Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1>>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH:29]1[CH2:33][CH2:32][N:31]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:30]1
Reactant: Clc1ccccc1C1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(2-chlorophenyl)pyrrolidine oxalate (16.3 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (2.5 mg). Calcd for C21H19ClN2O2: 366.1135, found 366.1141.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.O=[C:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:17]2[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
4-(3,4-Dichlorophenoxy)piperidine (Method B, 1.44 g), ethyl 4-oxocyclohexanecarboxylate (1.0 g) and acetic acid (0.34 ml) were combined in THF 10 ml and the solution was cooled in ice. Sodium triacetoxy borohydride (1.45 g) was added and the mixture was stirred overnight and allowed to come to ambient temperature. The reaction mixture was poured onto a stirred saturated aq solution of sodium bicarbonate. The mixture was extracted with ethyl acetate thrice, the organic phases were washed with brine, dried, filtered and evaporated. The residue was purified on an SCX cartridge (International Sorbent Technology Isolute® Flash SCX-2), washed with methanol and then product eluted with 0.7M ammonia in methanol. Further purification by chromatography (silica, 90:9:1 DCM:methanol:triethylamine) gave the subtitle compound (1.59 g; MS [M+H]+ (APCI+) 400/402) as a mixture of cis/trans isomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([CH2:8][OH:9])[CH:7]=1>ClCCCl.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16])[CH:5]=[C:6]([CH:8]=[O:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1cc(Br)cc(C=O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
A solution of tert-butyl [3-bromo-5-(hydroxymethyl)phenyl]carbamate (13.3 g, 44.2 mmol) and manganese(IV) oxide (19.2 g, 221 mmol) in 1,2-dichloroethane (88 mL) was stirred at 80° C. for 3 h. The reaction mixture was treated with additional manganese(IV) oxide (11.5 g, 132 mmol) and stirred at 80° C. for 16 h. The reaction mixture was filtered over celite (2×) and washed with dichloromethane. The filtrate was concentrated to give the desired product (10.9 g, 82% for 2 steps) as a white solid. LCMS for C12H14BrNO3Na (M+Na)+: m/z=321.9, 323.9.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6](=[O:27])[N:7]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[CH:8]=1)#[CH:2].[NH:29]1[CH:33]=[N:32][CH:31]=[N:30]1>N1C=CC=CC=1>[C:1]([C:3]1[C:4]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[N:5][C:6](=[O:27])[N:7]([C@@H:9]2[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[C@@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@@H:10]2[O:11][C:12](=[O:14])[CH3:13])[CH:8]=1)#[CH:2]
Reactant: c1nc[nH]n1
Reactant: C#Cc1cn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O)c(=O)nc1-n1cncn1
Yield: 65.9 %

Procedure:
5Ethynyl-1-(2',3',5'-tri-O-acetyl-β-D-arabinofuranosyl)uracil from Example 5 (0.6 g, 1.5 mmol), 1,2,4-triazole (0.33 g, 4.8 mmol) and p-chlorophenylphosphodichloridate (0.8 ml, 4.8 ml) were stirred together in dry pyridine (20 ml) for 72 hr. The resulting dark solution was evaporated to dryness and the residue purified by column chromatography on silica eluting with ethylacetate/hexane (9:1) to give an apparently unsatable product (0.44 g) which was used in its crude from in the next stage of the synthesis.
Reaction SMILES: [CH:1]1([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]C)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:31]([F:34])([F:33])[F:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O1CCOC[CH2:38]1>>[CH:1]1([C:6]2[CH:30]=[CH:29][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[N:17]5[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=[O:26])[C:16]5=[C:15]([CH3:38])[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:31]([F:32])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Reactant: C1COCCO1
Agent: [Li+]
Agent: [OH-]
Product: Cc1c2n(c3ccc(OCc4ccc(C5CCCC5)c(C(F)(F)F)c4)cc13)CCC2CC(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Methyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.579 g, 1.192 mmol) was dissolved in 1,4-dioxane (10.74 mL). Aqueous 1.0 M lithium hydroxide (3.58 mL, 3.58 mmol) was added at 25° C. to give a slightly turbid solution. The reaction mixture was stirred at 60° C. for 1 h and cooled to 25° C. The solvent was evaporated in vacuo at 25° C. to a volume of 4 mL and added 0.5 M citric acid (14 mL) and MTBE (75 mL). The mixture was shaken. The organic layer was separated, washed with H2O (2×20 mL), brine (20 mL), and dried over MgSO4. The solvent was evaporated in vacuo to give the title compound (0.540 g) as white crystals. LCMS m/z=472.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55-1.73 (m, 4H), 1.79-1.90 (m, 2H), 2.01 (m, 2H), 2.15 (s, 3H), 2.19-2.29 (m, 1H), 2.40-2.48 (m, 1H), 2.70-2.82 (m, 2H), 3.20-3.28 (m, 1H), 3.60 (m, 1H), 3.92 (m, 1H), 4.03 (m, 1H), 5.14 (s, 2H), 6.76 (dd, J=8.72, 2.40 Hz, 1H), 7.02 (d, J=2.40 Hz, 1H), 7.14 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.00 Hz, 1H), 7.68-7.76 (m, 2H), 12.26 (bs, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([OH:33])=O)=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:33])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:28])[CH3:29])[C:14]=23)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1c(C(=O)O)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c2nccc(-c3ccc(F)cc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluorophenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c2) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:3]=12.C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH3:39])[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(OCC)(=O)C>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:6]1[N:5]=[C:4]2[S:17][C:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[C:3]2=[C:2]([C:33]2[CH:34]=[CH:35][C:30]([CH3:39])=[CH:31][CH:32]=2)[C:7]=1[CH:8]([O:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CCOC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of methyl 2-[4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]-2-ethoxyacetate (0.040 g; 0.113 mmol) in a mixture of DME-water (3:1) (0.48 mL) were added potassium carbonate (0.062 g; 0.452 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0065 g; 0.0056 mmol) and 4-tolylboronic acid (0.031 g; 0.226 mmol). The solution was stirred for 30 min at 140° C. under microwave irradiation. Ethyl acetate was added to the reaction mixture and the solution was washed with brine. The organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of ethylacetate (5-40%) in heptane furnished 0.025 g (54%) of the title compound as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@H:7]2[CH2:11][C@@H:10]([OH:12])[CH2:9][NH:8]2)=O)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH:1]1([NH:4][CH2:5][C@@H:7]2[NH:8][CH2:9][C@H:10]([OH:12])[CH2:11]2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)[C@H]1C[C@@H](O)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1CN[C@@H](CNC2CC2)C1
Yield: 36.3 %

