Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]C(P(O)O)(C)CCCC.C1(O)C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH:27]1([N:33]=[C:34]=[N:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1.CCOCC>[CH:36]1([NH:35][C:34]([NH:33][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:1])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CCCCC(C)(O)P(O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
1-Hydroxy-1,4-dimethylbutylphosphonous acid (0.166 g., 0.001M), phenol (0.094 g., 0.001M) and dimethylaminopyridine 0.01 g.) are stirred in tetrahydrofuran (5 ml.) at 5° C. Dicyclohexylcarbodiimide (0.23 g. 0.001M) is added portionwise over 2 hours. On completion of the reaction (31P NMR) ether (10 ml.) is added and the dicylohexyl urea formed is filtered off. Evaporation of the filtrate gives an oil which is purified on silica using 5% methanol in chloroform as eluant. There is obtained phenyl (1-hydroxy-1,4-dimethylbutyl)phosphinate.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[CH:8]3)=[O:17])[CH2:31]1
Reactant: CC1CNCC(C)N1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CC(C)NC(C)C4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 2,6-Dimethyl-piperazine to give (3,5-Dimethyl-piperazin-1-yl)-[1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-methanone. LC-MS: m/e 423 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.O1CCOCC1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)CCC>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.C(OCC)(=O)C>[N:30]1[CH:31]=[CH:32][N:33]=[CH:34][C:29]=1[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2ccc(-c3cnccn3)cc2cn1)C1CC1
Yield: 54.8 %

Procedure:
To a mixture of N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide 1 (42.8 mg, 0.147 mmol) and 1,4-Dioxane (1.5 mL, 19 mmol) was added 2-(tributylstannyl)pyrazine (51.0 uL, 0.162 mmol) and tetrakis(triphenylphosphine)palladium(0) (14.0 mg, 0.0121 mmol). The reaction mixture was subjected to microwave irradiation at 130° C. for 30 minutes. The reaction mixture is poured into ethyl acetate and washed with dilute NH4OH. The organic layer was dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 23.4 mg (55%) of N-(7-(pyrazin-2-yl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT=4.106, M+H=291.0, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.42 (s, 1H), 9.27 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=8.6 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 2.10 (s, 1H), 0.94-0.74 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:2]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:67]=[CH:68][CH:69]=1)[C:53]([NH:55][C:56]1[CH:65]=[C:64]2[C:59]([CH2:60][CH2:61][N:62]([CH3:66])[CH2:63]2)=[CH:58][CH:57]=1)=[O:54]>CN(C=O)C>[CH3:66][N:62]1[CH2:61][CH2:60][C:59]2[C:64](=[CH:65][C:56]([NH:55][C:53]([C:52]3[CH:51]=[C:50]([CH:69]=[CH:68][CH:67]=3)[CH2:49][NH:48][C:12]([C:10]3[S:11][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)=[O:14])=[O:54])=[CH:57][CH:58]=2)[CH2:63]1
Reactant: O=C(O)c1ccc(-c2cccnc2)s1
Reactant: CN1CCc2ccc(NC(=O)c3cccc(CN)c3)cc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCc2ccc(NC(=O)c3cccc(CNC(=O)c4ccc(-c5cccnc5)s4)c3)cc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
To a solution of 5-pyridin-3-yl-thiophene-2-carboxylic acid (31 mg, 0.15 mmol) in DMF (1 mL) add Hunig's Base (0.10 mL, 0.54 mmol) and TBTU (52 mg, 0.16 mmol) and stir at rt for 20 min. To this add 3-aminomethyl-N-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-yl)-benzamide dihydrochloride (50 mg, 0.1 mmol) and stir the solution for 18 h at rt. Concentrate the solution and purify the residue by prep-HPLC (10% to 90%, CH3CN/H2O) to provide the desired product 5-pyridin-3-yl-thiophene-2-carboxylic acid 3-(2-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ylcarbamoyl)-benzylamide (62 mg, 0.087 mmol). MS, electrospray 483.8 (M+H), rt 0.88 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:37])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]2[CH:35]=[CH:34][N:33]=[N:32]2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:11]1[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])=[CH:13][C:8]2[N:7]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([N:31]4[CH:35]=[CH:34][N:33]=[N:32]4)[CH:26]=3)[CH2:23][C:22](=[O:37])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M123) (0.17 g, 0.31 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (100 mg, 75%).
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[N:7]=[C:8]([F:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>C(Cl)Cl>[Cl:46][C:47]1[CH:53]=[CH:52][C:50]([NH:51][C:1]([CH2:4][CH2:5][C:6]2[N:7]=[C:8]([F:30])[N:9]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:10]=2)=[O:3])=[CH:49][CH:48]=1
Reactant: O=C(O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: Nc1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)Nc1ccc(Cl)cc1
Reaction time: 0.42 h

