Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH:2]1([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]3[CH:16]=2)[CH2:4][CH2:3]1.[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1>>[CH:2]1([C:5]2[N:6]=[C:7]3[CH:12]=[CH:11][C:10]([NH:13][C:31]([C:28]4[CH:27]=[CH:26][C:25]([C:22]5[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:34])[F:35])=[CH:20][CH:21]=5)=[CH:30][CH:29]=4)=[O:32])=[CH:9][N:8]3[CH:16]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: O=[N+]([O-])c1ccc2nc(C3CC3)cn2c1
Agent: Br
Product: O=C(Nc1ccc2nc(C3CC3)cn2c1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, to provide N-(2-cyclopropylimidazo[1,2-a]pyridin-6-yl)-4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxamide as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N+:10]([C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11].C(=O)(O)[O-].[Na+]>CO.C(Cl)Cl>[N+:10]([C:13]1[C:18]([O:19][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:17][CH:16]=[CH:15][N:14]=1)([O-:12])=[O:11]
Reactant: CCOC(=O)CCCBr
Reactant: O=[N+]([O-])c1ncccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCCOc1cccnc1[N+](=O)[O-]
Yield: 76 %

Procedure:
This compound was prepared from ethyl 4-bromobutyrate 2 and 2-nitro-3-pyridinol (39) via the procedure of Step (A), supra. Following flash chromatography (silica gel; 1.5% methanol/methylene chloride eluant) a dilute sodium bicarbonate wash of an ether solution of the product was necessary to remove traces of starting phenol. The product (40) was obtained in 76% yield as a pale yelow oil.
Reaction SMILES: [NH2:1][C@H:2]([CH2:4][OH:5])[CH3:3].C(=O)(O)[O-].[Na+].Cl[C:12]([O:14][CH3:15])=[O:13]>C1COCC1.O>[OH:5][CH2:4][C@@H:2]([NH:1][C:12](=[O:13])[O:14][CH3:15])[CH3:3]
Reactant: COC(=O)Cl
Reactant: C[C@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@@H](C)CO
Temperature: 25 °C

Procedure:
To a solution of (S)-alaninol (10 g, 130 mmol) and sodium bicarbonate (32.8 g, 390 mmol) in THF-H2O (1:1, 650 mL) at 0° C. was added dropwise methyl chloroformate (11.4 mL, 143 mmol). The mixture was stirred and allowed to warm to rt over 4 h, and was then extracted with ethyl acetate. The organic layer was washed with 1N aqueous sodium hydroxide solution and brine, and was then dried over sodium sulfate, filtered and concentrated to give the crude title compound, which was used without further purification. MS m/z 134.1 (M+1).
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[C:12]1([CH3:30])[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:28][CH:27]([OH:29])[CH2:26][C@@H:22]2[C:23](O)=[O:24])(=[O:20])=[O:19])=[CH:14][CH:13]=1>C1COCC1>[OH:24][CH2:23][C@H:22]1[CH2:26][C@H:27]([OH:29])[CH2:28][N:21]1[S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:30])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)N2CC(O)C[C@@H]2C(=O)O)cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N2C[C@@H](O)C[C@@H]2CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To 900 ml of THF was added 21.75 g (574.9 mmol) of sodium borohydride and the mixture was cooled to 10° C. before 97.92 ml (776.2 mmol) of borontrifluoride etherate was added dropwise over a period of 1 hour. Then 82 g (287.4 mmol) of N-(4-toluenesulfonyl)-4-hydroxy-D-proline was added carefully in 300 ml of THF at 0° C. and the mixture was warmed to room temperature and allowed to stir for 16 hours. The reaction was cooled to 0° C. and quenched with methanol; 10% aqueous HCl solution was then added and the mixture was gently heated to 60° C. for 1 hour. The pH of the reaction was adjusted to neutral with 50% aqueous sodium hydroxide solution and the volatiles were evaporated under reduced pressure. The product was then isolated via filtration and the filter cake was washed with water. Drying under vacuum at 60° C. for 12 hours yielded 78 g of the product as a white solid in 100% yield. M.P.=131°-132° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=[O:4].O=C1C[C:23]2[C:18](=[CH:19][C:20](C(O)=O)=C[CH:22]=2)N1.NC1C=CC=CC=1>>[O:14]=[C:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:3]([NH:2][C:1]3[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=3)=[O:4])[CH:6]=2)[NH:10]1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Reactant: CNC(=O)c1ccc2c(c1)CC(=O)N2
Solvent: Nc1ccccc1
Product: O=C1Cc2cc(C(=O)Nc3ccccc3)ccc2N1

