Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@H:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.C(Cl)Cl.[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27]>>[CH3:25][S:26]([NH:29][C:16](=[O:17])[C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:5]2[S:6][CH:7]=[C:3]([C:2]([F:21])([F:20])[F:1])[N:4]=2)=[CH:10][CH:11]=1)[CH3:19])(=[O:28])=[O:27]
Reactant: C[C@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Reactant: CS(N)(=O)=O
Solvent: ClCCl
Product: C[C@H](C(=O)NS(C)(=O)=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71875 %

Procedure:
To a solution of (2S)-2-4-{[4-trifluoromethyl)-1,3-thiazol-2yl]amino}phenyl)propanoic acid (3) (0.1 g, 0.32 mmol) in dry CH2Cl2 (2 mL) CDI (0.055 g, 0.34 mmol) was added and the resulting solution was stirred for 1 h at T=0° C. After ice-water bath removal methanesulfonamide (0.032 g, 0.34 mmol) and TEA (40 μl, 0.29 mmol) were added and the resulting mixture was stirred at room temperature for 12 h. At the complete disappearance of the starting material, a buffer H3PO4/H2PO4− solution (pH=2.0, 5 ml) was added and the reaction mixture was trasferred into a reparatory funnel. The two phases were separated and the organic one washed with the same buffer (3×5 mL), dried over Na2SO4 and evaporated under vacuum to give a crude which was purified by flash chromatography. Pure compound 11 (0.089 g, 0.23 mol) was isolated as a yellow oil (71%).
Reaction SMILES: [C:1]12([N:6]3[C:10]4[N:11]=[C:12]([NH:15][CH2:16][C:17]5[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=5)[N:13]=[CH:14][C:9]=4[C:8]([C:25]([C:27]4[CH:28]=[N:29][CH:30]=[C:31](Br)[CH:32]=4)=[O:26])=[CH:7]3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[C:34](=[NH:47])([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:34](=[N:47][C:31]1[CH:32]=[C:27]([C:25]([C:8]2[C:9]3[CH:14]=[N:13][C:12]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[N:11][C:10]=3[N:6]([C:1]34[CH2:2][CH:3]([CH2:5]3)[CH2:4]4)[CH:7]=2)=[O:26])[CH:28]=[N:29][CH:30]=1)([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccc(CNc2ncc3c(C(=O)c4cncc(Br)c4)cn(C45CC(C4)C5)c3n2)cc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncc3c(C(=O)c4cncc(N=C(c5ccccc5)c5ccccc5)c4)cn(C45CC(C4)C5)c3n2)cc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of [7-Bicyclo[1.1.1]pent-1-yl-2-(4-methoxy-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-(5-bromo-pyridin-3-yl)-methanone (Preparation 285, 1.18 g, 2 mmol) and benzophenoneimine (0.50 mL, 3 mmol) in dry toluene (50 mL), cesium carbonate (3.2 g, 10 mmol) was added and the reaction mixture was purged under N2 for 20 min and then Pd(OAc)2 (45 mg, 0.2 mmol) and BINAP (125 mg, 0.2 mmol) were added followed by degassing for another 10 min and refluxing overnight. The reaction mass was cooled to room temperature and filtered through a pad of Celite. The filtrate was partitioned between water (25 mL) and EtOAc (100 mL). The organic phase was washed with brine (10 mL), dried (Na2SO4) and evaporated in vacuo. Purification by column chromatography on silica gel (EtOAc:Hexane 25:75) afforded the title compound as a yellow solid in 85% yield, 1.1 g.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10](OCC)=[O:11])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[N:1]1[CH:2]=[C:3]([CH2:10][OH:11])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: CCOC(=O)c1cnc2cccnn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2cccnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
To a solution of ethyl imidazo[1,2-b]pyridazine-3-carboxylate (1.91 g, 10 mmol) in anhydrous THF (20 mL), lithium aluminium hydride (1.34 g, 35 mmol) was added in portions over 15 min. After stirring at RT for 16 h, the mixture was quenched with ice-water (20 mL) and then extracted with ethyl acetate (30 mL×2). The combined organic layers were washed with brine, dried over Na2SO4 then filtered. The filtrate was concentrated in vacuo to afford imidazo[1,2-b]pyridazin-3-ylmethanol (0.85 g, 57% yield).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[CH:15][C:16]=1[F:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[F:17])[O:18][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Product: O=Cc1ccc(Oc2ccc(F)c(Cl)c2)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 4-fluorobenzaldehyde and 3-chloro-4-fluorophenol.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7][CH2:6]2.[CH:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH2:25]([O:24][C:23](=[O:32])[NH:22][C@@H:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]1[CH2:14][NH:13][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([F:2])[CH:4]=2)[CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C[C@@H]1CCCC[C@H]1NC(=O)OCc1ccccc1
Reactant: NC1CCc2cc(F)ccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68.9 %