Procedure:
A solution of 4-(2-carboxyethyl)-2-fluoro-1-triphenylmethylimidazole in CH2Cl2 was treated with triethylamine. The mixture was cooled, isobutyl chloroformate added, and stirred for 25 min. 4-Chloroaniline was then added, and stirring continued for 1 hour. Extractive work-up, followed by chromatography, gave 4-[2-(4-chlorophenylcarbamoyl)ethyl]-2-fluoro-1-triphenylmethylimidazole, having the following n.m.r. spectrum in CDCl3 +d6DMSO: 2.4-2.75 (m, 4H); 6.25 (s, 1H); 6.9-7.65 (m, 19H); 9.9 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39](=[O:47])[NH:40][C@H:41]1[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:47])[NH:40][CH:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:33])[F:32])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1)([CH3:37])([CH3:35])[CH3:36].[NH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:3]=3[C:2]([F:33])([F:32])[F:1])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC(C)(C)OC(=O)NC1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Product: N[C@H]1CCCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and piperidin-3-(S)-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-(S)-Amino-piperidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Br[CH2:46][CH2:47][C:48](Cl)=[O:49]>ClCCl>[C:48]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:25]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:15]([C:13]([NH:12][C:5]5[C:4]([CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=5[CH2:10][CH3:11])=[O:14])=[N:16][N:17]([CH3:35])[C:18]=4[C:27]=3[N:26]=2)[CH2:34][CH2:33]1)(=[O:49])[CH:47]=[CH2:46]
Reactant: O=C(Cl)CCBr
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.4 mL, 2.2 mmol), and 3-bromopropionyl chloride (0.023 mL, 0.226 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 9/1) to 73 mg of the title compound. (75% yield)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:9]=2)[C:4](=[O:18])[N:3]1[C:19]1[CH:34]=[CH:33][C:22](C(NCCN2CCCC2)=O)=[C:21]([O:35]COC)[CH:20]=1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[OH:35][C:21]1[CH:20]=[C:19]([N:3]2[C:4](=[O:18])[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([O:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=3)[C:2]2=[O:1])[CH:34]=[CH:33][C:22]=1[O:43][CH2:41][CH2:40][N:3]1[CH2:4][CH2:5][CH2:10][CH2:2]1.[F:39][C:40]([F:45])([F:44])[C:41]([O-:43])=[O:42]
Reactant: COCOc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1C(=O)NCCN1CCCC1
Reactant: O=C(O)C(F)(F)F
Product: O=C([O-])C(F)(F)F
Product: O=C1c2ccc(Oc3ccccc3)cc2C(=O)N1c1ccc(OCCN2CCCC2)c(O)c1
Reaction time: 0.5 h

Procedure:
4-(1,3-Dioxo-5-phenoxy-1,3-dihydro-isoindol-2-yl)-2-methoxymethoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide [Example G2] was treated with trifluoroacetic acid (1 ml, 1 M in dichloromethane). After 30 minutes, the solvent was removed to afford the title compound as a trifluoroacetate salt.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH:5]=1.[H][H]>C(O)C.[Pd]>[ClH:1].[ClH:1].[CH3:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:22][CH2:23]3)=[CH:11][CH:12]=2)[NH:7][C:6](=[O:30])[CH2:5]1
Reactant: Cc1cc(=O)[nH]c2cc(OCCCN3CCN(c4ccccc4)CC3)ccc12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1CC(=O)Nc2cc(OCCCN3CCN(c4ccccc4)CC3)ccc21
Reaction time: 8 h
Yield: 60 %

