Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]2)=[N:30][CH:31]=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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:38]([CH:35]3[CH2:36][CH2:37][N:32]([C:29]4[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][N:30]=4)[CH2:33][CH2:34]3)=[O:39])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: Cc1ccc(N2CCC(C(=O)O)CC2)nc1
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: Cc1ccc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(Cl)cc4)C3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 26.7 mg (0.085 mmol)[(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester, 15 mg (0.068 mmol) 1-(5-methyl-2-pyridinyl)-4-piperidinecarboxylic acid (commercially available), 31 mg (0.082 mmol) HATU and 70 uL (0.409 mmol) DIPEA in 2 mL DMF was shaken for 1 h at room temperature. The mixture was subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions the title compound as off-white solid. MS m/e: 551.4 [M]+.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@@H:34]12>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@H:34]4[CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C1C[C@H]2CNCCN2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCC[C@H]4C3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as an orange solid (131 mg, 46%).
Reaction SMILES: CCCCCC.C([Li])CCC.C(NC(C)C)(C)C.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[C:27]([C:35]1[C:36]([NH:41][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])=[N:37][CH:38]=[CH:39][CH:40]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.O1CCCC1.CCOCC>[C:42]([NH:41][C:36]1[C:35]([C:27]([OH:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:20][C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:40][CH:39]=[CH:38][N:37]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)C(=O)Nc1ncccc1C(=O)c1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)CC(O)(c1ccccc1)c1cccnc1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
In an atmosphere of argon, 1.69M n-butyl lithiumhexane solution (53 ml, 90.0 mmol) was added dropwise to an ether solution (150 ml) of diisopropylamine (9.61 g, 95.0 mmol) which was cooled at -78° C. After 15 minutes of stirring, an ether solution (20 ml) of tert-butyl acetate (10.5 g, 90.5 mmol) was slowly added dropwise. After 30 minutes of stirring, a tetrahydrofuran solution (30 ml) of 3-benzoyl-2-pivaloylaminopyridine (12.0 g, 42.6 mmol) was added dropwise. After 30 minutes of stirring, this was warmed up to room temperature and stirred for 5 hours. The reaction solution was poured into water and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the resulting filtrate was concentrated under reduced pressure to give tert-butyl 2-pivaloylamino-β-hydroxy-β-phenyl-3-pyridinepropanoate (16.9 g, 100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:24])[NH:17][CH2:18][C:19]1([CH2:22][OH:23])[CH2:21][CH2:20]1)([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl.O>[C:11]([O:15][C:16](=[O:24])[NH:17][CH2:18][C:19]1([CH:22]=[O:23])[CH2:20][CH2:21]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C=O)CC1
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
Under an argon atmosphere oxalyl chloride (1.17 mL, 13.8 mmol) was dissolved in DCM (30 mL) and cooled to −70 C. DMSO (1.95 mL, 27.6 mmol) in DCM (2.5 mL) was added over 5 min and stirred for 10 min. (1-Hydroxymethyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (2.6 g, 12 mmol) in DCM (8.5 mL) was added at −70 C over 5 min and the mixture was stirred for 30 min. Et3N (6.4 mL, 45.6 mmol) was added over 5 min and the temperature was allowed to reach RT over 1 h. H2O was added and the aqueous phase was extracted with DCM (×2). The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica using heptane:EtOAc 1:15 as eluent to afford (1-Formyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (0.65 g) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][CH2:4][N:5]([CH3:49])[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[ClH:51]>>[ClH:51].[ClH:51].[CH3:1][N:2]([CH3:50])[CH2:3][CH2:4][N:5]([CH3:49])[C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[C:25]([CH3:48])=[N:26][NH:27][CH:28]=4)[CH:22]=3)[N:17]=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N(C)CCN(C)C)CC3)c2c1
Agent: Cl
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(=O)N(C)CCN(C)C)CC3)c2c1

Procedure:
