Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(CC)CC)C.C(O[CH:22]=[CH:23][C:24](=O)[C:25]([F:28])([F:27])[F:26])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:22]=[CH:23][C:24]([C:25]([F:28])([F:27])[F:26])=[C:3]([S:2][CH3:1])[C:4]=1[OH:11])[CH3:10]
Reactant: CCOC(=O)CC(=O)CSC
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C(F)(F)F)c(SC)c1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
100 g of ethyl 4-(methylsulphanyl)-3-oxobutanoate and 27.8 g of triethylamine were initially charged in 260 ml of toluene and cooled to 0° C. under nitrogen. Then 102.8 g of 4-ethoxy-1,1,1-trifluorobut-3-en-2-one were added dropwise at 0-7° C. within 30 minutes and the mixture was stirred for a further 5 h. After 16 hours, the reaction was warmed up to 18° C. The reaction mixture was concentrated, admixed with 150 ml of acetonitrile and concentrated at 5 mbar. The crude product was admixed with 2 equivalents of 10% sodium hydroxide solution while stirring and cooling with ice-water and stirred for 1 h, and the solids were filtered off with suction, washed three times with 50 ml of 3.5% sodium hydroxide solution and dried by suction. The solids were then admixed with 150 ml of water and 150 ml of toluene, and adjusted to pH 1 with about 150 ml of 10% HCl, and further HCl was metered in with continued stirring until the pH remains below 3. Then the filtered phases were separated and the water phase was extracted once more with toluene. The combined toluene phases were dried and concentrated: Yield 122.3 g (78% of theory). 1H NMR (CDCl3, 400 MHz): δ=11.77 ppm (1H, s), 7.93 ppm (1H, d), 7.23 ppm (1H, d), 4.47 ppm (2H, q), 2.44 ppm (3H, s), 1.45 ppm (3H, t).
Reaction SMILES: CO[C:3]1C=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1N.CO[C:19]1[CH:20]=[C:21]([N:28]2CCN(C)C[CH2:29]2)[CH:22]=[CH:23][C:24]=1[N+:25]([O-])=O.CC[OH:37]>CO>[NH2:25][C:24]1[CH:23]=[CH:22][C:21]([N:28]2[CH2:3][CH2:4][CH2:5][CH:6]([C:7]([N:9]3[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]3)=[O:37])[CH2:29]2)=[CH:20][CH:19]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1N
Reactant: CCO
Reactant: COc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Solvent: CO
Product: CN1CCN(C(=O)C2CCCN(c3ccc(N)cc3)C2)CC1

Procedure:
[1-(4-Amino-phenyl)-piperidin-3-yl]-(4-methyl-piperazin-1-yl)-methanone was prepared in a similar manner as 2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenylamine of Example 33 after substituting (4-Methyl-piperazin-1-yl)-[1-(4-nitro-phenyl)-piperidin-3-yl]-methanone for 1-(3-Methoxy-4-nitro-phenyl)-4-methyl-piperazine, and using EtOH as the solvent rather than MeOH (75 mg, 99%). LC/MS (E/I+) 303.19 (M+H).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[C:1]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)C=Cc1ccccc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C=Cc2ccccc2)cc1
Yield: 60.6 %

Procedure:
In a manner similar to that described in Example 3, cinnamoyl chloride (0.057 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.049 g of 4-[4-(cinnamoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+324.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][CH2:15][CH2:16][CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20].C(N(C(C)C)CC)(C)C>>[CH2:19]([O:18][CH:17]([O:21][CH2:22][CH3:23])[CH2:16][CH2:15][NH:14][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:20]
Reactant: COc1cc(Cl)nc2ccccc12
Reactant: CCOC(CCN)OCC
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(CCNc1cc(OC)c2ccccc2n1)OCC
Temperature: 95 °C
Reaction time: 60 h
Yield: 12 %

Procedure:
To 2-chloro-4-methoxyquinoline (0.576 g, 3 mmol) was added 1-amino-3,3-diethoxypropane (0.515 g, 3.5 mmol) and diisopropylethylamine (5 ml). The mixture was stirred under argon at 95° C. for 60 h. Volatile material was removed in vacuo and the residue partitioned between ethyl acetate and water. The ethyl acetate soluble material was purified by chromatography on silica gel eluting with 0-10% (9:1 MeOH/NH3) in dichloromethane to give the title compound as a yellow gum (110 mg, 12%). δH (CD3OD) 1.1 (6H, t), 1.85 (2H, m), 3.35-3.7 (6H, m), 3.9 (3H, s), 4.6(1H, t), 6.05(1H, s), 7.0(1H, t), 7.35 (1H, t), 7.45 (1H, d), 7.8 (1H, d); MS (ES+) 305 (63%, MH+). 259 (28), 213 (42), 187 (100).
Reaction SMILES: CO[C:3]([C@@H:5]1[C@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12](OC(C)(C)C)=O)[CH2:6]1)=[O:4].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.BrC[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[NH2:11][C@@H:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:6][C@@H:5]1[C:3]([N:21]1[CH2:22][CH2:23][S:19][CH2:20]1)=[O:4]
Reactant: C1CSCN1
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: BrCCc1ccccn1
Product: N[C@@H]1CCN(CCc2ccccn2)C[C@@H]1C(=O)N1CCSC1