Procedure:
(2R,4R)-4-Hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (3 g) was reduced using LAH (2 g) in THF (150 mL) to give 1 g of (3R,5R)-5-cyclopropylaminomethyl-pyrrolidin-3-ol.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:14][CH2:13]1)[CH2:6][CH2:5]2.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([N:12]1[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[CH2:16][CH2:17]1)[CH2:6][CH2:5]2)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1N1CCN(C2CCc3cc(O)ccc3C2)CC1
Solvent: c1ccncc1
Product: COc1ccccc1N1CCN(C2CCc3cc(OC(C)=O)ccc3C2)CC1
Reaction time: 3 h

Procedure:
170 mg of 1,2,3,4-tetrahydro-6-hydroxy-2-[4-(2-methoxyphenyl)-1-piperazinyl]-naphthalene are added to 2 ml of pyridine, 70 μl of acetic anhydride are added dropwise and the solution left to stand at room temperature for 3 hours. The reaction solution is finally evaporated to dryness, the residue taken up in ethyl acetate, washed with IN sodium carbonate solution, dried and evaporated to dryness. The raw title product so obtained is converted to the hydrochloride salt form and recrystallized from methanol/ether. M.P. 249°-253° [Hydrochloride salt form].
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[NH:41]1[CH2:46][CH2:45][C:44]2([C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[CH2:48][CH2:47]2)[CH2:43][CH2:42]1>C(#N)C>[F:36][C:35]([F:38])([F:37])[C:33]1[CH:32]=[C:5]([CH:4]=[C:3]([C:2]([F:39])([F:1])[F:40])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:41]2[CH2:46][CH2:45][C:44]3([C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[CH2:48][CH2:47]3)[CH2:43][CH2:42]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reactant: c1ccc2c(c1)CCC21CCNCC1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCC3(CCc4ccccc43)CC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 90.1 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (200 mg) and spiro[indan-1,4'-piperidine] (70 mg) in acetonitrile (3 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated under reduced pressure and then the residue was purified by column chromatography on silica gel using dichloromethane-methanol (10:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[3-(spiro[indan-1,4'-piperidine]-1'-yl)propyl]-2-(1H-indol-3-ylmethyl)piperazine (208 mg) as a powder.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br.Br[CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>CN(C)C=O>[N:19]1([CH2:18][CH2:17][CH2:16][CH2:15][N:5]2[C:1](=[O:11])[C:2]3[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4]2=[O:6])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: BrCCCCn1ccnc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Br
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCn1ccnc1
Reaction time: 3 h

