Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:32][NH:33][S:34]([CH:37]1[CH2:39][CH2:38]1)(=[O:36])=[O:35].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:33]([CH3:32])[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)C1CC1
Reactant: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 70 °C

Procedure:
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (147 mg, 0.319 mmol; Example 202, Step B) and N-methylcyclopropanesulfonamide (129 mg, 0.958 mmol) were dissolved in toluene (2 mL). The mixture was evacuated and backfilled with argon (5×). Cyanomethylenetributylphosphorane (0.251 mL, 0.958 mmol) was added. The mixture was evacuated and backfilled with argon (5 X). The mixture was heated at 70° C. for 2 hours. The mixture was loaded onto silica gel and the product was eluted with 5 to 75% ethyl acetate/hexanes to afford the title compound.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27](=[O:28])[O:26]1>C(Cl)(Cl)Cl>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27](=[O:28])[O:26]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 6.3 g of 4-biphenylylacetic acid in 30 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness. The residue, crystallized from petroleum ether, gives the phthalidyl 4-biphenylylacetate.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17](=O)[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1.C1(O)C=CC=CC=1>C([O-])(O)=O.[Na+]>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][CH2:16][C:17]2[N:7]=[CH:5][NH:6][C:19](=[O:20])[CH:18]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)CC(=O)CSc1ccc(Cl)cc1
Reactant: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Oc1ccccc1
Solvent: CC(=O)O
Product: O=c1cc(CSc2ccc(Cl)cc2)nc[nH]1
Temperature: 140 °C
Reaction time: 18 h
Yield: 22 %

Procedure:
A mixture of formamidine acetate (1508 mg, 14.48 mmol), ethyl 4-(4-chlorophenylthio)-3-oxobutanoate Part A (790 mg, 2.90 mmol) and phenol (8178 mg, 87 mmol) was stirred at 140° C. for 18 hours. After the reaction cooled to RT, the mixture was diluted with saturated NaHCO3 (65 mL) and extracted with EtOAc (80 mL). The EtOAc layer was dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient, using LC-MS to identify fractions containing the desired product) to afford 6-((4-chlorophenylthio)-methyl)pyrimidin-4(3H)-one 10B (169 mg, 22% yield). 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (1H, s), 7.07-7.25 (4H, m), 6.06 (1H, s), 3.80 (2H, s).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: [Li]C
Product: CC1(O)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-piperidin-4-one was reacted with methyllithium according to Method AI and the 1-benzyl-4-methyl-piperidin-4-ol obtained was hydrogenated in debenzylating conditions according to Method AH. In this way the product was obtained with molecular weight 115.1 (C6H13NO); MS (ESI): 116 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C@@H:30]([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(Cl)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](C)Oc1cc(C)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the 2-chloro-5-methylphenol (4.0 g, 28 mmol) in anhydrous THF (24 mL) at 0° C. under argon protection was added triphenylphosphine (9.5 g, 36.4 mmol), followed by addition of the (R)-methyl 2-hydroxypropanoate (3.89 g, 31 mmol). Then DIAD (8.2 mL, 42 mmol) was added slowly to the solution at 0° C. The reaction mixture was stirred at room temperature for 20 h. The solvent was removed and the crude was purified by flash chromatography (AcOEt/hexane 0˜30%) to obtain the title compound.