Procedure:
This material was obtained as described in example 34 from the opposite enantiomer (3S, 4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester, thiazolidine and 2-(2-bromo-ethyl)-pyridine (synthesized according to Synthesis, 5, 1987, 452-455). Yellow oil. MS (ESI): 321.4 (MH+).
Reaction SMILES: O.[CH3:2][C:3](C1C=CC(O)=CC=1)([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[CH3:4].[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[C:8]1([OH:11])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1.[C:3]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[OH:25])([CH3:4])=[CH2:2]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: Oc1ccccc1
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)c1ccccc1O

Procedure:
The mother liquor from the primary system contains water, acetone, impurities and residual BPA. This mother liquor is passed through preheaters into a flash chamber where the water, acetone and a portion of the phenol is flashed to a vapor. This vapor is fed to a distillation column for separating the water and acetone from the lower vapor pressure phenol. The bottoms stream from the flash chamber includes a concentration of impurities and residual BPA in a phenol carrier. From this stream, a small purge is taken to a catalytic decomposition zone where the phenol is distilled overhead and the BPA and impurities are cleaved at high temperature to form phenol and isopropenyl phenol. Phenol is recovered as raw material and recycled to the reaction zone. Uncleavable "heavies" and polymers are purged from the system as "tars." The balance of the flash pot bottoms stream is recycled to the reaction zone.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[N:21][CH:22]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1ccc(Br)cn1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Glycine ethyl ester hydrochloride (9C2) (161 mmol, 22.51 g) was dried under vacuum then dissolved in methanol (200 ml). Triethylamine (137 mmol, 13.87 g) was added with stirring and the resulting solution was added dropwise to a solution of 5-bromo-2-formylpyridine (9B1) (81 mmol, 15 g) in methanol (200 ml) under nitrogen. After 30 min, sodium triacetoxyborohydride (194 mmol, 41.0 g) was added portionwise over 30 min and the reaction was then stirred at room temperature under nitrogen overnight. The reaction was quenched with saturated sodium bicarbonate solution and extracted three times with DCM. The combined organic layers were washed with water, brine and dried using a hydrophobic frit, then concentrated under reduced pressure. The reside was purified on silica eluting with heptane/EtOAc/EtOH 8/1.6/0.4 to 5/4/1 to give ethyl 2-((5-bromopyridin-2-yl)methylamino)acetate (9J1) 11.4 g (51.6%); 1H NMR (400 MHz, CDCl3) 8.61 (s, 1H) 7.78 (d, 1H) 7.27 (d, 1H) 4.20 (q, 2H) 3.91 (s, 2H) 3.46 (s, 2H) 2.31 (bs, 1H) 1.27 (t, 3H).
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].[CH2:49]([S:56]([CH2:59][C@@H:60]([NH2:68])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)(=[O:58])=[O:57])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=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:68][C@@H:60]([CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[CH2:59][S:56]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:58])=[O:57])=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1
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
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](Cc1ccccc1)CS(=O)(=O)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)-1-(benzylsulphonyl)-3-phenylpropan-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) of 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 9.3 mg (20 μmol) of (2S)-1-(benzylsulphonyl)-3-phenylpropan-2-amine
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[O:20]C>Br.O>[OH2:15].[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1[OH:20]
Reactant: COc1c(F)cc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Agent: Br
Solvent: O
Product: CC1CCc2c(O)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A solution of 1.2 g of 6,7-dihydro-9-fluoro-8-methoxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in 25 ml of 48% hydrobromic acid was heated at reflux for three hours, and was then cooled and diluted with about 100 ml of water. The product was separated by filtration and recrystallized from aqueous N,N-dimethylformamide to provide white solid 6,7-dihydro-9-fluoro-8-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid hydrate, m.p. 293°-294° C. Analysis: Calculated for C14H12FNO4.0.25H2O=%C, 59.7; %H, 4.5; %N, 5.0; Found: %C, 59.5; %H, 4.2; %N, 5.0.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24](CO)[CH:23]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:32])=O.[CH2:34]([Cl:36])Cl>>[Cl:32][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH2:34][Cl:36])[CH:23]=3)[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: ClCCl
Reactant: OCc1cccc(C2(c3cccc(CO)c3)c3ccccc3-c3ccccc32)c1
Product: ClCc1cccc(C2(c3cccc(CCl)c3)c3ccccc3-c3ccccc32)c1
Temperature: 25 °C