Procedure:
A mixture of 0.02 mole of potassium phthalimide, 0.01 mole of N-(4-bromobutyl)imidazole hydrobromide and 100 ml. of dimethyl formamide was gradually heated to 80° C. and held at this temperature for 3 hours. The solvent was removed in vacuo and the residue was purified by HPLC using ethyl acetate and a silica gel column.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24](=S)[CH2:25][C:26](=O)[CH3:27])=[O:4].Cl.[O:31]1[CH2:36][CH2:35][CH:34]([NH:37][NH2:38])[CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24]1[N:37]([CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)[N:38]=[C:26]([CH3:27])[CH:25]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=S)CC(C)=O
Reactant: NNC1CCOCC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1c1cc(C)nn1C1CCOCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester (example 388 d) was reacted with (tetrahydro-pyran-4-yl)-hydrazine hydrochloride (CAS Reg. No. 116312-69-7) to give the title compound as brown solid. MS (ESI): m/z=520.3 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH:25]([CH3:27])[CH3:26])=[CH:14][C:13]1=[O:28])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH:25]([CH3:26])[CH3:27])=[CH:14][C:13]2=[O:28])[C:3]([OH:29])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2ccccc2OC(C)C)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Temperature: 23 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (710 mg, 0.002 mol) in tetrahydrofuran-water (3:1, 15 mL) was added lithium hydroxide (223 mg, 0.009 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2-isopropoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (620 mg, 90%) as a light brown solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCCc1cccc(O)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(3-methoxyphenyl)propanenitrile (Step A, 1.71 g, 10.6 mmol) in dry CH2Cl2 (20 ml) was added BBr3 (1M in CH2Cl2, 5.32 g, 21.2 mmol) at −78° C. under argon. The reaction mixture was stirred at the same temperature for 2 hours and then at 0° C. for 4 hours or until all the starting material is consumed, quenched with ice, extracted with EtOAc (30 ml×3), the combined organic layer was washed carefully with sat NaHCO3, brine and dried over Na7SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25](C(O)=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C[N:51]([C:53]([O:57]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([N:4]([C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C@H:5]1[C:14]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([C:53]([NH2:51])=[O:57])[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N3CCCC(C(=O)O)C3)cc2)c2ccccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N3CCCC(C(N)=O)C3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid amide was prepared from (2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid. The acid (0.2 g, 0.366 mmol) was dissolved in DMF (3 mL) at room temperature and HOBt (0.74 g, 0.55 mmol), HATU (0.209 g, 0.55 mol), and diisopropylethylamine (0.25 mL,) was added followed by ammonium chloride (0.040 g, 0.74 mmol) and stirred at room temperature for 16 h. The reaction was diluted with ethyl acetate, washed with 1N NaOH, 1N HCl and brine. The organics were dried over MgSO4, filtered and concentrated down. The crude residue was purified HPLC purification.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][N:9]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[C:8]2=[O:18])=[C:4]([Cl:21])[CH:3]=1.[C:22]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:20]=[CH:19][C:5]([CH2:6][CH:7]3[CH2:11][CH2:10][N:9]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)[C:8]3=[O:18])=[C:4]([Cl:21])[CH:3]=2)=[CH:31][CH:30]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)c1ccc(B(O)O)cc1
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCN1C1CCCCC1
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(CC3CCN(C4CCCCC4)C3=O)c(Cl)c2)cc1
Yield: 78.3 %

Procedure:
Using the procedure to synthesize Example 81 and using reagents 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-pyrrolidin-2-one (500 mg, 1.35 mmol) and 4-(tert-butoxycarbonyl)phenylboronic acid (900 mg, 4.0 mmol) affords 495 mg (78%) of the title compound: Mass spectrum (apci) m/z=468.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=O)[NH:6][CH:7]=1)#[N:2].[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[C:20]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:19]=2)[CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:13][CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:8]([C:5]3[NH:6][CH:7]=[C:3]([C:1]#[N:2])[CH:4]=3)=[O:10])=[C:20]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:19]=2)[CH2:16][CH2:17]1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1c[nH]c(C(=O)O)c1
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Yield: 55.1 %

Procedure:
The procedure of Example 53 was followed using 4-cyano-1H-pyrrole-2-carboxylic acid (as prepared in Example 2, 56 mg, 0.22 mmol) and 4-(4-methyl-piperazin-1-yl)-2-(4-methyl-piperidin-1-yl)-phenylamine (as prepared in Example 13, step (a), 61 mg 0.21 mmol). Purification of the resulting residue by silica gel preparative TLC eluting with 10% methanol in dichloromethane yielded 47 mg (55%) of the title compound as an off-white solid. 1H-NMR (400 MHz, CDCl3): δ 9.60 (br s, 1H), 8.30 (d, 1H, J=8.9), 7.24 (d, 1H, J=3.7 Hz), 7.21 (d, 1H, J=3.7 Hz), 6.79 (d, 1H, J=2.7 Hz), 6.73 (dd, 1H, J=8.9, 2.7 Hz), 3.20 (m, 4H), 3.00-2.97 (m, 2H), 2.76-2.70 (m, 2H), 2.59 (m, 4H), 2.37 (s, 3H), 1.85-1.82 (m, 2H), 1.56-1.46 (m, 2H), 1.07 (d, 3H, J=6.2 Hz). LC-MS (ESI, m/z): Calcd. for C23H31N6O, 407.3 (M+H); found: 407.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:32])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([CH2:29][CH3:30])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc2s1
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: CCc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3ccc(C(=O)OC)cc3)nc2s1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(N)(=O)=O)cc4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 4-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (136 mg, 55%). MS (ISN) 489.0 [(M−H)−]; mp 275° C.