67 mg N-[2-(dimethylamino)ethyl]-N-methyl-4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 198 and 0.72 mL of 5 N hydrochloric acid were reacted in the same manner as in Example 163, to give 37 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:19]([OH:20])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[C:4]2=[N:3]1.C1(C)C=CC(S(O[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])(=O)=O)=CC=1>>[CH3:1][N:2]1[C:19]([O:20][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31])=[C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:13])[C:4]2=[N:3]1
Reactant: CCCCOC(=O)CSc1ncnc2c(O)n(C)nc12
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Product: CCCCCCCCCCCCCCCCOc1c2ncnc(SCC(=O)OCCCC)c2nn1C
Yield: 75 %

Procedure:
2-Methyl-3-hydroxy-7-n-butoxycarbonylmethylthiopyrazolo[4,3-d]pyrimidine and n-hexadecyl p-toluenesulfonate were reacted and treated in the same manner as in Synthesis 2 of Example 1 to obtain the desired compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([CH3:47])([CH3:46])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[C:19]([O:26][CH2:27][CH3:28])[CH:18]=[C:17]2[O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)(C(C)(C)C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH2:27]([O:26][C:19]1[CH:18]=[C:17]([O:29][C@H:30]2[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]2)[C:16]2[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14](/[CH:13]=[CH:12]/[CH2:11][C:10]([CH3:47])([CH3:46])[CH2:9][OH:8])[CH:15]=2)[N:20]=1)[CH3:28]
Reactant: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(/C=C/CC(C)(C)CO[Si](C)(C)C(C)(C)C)c(OC)cc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(O[C@@H]2C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C2)c2cc(/C=C/CC(C)(C)CO)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(HF)3-Et3N (523 mL, 3210 mmol) was added to a solution of the product from Step 2 (54 g, 80 mmol) in THF (802 mL) at 0° C. The mixture was then warmed to RT. After 15 hours, the solvent was removed in vacuo, and the residue was taken up in EtOAc (500 mL) and water (450 mL). Na2CO3 (553 g, 5216 mmol) then was added slowly. The solution then stirred 15 minutes, and the organic layer was then extracted with 10% NaHCO3 (1×) and brine (1×) and dried over MgSO4; and the solvent was removed in vacuo. The original aqueous layer was back-extracted with EtOAc and combined with the first extraction. The crude material was then purified on silica (gradient elution, 0-80% EtOAc/hexane) to yield of the title compound. LRMS ESI+ (M+H)+ 559.3, calcd for C30H43N2O8: 559.3.
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18]Cl)=[O:4].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[CH3:1][NH:2][C:3]([N:5]1[CH2:9][CH2:8][S:7][CH:6]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][CH2:18][N:29]1[CH2:30][CH2:31][N:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1)=[O:4]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CNC(=O)N1CCSC1c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2ccccc2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A mixture of 1.81 g of N-methyl-2-{2-(2-chloroethyloxy)phenyl]thiazolidine-3-carboxamide, 0.97 g of N-phenylpiperazine, 0.83 g of potassium carbonate, 0.90 g of sodium iodide and 25 ml of dimethylformamide is stirred at 90° C. for 18 hours. The mixture is concentrated under reduced pressure to remove solvent. Water is added to the residue, and the aqueous mixture is extracted with ethyl acetate. The extract is washed with water, dried and then concentrated under reduced pressure to remove solvent. The residue is crystallized with isopropyl ether, and the crystals are recrystallized from a mixture of ethyl acetate and n-hexane. 1.48 g of N-methyl-2-{2-[2-(4-phenylpiperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained. Yield: 57.8%
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[K+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 52.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2-propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and potassium hydroxide (990 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.03 g (yield 52.6%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:17]1([CH2:23][CH2:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:16][C:29]([CH2:28][NH:27][C:25](=[O:26])[CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:30])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.1 from C,C-bis-(4-chloro-phenyl)-methylamine (CA [14212-38-5]) and (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]).