Procedure:
A mixture of (RS)-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)amine hydrochloride (200 mg, 0.99 mmol) and benzyl [(1R,2R)-2-formylcyclohexyl]carbamate (258 mg, 0.99 mmol) in 1,2-dichloroethane (4 mL) was treated with triethylamine (275 μL, 1.98 mmol) whereupon a clear solution resulted. Sodium triacetoxyborohydride (272 mg, 1.28 mmol) was added and the mixture was stirred at room temperature for 3.5 hours. Aqueous sodium hydroxide (1.0 N) was then added, and the mixture was extracted with ether. The organic phase was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane, containing 0.5% aqueous ammonia, to provide a colorless oil (280 mg, 69%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41]>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:46]=[CH:45][CH:44]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COC(=O)c1cccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)c1

Procedure:
Analogously to Method D, 2.08 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 1.13 g of methyl 3-(bromomethyl)benzoate are used to obtain the title compound as a slightly yellowish oil. Rf=0.31 (1:2 EtOAc-heptane); Rt=6.06.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:7].O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:7]
Reactant: COc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(4-methoxybenzyl)-4-benzylpiperazine (4.90 g) in ethanol (50 ml) were added water (5 ml), ammonium formate (1.44 g), and 10% palladium on activated carbon [50% wet] (0.49 g) under nitrogen atmosphere. The reaction mixture was heated at 60° C. with stirring for 2 hours. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate (40 ml) and water (40 ml) were added to the residue, and the organic layer was separated, washed with brine, and dried over magnesium sulfate. After removal of the solvent by evaporation, the resulting residue was purified by column chromatography on silica gel (70 g) using a mixed solvent of ethyl acetate and methanol (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4-methoxybenzyl)piperazine (3.18 g) as syrup.
Reaction SMILES: [CH:1]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=O)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]1[C:12]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1Nc2ccccc2C=Cc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C1=Cc2ccccc2NCc2ccccc21
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A suspension of 1 (7.4 g, 33.4 mmol) and lithium aluminum hydride (2.494 ml, 66.9 mmol) in anhydrous ether (200 mL) was refluxed for 15 hours. The reaction mixture was quenched by water, filtered, and the filter cake was washed with ether. The filter cake was dispersed in ether (100 mL), stirred for 10 minutes, and filtered. The combined organic layers were dried over MgSO4, solvent was removed under vacuum, and the product purified by chromatography to provide 4.04 g (19.49 mmol, 58%) of 5,6-dihydrodibenzo[b,f]azocine (2). 1H, 7.27-7.23 (m, 1H), 7.2-7.1 (m, 3H), 6.96-6.9 (m, 1H), 6.9-6.8 (m, 1H), 6.65-6.55 (m, 1H), 6.54-6.48 (m, 1H), 6.40 (d, J=8 Hz, 1H), 6.38-6.29 (m, 1H), 4.51 (d, J=6.8 Hz, 2H), 4.2 (br s, 1H); 13C: 147.3, 139.3, 138.3, 134.9, 132.7, 130.3, 129.0, 128.1, 127.8, 127.6, 127.5, 121.8, 118.1, 117.9, 49.6. HRMS (ESI+) calcd for C15H14N [M+H]+ 208.1126. found 208.1120.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc([N+](=O)[O-])cc4)nc23)CC1
Yield: 35.6 %