Procedure:
The title compound was synthesized according to the method described for N-methyl-2-oxoindoline-5-carboxamide from 2-oxoindoline-6-carboxylic acid (89 mg, 0.500 mmol) and aniline (0.14 mL, 1.50 mmol) to obtain 45 mg, 36%. 1H NMR (400 MHz, CD3OD) δ 7.88 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J=7.9 Hz, 2H), 7.36 (t, J=7.9 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 3.34 (s, 2H); MS ESI 253.0 [M+H]+, calcd for [C15H12N2O2+H]+ 253.10.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[N:5]([CH2:6][CH2:7][CH2:8]2)[C:4](=[O:15])[CH:3]=1
Reactant: COC(=O)c1c(Cl)cc(=O)n2c1CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1c(Cl)cc(=O)n2c1CCC2
Yield: 84.7 %

Procedure:
Compound 1b (800 mg, 3.52 mmol) was stirred in a solution of THF (10 mL), MeOH (5 mL), and 1N NaOH (5 mL) at r.t. for 20 h. The solution was made acidic with 1N HCl and extracted (3×) with CHCl3. Organics were dried (MgSO4) and concentrated in vacuo to give 637 mg (85%) of compound 9a as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.17 (s, 1H), 6.43 (s, 1H), 3.99 (t, 2H, J=7.4 Hz), 3.32 (t, 2H, J=7.8 Hz), 1.95-2.21 (m, 2H). MS (ES) [m+H] calc'd for C9H8ClNO3, 214. found 214.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CCN(CC)CC
Solvent: CO
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Yield: 62 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (Example 1, 500 mg, 0.654 mmol) in 7 mL of anhydrous methanol flushed with nitrogen was added 532 μL (3.3 mmol, 5 eq.) of triethylamine trihydrofluoride. The reaction was heated to 50° C. for 18 hours. On disappearance of the starting material as indicated by LC analysis, the reaction was allowed to cool which resulted in precipitation of a white solid. This was collected by filtration, rinsed with 3 mL of methanol and dried to provide 171 mg (62%) of the desired product as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:14]=[C:13](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)[CH:12]=[C:11]([O:23][CH3:24])[N:10]=2)[CH2:5][CH2:4]1.[CH3:25][C:26]1[CH:35]=[C:34]([CH:36]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=1>>[CH3:24][O:23][C:11]1[N:10]=[C:9]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][CH2:36][C:34]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:25])[CH:35]=3)[CH2:4][CH2:5]2)[N:14]=[C:13](/[CH:15]=[C:16]2/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/2)[CH:12]=1
Reactant: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CN)CC2)n1
Reactant: Cc1cc(C=O)c2ccccc2n1
Product: COc1cc(/C=C2\SC(=O)NC2=O)nc(N2CCC(CNCc3cc(C)nc4ccccc34)CC2)n1

Procedure:
(Z)-5-((6-methoxy-2-(4-((((2-methylquinolin-4-yl)methyl)amino)methyl)piperidin-1-yl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione was prepared using (Z)-5-((2-(4-(aminomethyl)piperidin-1-yl)-6-methoxypyrimidin-4-yl)methylene)thiazolidine-2,4-dione (Example 153), the general reductive amination procedure and 2-methylquinoline-4-carbaldehyde (45.8 mg, 63 mg theoretical, 72.2%). LC-MS m/z 505 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[C:4]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2].F[C:22](F)(F)S(OC)(=O)=O>>[CH2:1]([C:3]1[N:7]([CH3:22])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:5](=[O:15])[C:4]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:2]
Reactant: CCOC(=O)c1c(CC)[nH]n(-c2ccc(F)cc2)c1=O
Reactant: COS(=O)(=O)C(F)(F)F
Product: CCOC(=O)c1c(CC)n(C)n(-c2ccc(F)cc2)c1=O
Yield: 57 %

Procedure:
In the same manner as in Reference Example 64 and using ethyl 5-ethyl-2-(4-fluorophenyl)-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 11 mmol) and methyl trifluoromethanesulfonate (3.7 mL) as starting materials, the title compound (1.9 g, 57%) was obtained as a pale-yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.C[N:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=C([N+]([O-])=O)C1=O.N>>[CH3:1][CH:2]1[C:3]2[N:10]=[CH:15][C:14]([N+:16]([O-:18])=[O:17])=[CH:13][C:4]=2[CH2:5][CH2:6][CH2:7]1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Reactant: CC1CCCCC1=O
Agent: N
Product: CC1CCCc2cc([N+](=O)[O-])cnc21
Yield: 74.4 %

