ES+): m/e=683.3 (M+H+).
Reaction SMILES: [NH2:1](=S)[NH2:2].[C:4]([OH:7])(=O)[CH3:5].[C:8]1(C)[CH:13]=[CH:12]C=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[NH:1]1[C:10]2[CH:5]([CH2:12][CH2:13][CH2:8][CH:9]=2)[C:4](=[O:7])[NH:2]1
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C1NNC2=CCCCC12

Procedure:
The aminosulfide (IV) is then reacted with concentrated hydrochloric acid at a temperature of 0° to 40° C., followed by reacting the resultant hydrochloride with 1.0 to 1.5 equivalents of sodium nitrite at -10° to 5° C. to form the diazonium salt. The diazonium salt is reduced with 3.0 to 10 equivalents (in regard to the aminosulfide (IV)) of stannous chloride at 0° to -40° C. to obtain the hydrazine hydrochloride, which is neutralized with an aqueous alkaline solution (e.g. sodium hydroxide, potassium hydroxide, potassium carbonate) to obtain the hydrazine sulfide (V). The thus obtained hydrazine sulfide (V) is reacted with 1.0 to 1.2 equivalents of 2-alkoxycarbonylcyclohexanone in a solvent (e.g. acetic acid, toluene, xylene) at a temperature of 50° to 200° C. (preferably 80° to 150° C.) optionally while dehydration by azeotropic distillation or in the presence of molecular sieve is conducted to give the hexahydroindazol-3-one (II).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl.[NH2:13][OH:14].C([O-])([O-])=O.[Na+].[Na+]>CCO>[OH:14][NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[NH:11]
Reactant: N#Cc1ccc2occc2c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: N=C(NO)c1ccc2occc2c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 172.6 %

Procedure:
Prepared using General Procedure 1. To a flask containing benzofuran-5-carbonitrile (200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (176.7 mg, 2.54 mmol) and Na2CO3 (154 mg, 1.42 mmol). The mixture was stirred at 75° C. overnight then concentrated, re-dissolved in DCM and washed with NaHCO3. The combined organic layers were dried over Na2SO4, and concentrated to provide 222 mg of crude N-hydroxybenzofuran-5-carboximidamide INT-68 as a white solid which was used directly in the next step without purification. LCMS-ESI (m/z) calculated for C9H8N2O2: 176.2; found 177.1 [M+H]+, tR=0.83 min.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[CH2:45]([NH:53][C:54](N1C=CN=C1)=[O:55])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[CH2:45]([NH:53][C:54](=[O:55])[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: O=C(NCCc1ccccc1)n1ccnc1
Product: O=C(NCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1)NCCc1ccccc1

Procedure:
The titled compound is prepared from 9-[(1R,2S,3R,4S)-2,3-Dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide using an analogous procedure to Example 42 by replacing N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide with imidazole-1-carboxylic acid phenethyl-amide.
Reaction SMILES: CC1(C)[N:7]([C:8]2[N:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=2)C(=O)C2C=CC=CC=2O1.[ClH:28]>>[ClH:28].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(N2C(=O)c3ccccc3OC2(C)C)nc1
Agent: Cl
Product: CC(C)(C(=O)O)c1ccc(N)nc1
Temperature: 100 °C
Yield: 88 %

Procedure:
A stirred mixture of ethyl 2-[6-(2,2-dimethyl-4-oxo-4H-1,3-benzoxazin-3-yl)-pyridin-3-yl]-2-methylpropanoate (13.3 g, 36.1 mmol) in concentrated HCl (50 mL) was heated at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo and the residue washed exhaustively with chloroform to give the title compound as a colourless solid (6.90 g, 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:16]([S:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([S:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCSc1ccccc1N
Solvent: Cc1ccccc1
Product: CCSc1ccccc1N=Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 96.3 %

Procedure:
A mixture of 500 mg of 2-nitro-4-trifluoromethylbenzaldehyde, 349 mg of 2-(ethylsulfanyl)aniline and 4 ml of toluene was refluxed for 4 hours and then concentrated under reduced pressure. The resulting residue was washed with t-butyl methyl ether to obtain 777 mg of (2-ethylsulfanylphenyl) (2-nitro-4-trifluoromethylbenzylidene)amine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[K+]>C(O)C.O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[S:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-:14])=[O:13]
Reactant: SCc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1SCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 87.2 %

Procedure:
To a mixture of 225.6 g of 4-chloro-3-nitrobenzotrifluoride and 136 g of benzyl mercaptan in 1.5 l of ethyl alcohol, at reflux, was added a solution of 72.5 g of 85% KOH in 120 ml of water over a 45 minute period. Reflux was continued for an additional three hours. The reaction mixture was cooled to 5° C. The precipitate was filtered off, washed with ethanol and water and dried to give 273.2 g of 2-nitro-1-[(phenylmethyl)thio]-4-trifluoromethylbenzene as a bright yellow solid, m.p. 132°-136°.
Reaction SMILES: CN(C=O)C.[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=2)=[CH:15][C:10]2[NH:11][C:12](=[O:14])[S:13][C:9]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[C:36]#[CH:37]>O>[F:6][C:7]1[C:16]([C:17]2[C:18](=[O:28])[N:19]([CH3:27])[C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=2)=[CH:15][C:10]2[N:11]([CH2:37][C:36]#[CH:35])[C:12](=[O:14])[S:13][C:9]=2[CH:8]=1
Reactant: C#CCBr
Reactant: Cn1c(C(F)(F)F)ccc(-c2cc3[nH]c(=O)sc3cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(-c3ccc(C(F)(F)F)n(C)c3=O)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To 10 ml of DMF, 0.4 g (1.2 mmol) of 3-(6-fluoro-benzothiazolin-2-on-5-yl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone, 0.18 g (1.3 mmol) of potassium carbonate and 0.15 g (1.3 mmol) of propargyl bromide were added, followed by heating and stirring at 70° C. for 2 hours. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.32 g (yield: 72%) of the desired product. Melting point: 150-151° C. 1H-NMR (300 MHz, CDCl3) δ value: 2.30(1H,t), 3.73(3H,s), 4.73(2H,d), 6.80(1H,d), 7.27(1H,d), 7.45(1H,d), 7.56(1H,d)ppm.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH2:14]([Sn](CC)(CC)CC)[CH3:15]>CCOC(C)=O>[CH2:14]([C:2]1[C:10]2[S:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1)[CH3:15]
Reactant: CC[Sn](CC)(CC)CC
Reactant: O=[N+]([O-])c1cc(Br)c2scnc2c1
Solvent: CCOC(C)=O
Product: CCc1cc([N+](=O)[O-])cc2ncsc12
Yield: 75.9 %

Procedure:
A solution of 7-bromo-5-nitrobenzothiazole (0.15 g, 0.58 mmol), tetraethyltin (0.18 mL, 0.87 mmol) and catalytic amount of Cl2Pd(PPh3)2 in a sealed tube was stirred for 12 h at 90° C. The reaction mixture was diluted with EtOAc and washed with brine several times. Organic solution was dried over Na2SO4 and concentrated in vacuo, yielding an oil which was subjected to column chromatography (EtOAc, neat) to provide 91 mg (0.44 mmol, 75%) of the desired product.