Procedure:
20.0 g (52.9 mmol) of 9,9-bis-(3-hydroxymethylphenyl)-9H-fluorene are dissolved in 300 ml of DCM. A mixture of 16.0 ml of thionyl chloride in 100 ml of dichloromethane is added dropwise to the solution, and the mixture is subsequently stirred at room temperature until the evolution of gas is complete. The solution is washed three times with 200 ml of sat. sodium hydrogencarbonate solution each time and twice with 200 ml of water each time and then dried over magnesium sulfate. The oily residue obtained after removal of the solvent in vacuo is recrystallised twice from ethanol with addition of a little acetone. Yield: 16.0 g (38.5 mmol), 72.8%, about 97% pure according to 1H-NMR.
Reaction SMILES: [CH3:1][C:2](=[C:4]([C:10]([O:12]CC)=O)[C:5]([O:7]CC)=O)[CH3:3].[CH:15](/[S:23]([NH2:26])(=[O:25])=[O:24])=[CH:16]\[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[F:27][C:28]1[CH:37]=[CH:36][C:31]([NH:32][CH:33]([CH3:35])[CH3:34])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:37]=[CH:36][C:31]([N:32]([CH:33]([CH3:35])[CH3:34])[C:10](=[O:12])[C:4](=[C:2]([CH3:1])[CH3:3])[C:5]([NH:26][S:23](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:24])=[O:25])=[O:7])=[CH:30][CH:29]=1
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)C
Reactant: NS(=O)(=O)/C=C/c1ccccc1
Product: CC(C)=C(C(=O)NS(=O)(=O)/C=C/c1ccccc1)C(=O)N(c1ccc(F)cc1)C(C)C
Yield: 0.6 %

Procedure:
Diethyl (1-methylethylidene)malonate (5.00 g) was subjected to hydrolysis in the same manner as in Example 1 (1). The obtained carboxylic acid and trans-β-styrenesulfonamide (953 mg) were condensed in the same manner as in Example 152 (3), and the condensed product was subjected to hydrolysis in the same manner as in Example 1 (3). This and 4-fluoro-N-isopropylaniline (805 mg) were condensed in the same manner as in Example 1 (4) to give a crude product. This was purified by silica gel column chromatography to give the title compound (13 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23].[OH-].[Na+].Cl.C(Cl)Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[F:23]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC)cc3F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)c(F)c1
Temperature: 75 °C
Yield: 27.1 %

Procedure:
A mixture of methyl 6-chloro-5-(2-fluoro-4-methoxyphenyl)-1H-indole-3-carboxylate (50 mg, 0.15 mmol) in methanol (1.5 mL) and aqueous 1M sodium hydroxide (1 M, 0.50 mmol, 0.50 mL) was heated at 75° C. for 24 hours. The reaction was then acidified with 1M HCl to pH=2 and diluted with ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a crude solid. A small amount of methylene chloride was added and the crude material slurried for 5 minutes. The solid was then filtered and washed with ethyl acetate to provide the title compound (13 mg, 27% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C:20](=[O:22])[CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C@@H:10]([C@H:20]([OH:22])[CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution of 1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanone (0.52 g, 1.65 mmol) in THF (20 mL) at 0° C. were added portion wise LiAlH4 (55 mg, 1.45 mmol). Stirring was continued for one hour, and the reaction mixture was carefully quenched by addition of aq. NH4Cl, concentrated under vacuo and the product extracted with EtOAC. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The two diastereoisomeres were separated by column chromatography (SiO2, EtOAc/H, 1:1) to yield (R)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-B-8) 0.24 g (46%) as a white solid ES-MS m/e: 316.1 (M+H+) and (S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-ethanol (V-A-8) 0.25 g (47%) as a white solid ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: C([NH:8]CC(O)=O)(OC(C)(C)C)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=[O:18].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH3:8].[CH3:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cc1cc(C)cc(C(=O)N2CCNC(c3ccc(Cl)c(Cl)c3)C2)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N
Reaction time: 60 h