Procedure:
2-Methylcyclohexanone (170 mg, 1.52 mmol) was mixed with 1-methyl-3,5-dinitro-2-pyridone (296 mg, 1.49 mmol) in 1M methanolic ammonia (30 mL, 30 mmol) and heated at reflux for 3 h. The solvent was evaporated off and the residue was suspended in CHCl3 and flash chromatographed over silica gel (19 g) eluting with EtOAc/hexane (1:10) to afford a white solid (213 mg, 75% yield): mp 61°-63° C.
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Clc1nc2ccccc2o1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3nc4ccccc4o3)CC2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 5.11 g (15 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 2.46 g (16 mmol) of 2-chlorobenzoxazole and 2.18 g (15.8 mmol) of powdered K2CO3 in 55 ml of absolute N,N-dimethylformamide was warmed to 85° C., and 345 mg of powdered K2CO3 were added with stirring under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 1.035 g (7.5 mmol) of K2CO3). The mixture was stirred for a further 3 hours at 85° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the crystalline residue was mixed with 50 ml of water, and this mixture was shaken for 15 minutes. The mixture was then filtered under suction and the filter residue was washed with water and dried in vacuo. 4.30 g (97% of theory) of pure 1-(4-hydroxyphenyl)-4-(benzoxazol-2-yl)piperazine, melting point 161°-3° C., were obtained,
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH:16][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:28]([F:27])([F:38])[F:39])=[CH:30][CH:31]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-trifluoromethylbenzoyl chloride (87.5 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (178 mg, 88%).
Reaction SMILES: CN([CH:4]=[O:5])C.P(Cl)(Cl)(Cl)=O.[CH:11]1[C:19]([Br:20])=[CH:18][N:17]2[C:13](=[N:14][CH:15]=[CH:16]2)[CH:12]=1.[OH-].[Na+].C([O-])(O)=O.[Na+]>>[CH:11]1[C:19]([Br:20])=[CH:18][N:17]2[C:13](=[N:14][CH:15]=[C:16]2[CH:4]=[O:5])[CH:12]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2nccn2c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc2ccc(Br)cn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 250 mL RB flask was charged with DMF (21.3 ml, 274 mmol) and cooled to 0° C.; phosphorus oxychloride (2.46 ml, 26.4 mmol) was added dropwise. This was stirred for 1 hour, then 6-bromoH-imidazo[1,2-a]pyridine (2.00 g, 10.2 mmol) was added in one portion. This was stirred at 100° C. for 5 hours and at room temperature for 16 hours. The flask was cooled to 0° C. and slowly neutralized with 6N aq. NaOH and sat. aq. NaHCO3, resulting in the formation of a precipitate which was collected by filtration to give 6-bromoH-imidazo[1,2-a]pyridine-3-carbaldehyde as a yellow-orange solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH2:19][CH3:20]>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:6]=1[C:4]1[N:3]=[CH:2][N:1]([C:24]2[CH:25]=[CH:26][C:21]([CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=2)[CH:5]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: CCCc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 30 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-propylphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (52 mg, 30%) which was obtained as a white solid. MS (ESI): m/e=344.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[OH:3][CH:1]([C:4]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:5]=1[O:6][CH:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)=O)c1ccccc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C(C)O)c1ccccc1C

Procedure:
A stirred solution of ethyl (RS)-4-[2-acetyl-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (1 g) in methanol (50 mL) is treated, portionwise, with sodium borohydride (0.1 g), and stirred at ambient temperature for one hour. It is then treated with dilute acetic acid (50 mL; 1 N) and extracted with ethyl acetate (2×50 mL). The combined organic extracts are washed with water (2×50 mL) dried over magnesium sulphate, filtered and concentrated in vacuo. Flash chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:5 v/v) gives ethyl (RS,RS)-4-[2-(1-hydroxyethyl)-5-(3-thienylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]2[N:9]([CH2:27][CH2:28][O:29][CH3:30])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].CO>C1COCC1>[CH3:30][O:29][CH2:28][CH2:27][N:9]1[C:8]2[CH:31]=[CH:32][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=2[N:11]=[C:10]1[NH:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([O:22][C:23]([F:25])([F:24])[F:26])[CH:19]=[CH:18][C:16]=2[N:17]=1
Reactant: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)OC)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Yield: 89.9 %