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:15][C@H:14]([C:16]2([NH:19]C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[C@@H:13]([O:27][CH3:28])[CH2:12]1)=O)C1C=CC=CC=1.[NH2:29][C:30]1[C:39]([F:40])=[C:38](F)[C:37](C)=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46].C(N(CC)CC)C>C(O)C.[C].[Pd]>[NH2:29][C:30]1[C:39]([F:40])=[C:9]([N:11]2[CH2:15][C@H:14]([C:16]3([NH2:19])[CH2:17][CH2:18]3)[C@@H:13]([O:27][CH3:28])[CH2:12]2)[C:37]([CH3:38])=[C:36]2[C:31]=1[C:32](=[O:50])[C:33]([C:47]([OH:49])=[O:48])=[CH:34][N:35]2[C@@H:43]1[CH2:45][C@@H:44]1[F:46]
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1(NC(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn([C@@H]4C[C@@H]4F)c3c2C)C[C@@H]1C1(N)CC1
Reaction time: 4 h
Yield: 15.9 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-tert-butoxycarbonylaminocyclopropyl)-3-(R)-methoxypyrrolidine (550 mg, 1.41 mmol) was dissolved in ethanol (40 ml), and the solution was mixed with a 5% palladium-carbon catalyst (water content, 55.6%; 550 mg) and stirred for 4 hours under a pressured hydrogen atmosphere (4.5 kg/cm2). The catalyst was removed by celite filtration (methanol washing), and the filtrate was concentrated under reduced pressure. The thus obtained residue was dissolved in dimethyl sulfoxide (5 ml), and the solution was mixed with 5-amino-6,7-difluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (249.8 mg, 0.80 mmol) and triethylamine (3 ml) and stirred for 2 days in an oil bath of 120° C. under a nitrogen atmosphere. After cooling, dimethyl sulfoxide was evaporated under reduced pressure, the thus obtained residue was dissolved-in chloroform (100 ml) and washed with a 10% citric acid aqueous solution (50 ml×2) and saturated brine (100 ml) in that order and then the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. To the thus obtained residue, which was cooled in an ice bath, was added dropwise concentrated hydrochloric acid (10 ml), followed by 1 hour of stirring at room temperature. After adding water (20 ml) to the reaction solution, the aqueous solution was washed with dichloromethane (50 ml×3), adjusted to pH 11 with sodium hydroxide aqueous solution and then washed with dichloromethane (50 ml×2). This was adjusted to pH 7.4 with concentrated hydrochloric acid and extracted with chloroform (150 ml×3). The organic layers were combined, dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The thus obtained residue was subjected to preparative silica gel thin layer chromatography (development with the bottom layer of a mixture of chloroform:methanol:water=7:3:1), and the resulting crude product was purified by recrystallizing from ethanol-diisopropyl ether and then dried under a reduced pressure to obtain 57 mg (16%) of the title compound as a yellow powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>O1CCOCC1.O>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH:13]2[C:17]([OH:19])=[O:18])(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2C(=O)O)cc1
Reaction time: 1 h