Reaction SMILES: OO.[Br:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2.S([O-])([O-])=[O:15].[Na+].[Na+].C(=O)([O-])[O-].[K+].[K+]>C[Re](=O)(=O)=O.C(OCC)(=O)C.C1COCC1>[Br:3][C:4]1[C:5](=[O:15])[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: Brc1cnc2ccccc2c1
Reactant: O=S([O-])[O-]
Agent: C[Re](=O)(=O)=O
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2cc1Br
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Hydrogen peroxide solution (5.9 ml) was added to a THF solution (16 ml) of methyltrioxorhenium (VII) (24 mg). The mixture was stirred for 10 minutes at room temperature. 3-Bromoquinoline (4.0 g) was added thereto, and the mixture was stirred at room temperature for four days. Ethyl acetate (20 ml) was added to the reaction mixture. 20% Sodium sulfite aqueous solution (30 ml) was added slowly to the mixture under ice cooling. The mixture was stirred at room temperature. The organic layer was condensed to a half volume under reduced pressure. Ethyl acetate (20 ml) and 15% potassium carbonate aqueous solution (19 ml) were added thereto, and the organic layer was extracted. 15% Potassium carbonate aqueous solution (19 ml) of p-toluenesulfonyl chloride (4 g) were added thereto. The mixture was stirred for 10 minutes at room temperature. The generated insoluble matter was separated, washed with ethyl acetate, water, and then with ether, and dried to give the title compound (3.2 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CN(C=O)C>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17](=[O:19])[C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(CCCCC(=O)O)s2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc3c(s2)CCCCC3=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.2 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-[5-(4-methylphenyl)thiophen-2-yl]valeric acid (2.60 g) in tetrahydrofuran (30 ml) was added oxalyl chloride (1.24 ml) at room temperature and then a drop of DMF, and the mixture was stirred 1 hour. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in dichloromethane (30 ml). To the mixture was added tin tetra-chloride (1.5 ml) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to water to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give 2-(4-methylphenyl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene (2.07 g) as pale yellow crystals.
Reaction SMILES: B.CSC.[F:5][C:6]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([NH2:9])=O.CO.Cl>C1COCC1>[F:5][C:6]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:7][NH2:9]
Reactant: NC(=O)C(F)(F)c1ccccc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.7 %

Procedure:
Borane·dimethylsulfide (1.5 ml; 15.4 mmol) was added dropwise over 30 minutes to a solution of the title compound of Step (B) (1 g; 5.84 mmol) in 6 ml of THF at room temperature. After stirring 18 hr at room temperature and 2 hr at reflux, the reaction mixture was cooled to 0° C. and 3 ml of methanol were added carefully over 15 minutes. The solution was saturated with HCl (g) and the cloudy mixture was stirred 6 hr at room temperature, 30 minutes at reflux and 60 hr at room temperature. After removing the volatiles in vacuo, the residue was partitioned between ether (50 ml) and 1N HCl (30 ml). The ether layer was extracted with 1N HCl (10 ml) and the combined aqueous was backwashed with ether (50 ml). After adjusting the pH to 8 with solid NaHCO3, 1N NaOH (1 ml) was added and the aqueous layer was extracted with ether (50 ml). After washing with saturated NaHCO3 solution (25 ml), water (25 ml) and brine (25 ml), the ether layer was dried (MgSO4) and concentrated to afford 355 mg (39%) of the title compound of this step as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[NH:10][C@@H:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH3:12])=[CH:5][CH:4]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:10][C@@H:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)[CH3:12])[C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(N[C@H](C)c2cccc3ccccc23)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(N[C@H](C)c2cccc3ccccc23)c2cccc(N)c2)cc1

Procedure:
Following a similar reaction, separation and purification procedure to that described in Example (59b), 8.32 g of N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]-N-[(R)-1-(naphthalen-1-yl)ethyl]amine [prepared as described in step (a) above], 9.51 g of nickel chloride hexahydrate and 3.03 g of sodium borohydride were reacted, to obtain 1.15 g of isomer A and 462 mg of isomer B of the title compound, each as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=[N:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[CH3:23][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CN(C)CCCOc1ccccc1C=NCCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCCOc1ccccc1CNCCc1ccccc1