Procedure:
1.0 Gram of 4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]carbostyril dihydrochloride and 0.3 g of palladium black are dispersed in 200 ml of ethanol under 2 atmospheres of hydrogen pressure at room temperature and catalytic reduction is carried out at 70°-80° C. for 8 hours. After cooling the reaction mixture, the palladium black is removed by filtration and the mother liquor is concentrated to dryness. The residue is recrystallized from a mixture of methanol-ether to obtain 0.6 g (yield: 60%) of 4-methyl-7-[3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril.dihydrochloride.dihydrate in the form of colorless crystals with a melting point of 260°-265° C.
Reaction SMILES: [CH2:1]([NH2:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:18]1[O:20][CH:19]1[CH2:21][OH:22]>C(O)C>[OH:20][CH:19]([CH2:21][OH:22])[CH2:18][NH:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCC1CO1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNCC(O)CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Hexadecylamine (767 g, 3.17 mole) was dissolved in absolute ethanol. Glycidol (112 g, 1.58 mole) was added to the amine dropwise. The reaction was refluxed under nitrogen for 16 hours and then stirred at room temperature overnight. A white solid was obtained and filtered. The solid was washed with ether, filtered and recrystallized from hot ethanol. (yield 245 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>>[CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[CH:35][C:26]=1[CH2:25][O:24][CH:12]1[CH:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:37][C:38]3[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:6][CH:7]=2)[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: ClCc1cccnc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOCc3cccnc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g) by alkylating tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 53(c)] with 3-chloromethyl-pyridine there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[2-(pyridin-3-ylmethoxy)-ethoxy]-phenyl}-piperidine-1-carboxylate; MS: 569 (M+H)+.
Reaction SMILES: C(OC(=O)[N:10]([CH2:18][CH2:19][O:20]CC1C=CC=CC=1)[C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13])C1C=CC=CC=1.[H][H]>CCO.[Pd]>[OH:20][CH2:19][CH2:18][NH:10][C@@H:11]([CH3:17])[C:12]([N:14]([CH3:16])[CH3:15])=[O:13]
Reactant: C[C@@H](C(=O)N(C)C)N(CCOCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NCCO)C(=O)N(C)C
Temperature: 45 °C
Reaction time: 24 h
Yield: 64.1 %

Procedure:
Under nitrogen atmosphere, to a solution of 2.75 g of the compound obtained in Step 79-2 in EtOH (30 ml) was added palladium-activated carbon (10% Pd, 0.30 g), and the inside of the reaction system was displaced with hydrogen gas. The solution was stirred for 24 hours at 45° C., then, the reaction solution was filtered, and the solvent was filtered out under reduced pressure. To a solution of the obtained residue in EtOH (30 ml) solution was added palladium-activated carbon (10% Pd, 0.30 g), and the reaction system was displaced with hydrogen gas, again. The solution was stirred for one day at 45° C., then, the reaction solution was filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 4/1; v/v) to obtain 734 mg of the title compound (colorless oil).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C(S[C:15]1[S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[N+:19]=1[CH2:20][CH3:21])C.[C:26]([CH2:31][N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[S:38])([O:28][CH2:29][CH3:30])=[O:27]>C(N(CC)CC)C>[C:26]([CH2:31][N:32]1[C:36](=[O:37])[C:35](=[S:16]2[C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[N:19]([CH2:20][CH3:21])[CH2:15]2)[S:34][C:33]1=[S:38])([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CN1C(=O)CSC1=S
Reactant: CCSc1sc2ccccc2[n+]1CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1C(=O)C(=S2CN(CC)c3ccccc32)SC1=S