Procedure:
To a solution of (+)4-benzyloxycarbonyl-2-piperazinecarboxylic acid (1.90 grams, 7.2 mmol) in dioxane-water (10 ml, ca. 1:1) is added 1N sodium hydroxide solution (15 ml, 15 mmol) followed by 4-methoxybenzenesulfonyl chloride. The solution is stirred for 1 hour, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The combined extracts are dried (sodium sulfate), filtered and concentrated. The crude product is purified by silica gel chromatography (elution with 2:1 ethyl acetate-hexanes with 1% acetic acid) to provide (+)-1-(4-methoxybenzenesulfonyl)-4-benzyloxycarbonyl-2-piperazinecarboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25](O)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:16]=[C:11]2[CH:10]=[C:9]1[C:25]([N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1)=[O:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)n1c(C(=O)O)cc2cc(OCc3ccccc3)cnc21
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1c(C(=O)N2CCOCC2)cc2cc(OCc3ccccc3)cnc21
Yield: 70 %

Procedure:
The title compound was synthesized in analogy to example 9, intermediate a), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester (intermediate G), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, morpholine and N,N-diisopropylethylamine in DMF to give the desired product as colorless foam (70%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5](=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:6](=[O:8])[N:7]=1.[OH:23][C@@H:24]([CH2:37][NH2:38])[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)(=O)C>[OH:23][C@@H:24]([CH2:37][NH:38][CH:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:9]=[C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]3=[O:8])=[CH:11][CH:12]=2)[CH2:17][CH2:18]1)[CH2:25][O:26][C:27]1[C:35]2[NH:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: CNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
1-[4-(2-Methylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 18)(0.15 g, 0.47 mmol) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) (0.11 g, 0.47 mmol) were mixed in dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.15 mL). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was poured into a saturated aqueous sodium bicarbonate solution. The precipitate was collected and purified by column chromatography (eluent: methanol/methylene chloride) to give the title compound as a pale yellowish solid(0.16 g, 65%); mp>160° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.45 (m, 2 H), 1.75-2.00 (m, 2 H), 2.60-3.00 (m, 5 H), 3.05 (s, 3 H), 3.75-4.15 (m, 5 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.02 (d, J=8.7 Hz, 2 H), 7.38 (d, J=8.7 Hz, 2 H), 7.47 (s, 1 H), 10.56 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 262.1 ((M+2H)2+, 100%); 522.9 (MH+, 75%); HRMS Calcd. for C26H31N6O4S (MH+): 523.2128. Found: 523.2142.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13].[H][H]>[Ni].CO>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Sc1c(Cl)cccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC(C)Sc1c(N)cccc1Cl
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
40 g of 2-chloro-6-nitrophenyl-isopropylsulfane, 160 g of methanol and 2.4 g of Raney nickel 37-1 (methanol-moist) were initially introduced into a 0.7 l steel autoclave. After rinsing with nitrogen, 70 bar of hydrogen were forced in and the contents of the autoclave were heated to 100° C., while stirring. The hydrogen pressure was increased to 80 bar. After 50 minutes, the uptake of hydrogen had ended. The mixture was kept under the reaction conditions for a further 30 minutes. After cooling, letting down the hydrogen and removing the catalyst, the solvent was distilled off. Crude 2-amino-6-chlorophenyl-isopropylsulfane was already obtained as a 99% pure product (GC) which contained only 0.2% of 2-aminophenyl-isopropylsulfane (formed by dechlorination) and only 0.3% of m-chloroaniline (formed by desulfurization). The yield was 34.5 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[CH2:20]([C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=[O:35])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:13][O:14][CH:15]([CH:34]([OH:35])[C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COCC(=O)OC
Reactant: CCCCCCCCCCCCc1ccccc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCc1ccccc1C(O)C(OC)C(=O)OC
Reaction time: 0.25 h