Temperature: 35 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
A stirred solution of 36.0 g of N-[[2-[3-(dimethylamino)propoxy]phenyl]methylene]benzeneethanamine in 200 ml of methanol is treated portionwise with 13.0 g of sodium borohydride. The temperature is maintained at 35° C. using a cold water bath. After 3 hours, the solvent is evaporated and the semi-solid residue is treated with 300 ml of water. The product is extracted twice with 100 ml portions of ether. The solvent fractions are combined, treated with water, dried and concentrated to give 33.8 g of an oily product. Distillation yields 19.9 g of the title compound, boiling point 165°-170° C. at 0.15 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([OH:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[OH-].[K+:25]>C(O)C>[Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O-:17])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[K+:25]
Reactant: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(CC(=O)O)ccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(Cc2cccc(Cl)c2Cl)c2cc(CC(=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of the compound [99](37 mg) in ethanol (2 mL) was added an aqueous solution of 1N-potassium hydroxide (106 μL) at room temperature, and then the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to give the titled compound (38 mg) as a white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][O:19]C(Cl)Cl>C(Cl)Cl.Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:18]=[O:19])[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2
Reactant: COC(Cl)Cl
Reactant: COc1ccc2c(c1)CCC(=O)N2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)NC(=O)CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 0.29 gm (2.19 mmol) aluminum chloride in 5 ml of methylene chloride was prepared under nitrogen gas N2 and stirred for 15 minutes and then cooled to 0° C. The mixture was treated with 0.2 gm (1.13 mmol) 6-Methoxy-3,4-dihydro-1H-quinolin-2-one in 5 ml of methylene chloride. The reaction mixture was stirred for 10 minutes at this temperature and was then cooled to −5° C. α,α-dichloromethyl methyl ether 0.28 ml (3.07 mmol) was added over a 5 minutes period and the green reaction mixture was slowly warmed to room temperature and stirred for 6 hours. The reaction mixture was diluted with 2N HCl and extracted with methylene chloride (4×10 ml). The combined organics were dried over sodium sulfate, filtered and concentrated to yield an off white solid. The crude product was chromatographically purified on silica gel, eluting with 7/3 ethyl acetate/hexane. There was obtained 125 mg (54%) of an off white solid. MS APCI m/e 206 (p+1)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH2:21][CH2:22][C@@H:23]1[O:27][C:26](=[O:28])[N:25]([C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][C:36]3=[O:41])=[CH:31][CH:30]=2)[CH2:24]1.O>CN(C1C=CN=CC=1)C.ClCCl>[CH:33]1[C:32]([N:35]2[C:36](=[O:41])[CH2:37][O:38][CH2:39][CH2:40]2)=[CH:31][CH:30]=[C:29]([N:25]2[C:26](=[O:28])[O:27][C@@H:23]([CH2:22][NH:21][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[CH2:24]2)[CH:34]=1
Reactant: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)c1ccc(Cl)s1
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
4-(N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5° C. and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride (19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at −5° C. The resulting solution was stirred for 1 hour at −5° C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30° C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85° C. for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>ClCCl.C(O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 97 %

Procedure:
To a 0° C. solution of the 4-chlorobenzoyl chloride (4.50 g) in dichloromethane (10 mL) was added an 8M solution of methylamine in ethanol dropwise. The solution was stirred for 16 h and then evaporated to dryness. The residue was diluted with saturated sodium bicarbonate solution (10 mL) and extracted three times with ethyl acetate (3×20 mL), the organics washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo to afford the sub-title compound as a white solid (4.33 g; 97%). 1H NMR (400 MHz, CDCl3) δ 3.00 (3H, s), 7.40 (1H, br) 7.40 (1H, d), 7.70 (1H, d) ppm.