Procedure:
1-(2-Methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (723.0 mg) was prepared by following General Procedure E starting from 1-(2-methoxy-ethyl)-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (829.0 mg) and sodium hydroxide (2.0 N solution, 3.0 mL) MeOH (1.0 mL) and THF (3.0 mL). LCMS: m/z 454; and 1H NMR (DMSO-d6, 400 MHz): δ 8.14 (1H, s), 7.95 (1H, m), 7.84-7.82 (1H, m), 7.63 (1H, br. m), 7.51 (1H, m), 7.55-7.52 (1H, m), 7.39-7.36 (1H, m), 4.39-4.36 (2H, t), 3.74-3.71 (2H, t), 3.24 (3H, s), —COOH proton signal was not observed.
Reaction SMILES: Br[CH:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH:3]=O.[CH:16]1([NH:22][C:23]([NH2:25])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[CH:16]1([NH:22][C:23]2[S:24][C:2]([C:5]3[CH:14]=[C:13]4[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]4)=[CH:7][CH:6]=3)=[CH:3][N:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=CC(Br)c1ccc2c(=O)[nH]cnc2c1
Reactant: NC(=S)NC1CCCCC1
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2cc(-c3cnc(NC4CCCCC4)s3)ccc12

Procedure:
A solution of bromo-(4-oxo-3,4-dihydro-quinazolin-7-yl)acetaldehyde and N-cyclohexylthiourea in dimethylformamide is heated at 70° C. until completion of the reaction (5-12 hours). The mixture is quenched with 10% dimethylamine in ethanol and the solvent is removed under reduced pressured. The crude is purified by chromatography on silica gel to isolate the desired compound.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=2[C:3]=1[C:13]([OH:15])=O.[CH:16]([NH2:18])=O.O>CN(C)C=O>[O:9]=[S:6]1(=[O:10])[C:5]2=[CH:11][CH:12]=[C:2]3[C:3]([C:13](=[O:15])[NH:18][CH:16]=[N:1]3)=[C:4]2[CH2:8][CH2:7]1
Reactant: Nc1ccc2c(c1C(=O)O)CCS2(=O)=O
Reactant: NC=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnc2ccc3c(c12)CCS3(=O)=O
Reaction time: 0.67 h
Yield: 48.6 %

Procedure:
0.87 g (3.83 mmol) of 5-amino-1,1-dioxo-2,3-dihydro-1H-1λ6-benzo[b]-thiophene-4-carboxylic acid was suspended in 2.0 ml of N,N-dimethyl-formamide and, after addition of 0.76 ml (19.14 mmol) of formamide, reacted in a microwave at 150° C. and 60 W for 40 min. During the reaction, the pressure in the microwave rose to 20 bar. The reaction mixture was then added to water. The precipitated solid was filtered off with suction and washed successively with water and diethyl ether and dried in vacuo overnight. 440 mg of the desired compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C:2]1[C:3]([C:24]([NH:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:25])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(CCO)cc2)nc1C(=O)Nc1cccnc1
Yield: 81.7 %

Procedure:
A solution of the product of step (ii) (4.1 g, 9.13 mmol) and tetrabutyl ammonium fluoride (4.8 g, 18.3 mmol) in THF (150 mL) was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue extracted with dichloromethane and washed with water. The combined organic layers were dried overanhydrous sodium sulphate, filtered and concentrated in vacuo to obtain the subtitle compounds (2.5 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[C:10]2[O:9][C:8]([CH:15]([Cl:20])[C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1OC(C(Cl)C(F)(F)F)(C(F)(F)F)O2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)C1(C(F)(F)F)Oc2cccc(CBr)c2O1

Procedure:
64 g of 4-methyl-2-(1-chloro-2,2,2-trifluoroethyl)-2-trifluoromethyl-1,3-benzodioxole from Example 9 were dissolved in 500 ml of carbon tetrachloride, and 36 g of N-bromosuccinimide and 0.5 g of AIBN (azoisobutyronitrile) were added. The mixture was stirred under reflux for 3 hours and then cooled and filtered. The solvent was stripped off and the residue was distilled in vacuo. The yield was 57 g (71% of theory), and the boiling point was 80°-82° C. under 0.1 mbar. The NMR spectra showed the following characteristic absorptions: 1H-NMR: 4.72 ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:49]1([CH2:55][C@H:56]([NH2:65])/[CH:57]=[CH:58]/[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:65][C@H:56](/[CH:57]=[CH:58]/[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@H](/C=C/c1ccccc1)Cc1ccccc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](/C=C/c1ccccc1)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
N-(tert-Butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S,3E)-1,4-diphenylbut-3-en-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was prepared in analogy to the synthesis of Intermediate 55, by reaction of 20 mg (29 μmol) N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide with 7.1 mg (32 μmol) of (2S,3E)-1,4-diphenylbut-3-en-2-amine.