Procedure:
To a solution of BOC glycine (0.918 g, 5.24 mmol), (+)-(3,5-dimethylbenzoyl)-3-(3,4-dichlorophenyl)piperazine (enantiomer B)(1.80 g, 4.95 mmol) (prepared in Example 19), DEC (0.983 g, 5.13 mmol), HOBT (0.687 g, 5.07 mmol) and Hunig's base (0.92 mL, 5.1 mmol) in CH2Cl2 (100 mL) was left stirring for 2.5 d. The reaction mixture was added to CH2Cl2 (200 mL) and washed with sat. NaHCO3 (3×100 mL), brine (100 mL), dried with MgSO4 and concentrated. The crude material was treated with MeOH saturated HCl (25 mL) for 10 h and concentrated. The resulting residue suspended in 0.3N NaOH (150 mL) and extracted with CH2Cl2, (3×50 mL). The combinded organic layers were washed with brine (50 mL), dried with MgSO4, concentrated, and purified by flash chromatography on silica gel, eluting with 20:1:0.2 CH2Cl2 /MeOH/conc. aq. NH3 to give 0.95 g of the titled product as a white solid. HRMS (FAB, M+H+); m/e calc'd [C31H24Cl2N3O2 ]+ : 420.1246 found 420.1254.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]([CH3:34])[C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[C@H:30]([O:29][CH3:28])[CH3:34])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CO[C@H](C)C(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CO[C@H](C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (69 mg, 66%), MS (ISP) m/z=417.4 [(M+H)+], mp 170.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (R)-2-methoxy-propanoic acid.
Reaction SMILES: [O:1]1[CH:10]2[CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[OH:1])[CH2:14][CH2:13]1
Reactant: c1ccc2c(c1)CC1OC21
Reactant: CN1CCNCC1
Product: CN1CCN(C2c3ccccc3CC2O)CC1

Procedure:
Using the procedure of Example 23, Step A, 14.57 g of 2,3-epoxy-indane and 12.4 ml of N-methyl piperazine were reacted to obtain 6.447 g of [trans (±)] 2,3-dihydro-1- (4- methyl-1-piperazinyl)-1H-inden-2-o1 melting at 132° C.
Reaction SMILES: Cl[C:2]1N(C2C=CC(C(OC)=O)=CC=2)N=C[C:3]=1C(=O)NC1CCCCC1.[CH:26]1([NH:32][C:33]([C:35]2[CH:36]=[N:37][N:38]([C:46]3[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=3)[C:39]=2[S:40][CH:41]2[CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH:41]1([S:40][C:39]2[N:38]([C:46]3[CH:55]=[CH:54][C:49]([C:50]([O:52][CH3:53])=[O:51])=[CH:48][CH:47]=3)[N:37]=[CH:36][C:35]=2[C:33](=[O:34])[NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:42][CH2:43][CH2:3][CH2:2][CH2:44][CH2:45]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCC2)cc1
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2SC2CCCCCC2)cc1

Procedure:
Methyl 4-[5-cycloheptylsulfanyl-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate was prepared from cycloheptylthiol and methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate #15) by the same process used for Intermediate #96.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH:9]1[O:13][CH2:12][CH2:11][O:10]1.Cl[C:15](OC(Cl)(Cl)Cl)=[O:16]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:15]=[O:16])=[CH:4][C:3]=1[CH:9]1[O:10][CH2:11][CH2:12][O:13]1
Reactant: Nc1ccc(Cl)c(C2OCCO2)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cl)c(C2OCCO2)c1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
2.0 g of 4-chloro-3-(1,3-dioxolan-2-yl)-aniline in 25 ml of ethyl acetate were added to a solution of 3.0 g of trichloromethyl chloroformate in 50 ml of toluene at about 20-25° C. This mixture was stirred for 2 hours at 20-25° C. and then for a further 5 hours at the reflux temperature. Thereafter, the reaction mixture was evaporated down and the residue was dried under greatly reduced pressure.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[CH:37][N:36]=2)[CH2:31][CH2:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH2:30][CH2:31][N:32]([C:35]2[CH:40]=[C:39]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([N:11]4[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]5[CH2:27][CH2:26][CH2:25][CH2:24][O:23]5)=[O:19])=[CH:12]4)(=[O:10])=[O:9])=[CH:4][CH:3]=3)[CH:38]=[CH:37][N:36]=2)[CH2:33][CH2:34]1
Reactant: CN1CCN(c2cc(B3OC(C)(C)C(C)(C)O3)ccn2)CC1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CN1CCN(c2cc(-c3ccc(S(=O)(=O)n4ccc(/C=C/C(=O)NOC5CCCCO5)c4)cc3)ccn2)CC1
Temperature: 100 °C
Yield: 64.3 %

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (6.8 g) and 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-pyridin-2-yl]-piperazine (5.0 g) are dissolved in DME (300 mL). Under an inert gas atmosphere are added (Ph3P)3PdCl2 (2.1 g) and 2M Na2CO3-solution (44 mL). The mixture is heated to 100° C. for 2.5 h. After filtration and extraction, the crude product from the organic phase is purified by silica gel flash chromatography. By means of chloroform/EtOH (30:1-19:1). 5.3 g of the title compound are obtained as brownish oil.