Procedure:
Beginning with 0.100 gm (0.43 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.103 gm (0.56 mMol) 4-nitrobenzoyl chloride, 0.058 gm (36%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][NH:13][CH2:14][CH:15]([CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH2:16])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:28][C:29]([CH:31]1[CH2:36][CH:35]([OH:37])[CH2:34][CH:33]([C:38](OCC)=[O:39])[NH:32]1)=O)C>>[O:39]=[C:38]1[NH:16][CH:15]([CH2:17][O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][NH:13][CH2:12][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:11][C:29](=[O:28])[CH:31]2[NH:32][CH:33]1[CH2:34][CH:35]([OH:37])[CH2:36]2
Reactant: NC(CNCC(N)COCc1ccccc1)COCc1ccccc1
Reactant: CCOC(=O)C1CC(O)CC(C(=O)OCC)N1
Product: O=C1NC(COCc2ccccc2)CNCC(COCc2ccccc2)NC(=O)C2CC(O)CC1N2

Procedure:
2,6-Bis(benzyloxymethyl)-1,4,7-triazaheptane (10 mmol), (described in WO-A-89/00557, Example 6 d) and 2,6-bis(ethyloxycarbonyl)-4-hydroxy-piperidine (10 mmol) (described in WO-A-90/08138)is reacted as described in Example 1 a) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)=[C:4]([NH2:23])[N:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br>C(Cl)(Cl)Cl>[Br:29][C:7]1[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[C:9]2[C:5]([N:6]=1)=[C:4]([NH2:23])[N:3]=[C:2]([Cl:1])[N:10]=2
Reactant: BrBr
Reactant: COC(=O)Cc1cccc(Cn2cnc3c(N)nc(Cl)nc32)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COC(=O)Cc1cccc(Cn2c(Br)nc3c(N)nc(Cl)nc32)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
After 2-chloro-9-(3-methoxycarbonylmethylbenzyl)adenine obtained by Reference example 38 (2.00 g, 6.03 mmol) and sodium acetate (2.95 g, 36.0 mmol) were dissolved in chloroform (100 ml), bromine (4.79 g, 30.0 mmol) was added thereto and the mixture was stirred at room temperature for 5 hours. After removing the solvent, the residue was poured into water and extracted with chloroform. The organic layer was washed with saturated sodium hydrogencarbonate, saturated sodium hydrogensulfite and saturated brine in that order, dried over anhydrous magnesium sulfate and concentrated to give the captioned compound (1.78 g, 4.34 mmol, yield: 72%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27](O)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:30])[NH:12][CH:11]3[C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[C:5]2=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:53][S:54]([NH2:57])(=[O:56])=[O:55].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][C:24]([CH3:26])([CH3:25])[C:27]([NH:57][S:54]([CH3:53])(=[O:56])=[O:55])=[O:28])=[C:16]([CH:15]2[CH2:14][C:13](=[O:30])[NH:12][CH:11]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])[C:10]32[C:5]2[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:8][C:9]3=[O:40])[CH:21]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-methoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (122 mg, 0.2 mmol) and CDI (65 mg, 0.4 mmol) in DMF (5 mL) was heated at 60° C. for 2 h. Then to this solution was added a mixture of methanesulfonamide (144 mg, 1.2 mmol) and NaH (48 mg, 60%, 1.2 mmol) in DMF (5 mL), which had been stirred for 3 h at room temperature. After the resulting mixture was stirred at room temperature for 1 h, it was poured into water (5 mL) and the aqueous solution was acidified to “PH” 2-3 by addition of concentrated hydrochloride acid. After the aqueous phase was extracted with EtOAc twice, the combined organic extracts were dried over anhydrous Na2SO4, concentrated and the residue was purified by flash column to give the title compound as a white solid (11 mg).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1.CN1CCOCC1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([C:28](O)=[O:29])=[CH:20]1.C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)/C=C\C(O)=O>C(O)(C)C.CCOCC.ClCCl>[CH3:3][N:4]([CH3:11])[CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:28]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:19][CH:20]=2)=[O:29])[CH2:6]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CN(C)C1CCCNC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)C1CCCN(C(=O)c2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-dimethylaminopiperidine dihydrochloride (1.8 g, 0.01 mol), N-methylmorpholine (2.5 g) and dichloromethane (50 ml) was stirred at ambient temperature for 1.5 h. Indole-3-carboxylic acid (1.92 g, 0.012 mol) was added, followed by dicyclohexylcarbodiimide (2.5 g) and the mixture stirred for 24 h. The mixture was filtered, the filtrate was washed thrice with 1M hydrochloric acid, the acid washings were combined, basified with ammonia and extracted with chloroform. The chloroform extract was dried and evaporated to yield the product base 1.6 g. The base was dissolved in isopropyl alcohol (20ml), acidified with maleic acid (0.72 g, 5% excess) and diluted with ether (10 ml). On standing the maleate salt crystallised and was collected by filtration, 1.04 g, mp 139-141.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[C:18]([O:19][CH3:20])=[CH:17][S:16][CH:15]=1)[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:20][O:19][C:18]1[C:14]2[NH:13][CH:12]=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[C:7](=[O:9])[C:15]=2[S:16][CH:17]=1
Reactant: CCCC(=O)C(=CNc1cscc1OC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCC(=O)c1c[nH]c2c(OC)csc2c1=O
Reaction time: 0.33 h