Procedure:
To a solution of di-i-propylamine (0.77 ml, 5 mmoles) in tetrahydrofuran (10 ml) at -78° C. was added n-butyl lithium (2.1 ml, 5.5 mmoles) under argon atmosphere. After 15 minutes, methyl methoxyacetate (0.52 g, 5 mmoles) in tetrahydrofuran (2 ml) was added dropwise, with stirring. The resulting enolate solution was stirred at -78° C. for 45 minutes. A solution of 2-dodecylbenzaldehyde (1.65 g, 6 mmoles) in tetrahydrofuran (2 ml) was added. The resulting light-blue mixture became a suspension after 1.5 hours. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with ether and ice-water. The aqueous phase was extracted with ether. The combined organic extract was washed with saturated sodium chloride solution, dried over magnesium sulfate, and evaporated to give the product, which was purified by flash column chromatography (silica, 15% ethyl acetate/hexane). The fractions were pooled to give 620 mg (33%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH3:33][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:15]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=3[C:38]3[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=3)[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:3])=[O:34]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccncc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 4-pyridyl boronic acid as in Example 38 to afford 0.011 g (9%). 1HNMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).
Reaction SMILES: CO[C:3](=[O:21])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[CH2:7]1.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C[O-].[Mg+2].C[O-].CO>>[Cl:20][C:15]1[CH:14]=[C:13]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH:8]([O:11][CH3:12])[CH2:7]2)[C:3]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Nc1nccs1
Reactant: COC(=O)C(CC1CCC(OC)C1)c1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: COC1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
2-(3,4-Dichloro-phenyl)-3-(3-methoxy-cyclopentyl)-propionic acid methyl ester (118.3 mg, 0.36 mmol) and 2-aminothiazole (35.8 mg, 0.36 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 2.6 mL, 1.79 mmol). The resulting reaction mixture was then heated under reflux for 30 h. The reaction mixture was allowed to cool to 25° C. and then filtered through celite. The celite was thoroughly washed with ethyl acetate, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 40% ethyl acetate/hexanes) afforded the 2-(3,4-dichloro-phenyl)-3-(3-methoxy-cyclopentyl)-N-thiazol-2-yl-propionamide (9.6 mg, 7%) as a white glass: (ES)+-HRMS m/e calcd for C18H20Cl2N2O2S (M+H)+ 399.0696, found 399.0700.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:42]=[CH:41][CH:40]=[C:39]3[C:35]=2[CH:36]=[N:37][NH:38]3)O1>>[NH:38]1[C:39]2[C:35](=[C:34]([C:2]3[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:8][C:6]=4[N:7]=3)[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)CCCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(3-methanesulfonyl-propyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in general procedure A. Purification by column chromatography yielded 384. NMR: CDCl3: 1.99-2.05 (2 H, m, CH2), 2.80 (2 H, t, J 7.2, CH2), 2.81 (3 H, s, Me), 3.10-3.13 (2 H, m, CH2), 3.85-3.88 (4 H, m, CH2), 4.01-4.06 (6 H, m), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 487.20
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2)#[CH:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.S([C:33]#[N:34])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[C:2][C:33]#[N:34])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: C#Cc1ccc2cnccc2c1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC#Cc1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a solution of 6-ethynylisoquinoline (0.10 g, 0.65 mmol) in 6.5 mL of THF at −78° C. was added LiHMDS, (0.78 mL, 1.0 M in THF). After 5 minutes, the mixture was warmed to 0° C. The mixture was stirred for 30 minutes and then chilled to −78° C. Tosyl cyanide (0.18 g, 0.98 mmol) was added. After 5 minutes, the reaction was warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 10 mL of aq. NH4Cl. The biphasic mixture was extracted twice with 10 mL of EtOAc and the combined organic extracts were washed with 15 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 20% EtOAc/hexanes) afforded 3-(isoquinolin-6-yl)propiolonitrile (0.065 g, 0.36 mmol, 56% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8].[NH:19]([C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)=[S:22])[NH2:20].CN(C)C=O>Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:20][NH:19][C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[S:22])[CH3:16])[C:10]=2[OH:18])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C)c(C)c2)c1O
Yield: 68.2 %

Procedure:
1-[5-(3,4-Dimethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.2423 mmol, HPLC purity 84.3%, 70.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.2423 mmol, 51.2 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.3 mg, yield 68%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[N:6]=1.[NH2:18][C:19]1[CH:20]=[C:21]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:30]=2)=[O:28])[CH:22]=[CH:23][C:24]=1[CH3:25]>>[CH3:25][C:24]1[CH:23]=[CH:22][C:21]([NH:26][C:27]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)[CH:30]=2)=[O:28])=[CH:20][C:19]=1[NH:18][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Reactant: Cc1nc(COc2ccc(C(=O)O)cc2)cs1
Product: Cc1nc(COc2ccc(C(=O)Nc3cc(NC(=O)c4ccnc(N5CCOCC5)c4)ccc3C)cc2)cs1

Procedure:
Using an analogous procedure to that described in the first paragraph of Example 26, 4-(2-methylthiazol4-ylmethoxy)benzoic acid was reacted with N-(3-amino4-methylphenyl)-2-morpholinopyridine-4-carboxamide. The reaction product was purified by column chromatography on silica using a 97:3 mixture of methylene chloride and methanol as eluent. There was thus obtained to give the title compound; NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 2.44 (s, 3H), 3.5 (t, 4H), 3.7 (t, 4H), 5.19 (s, 2H), 7.11 (m, 3H), 7.23 (m, 2H), 7.4 (t, 2H), 7.54 (m, 3H), 7.68 (d, 1H), 7.78 (d, 1H), 7.96 (d, 2H), 8.24 (d, 1H), 9.73 (s, 1H), 10.27 (s, 1H); Mass Spectrum: M+H+ 544.