Procedure:
To a refluxing solution of diphenyl ether (200 ml) was added ethyl 2-butyryl-3-(4-methoxy-3-thienylamino)-prop-2-enoate (16 g, 0.0539 mol) portionwise. On completion of the addition refluxing was continued for a further 20 minutes. The reaction mixture was allowed to cool and then diluted with petroleum ether to give a pale yellow solid, 11.85 g, m.p. 222°-225°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:17]2[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:16])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([C:17]2[C:18]([CH:23]([F:25])[F:24])=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)N2CCC[C@H]2C(=O)c2ccc(Cl)cc2)c(C(F)F)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(C(=O)N2CCC[C@H]2C(O)c2ccc(Cl)cc2)c(C(F)F)n1
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of (4-chloro-phenyl)-[(S)-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl)-pyrrolidin-2-yl]-methanone (370 mg; 1.0 mmol), which was prepared as described in example P5, in methanol (5 ml) at 0° C. was added portionwise sodium borohydride (35 mg; 1.0 mmol). The reaction mixture was stirred for 0.5 hours and 1N HCl was added until pH 7 reached. Solvent was removed under pressure and the remaining mixture was extracted with ethylacetate (2×20 ml). The combined organic layer was dried over Na2SO4, filtered, concentrated and dried in vacuo to give 0.31 g (83.3% of theory) of {(S)-2-[(4-chlorophenyl)-hydroxy-methyl]-pyrrolidin-1-yl}-(3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-methanone as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:8](=O)[CH:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]1[CH2:31][C:30]3[C:25](=[C:26]([O:36][CH3:37])[C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[CH:29]=3)[C:24]1=O)[CH2:6]2.Cl(O)(=O)(=O)=O>C(O)(=O)C.[Pd]>[CH3:37][O:36][C:26]1[C:27]([O:34][CH3:35])=[C:28]([O:32][CH3:33])[CH:29]=[C:30]2[C:25]=1[CH2:24][CH:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:7]1[CH2:8][C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([O:12][CH3:13])[C:10]=3[O:14][CH3:15])[CH2:6]1)[CH2:31]2
Reactant: COc1cc2c(c(OC)c1OC)C(=O)C(CCCCCCC1Cc3cc(OC)c(OC)c(OC)c3C1=O)C2
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1OC)CC(CCCCCCC1Cc3cc(OC)c(OC)c(OC)c3C1)C2

Procedure:
To a solution of 5,6,7-trimethoxy-2-[6-(5,6,7-trimethoxy-1-oxo-2,3-dihydro-1H-2-indenyl)hexyl]-1-indanone in acetic acid (50 ml) were added 10% Pd—C (1 g) and perchloric acid (1 ml), and the reaction mixture was hydrogenated under hydrogen atmosphere (4 to 5 atm) at 50° C. for 6 hr. The catalyst was filtered off and the filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, dried, concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate) and then with recrystallization from ethyl acetate-hexane gave the entitled compound (4.5 g) as crystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17]CC)=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 9, using 250 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of Example 1 and 0.90 ml of 3-fluoroaniline in place of the 2-fluoroaniline. 160 mg of N-(3-fluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24][CH3:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24]([CH3:25])=[O:34])[CH:3]=1
Reactant: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2CS(C)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methylsulfanylmethyl-phenyl)-amide (0.46 g) (cf. example 13a) in chloroform (25 ml) was added m-chloroperbenzoic acid 85% (0.272 g). The reaction mixture was stirred at rt for 18 h, concentrated, and the crude residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.31 g) as an off-white solid. MS (ISN): 473.9, 476.0 (M−H)−