Procedure:
To 30 ml of an ethanol solution of 13.0 g of the intermediate product obtained in Preparative Example 2, viz., 2-ethylmercapto-3-ethylbenzothiazolium p-toluenesulfonate, was added 4.4 g of 3-carboethoxymethylrhodanine, while stirring the mixture at room temperature (about 20° C.), 6.1 g of triethylamine was added dropwise to the solution over a 3 minute period, and thereafter the resultant mixture was refluxed for 10 minutes. After cooling the reaction mixture, precipitates formed were recovered by filtration and recrystallized from a mixture of chloroform and ethanol to provide 1.1 g of 3-carboethoxymethyl-5-(3-ethylbenzothiazolylidene)rhodanine (melting point 250° to 252° C.).
Reaction SMILES: FC(F)(F)S(OC1C=[CH:11][C:10]([C:13]#[N:14])=[CH:9][C:8]=1OC)(=O)=O.[O:19]=[C:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[C:28](C=O)[C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2.C(O)(=[O:37])C.N1CCCCC1>ClCCl>[O:37]=[C:9]([CH3:8])[C:10](=[CH:11][C:28]1[C:27]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:19])[C:32]=2[CH:31]=[CH:30][CH:29]=1)[C:13]#[N:14]
Reactant: O=Cc1cccc2c1-c1ccccc1C2=O
Reactant: CC(=O)O
Reactant: COc1cc(C#N)ccc1OS(=O)(=O)C(F)(F)F
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(=O)C(C#N)=Cc1cccc2c1-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound from example 11A (5.21 g, 25.0 mmol) is introduced into 180 ml of dichloromethane, and the compound from example 16A (2.89 g, 27.5 mmol), acetic acid (1.72 ml, 30.0 mmol) and piperidine (0.25 ml, 2.50 mmol) are added. The mixture is stirred at the boiling point with a water trap for 4 h. Cooling to RT is followed by dilution with 30 ml of dichloromethane and washing with water (2×50 ml), the organic phase is dried over sodium sulfate and the solvent is removed in a rotary evaporator. The resulting crude product is purified by chromatography on silica gel 60 with dichloromethane as mobile phase. Combining the product fractions and removing the solvent results in 5.40 g (79% of theory) of the title compound as mixture of E/Z isomers.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(#N)N(C)C>[C:2]1([C:1]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][Br:22])=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[O:8])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(C(=O)c3ccccc3)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C#N
Product: O=C(c1ccccc1)c1ccc(-c2ccc(CBr)cc2)cc1
Reaction time: 4 h
Yield: 88.8 %

Procedure:
A mixture of 26.1 g of 4-benzoyl-4'methylbiphenyl, 18.6 g of N-bromosuccinimide and 0.18 g of azaisobutyronitrile in 600 mL of carbon tetrachloride was heated to boiling for 4 hours. The brown solution obtained was filtered and evaporated. The residue was recrystallized from cyclohexane. There are obtained 29.9 g (89%) of 4'-(bromomethyl)-4-biphenylyl phenyl ketone as colorless crystals with a m.p. of 110°-112° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:21]=[C:20](Cl)[N:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[N:11][CH:12]=[CH:13][CH:14]=4)[NH:9][C:8]3=[O:16])[CH2:5][CH2:6]2)[CH:21]=[C:22]([C:24]([N:26]2[C:34]3[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)=[O:25])[CH:23]=1
Reactant: O=C(c1cc(Cl)nc(Cl)c1)N1CCc2cc(F)ccc21
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cc(Cl)nc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1)N1CCc2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.74 g (3.4 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one, 1.0 g (3.2 mmol) (2,6-dichloro-pyridin-4-yl)-(5-fluoro-2,3-dihydro-indol-1-yl)-methanone and 0.65 mL (3.8 mmol) DIPEA in 10 mL DMF were stirred for 2 h at RT. Then the reaction mixture was evaporated down, the residue was mixed with water and stirred for 30 min at RT. The precipitated solid was suction filtered, stirred with diisopropylether and isopropanol and suction filtered again. After drying the crude product was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [Cl:1][C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncccc1-n1cccn1
Yield: 39 %

Procedure:
A solution of 2-chloro-3-fluoro-pyridine (1.3 g, 10.0 mmol), 1H-pyrazole (749 mg, 11.0 mmol) and K2CO3 (4.1 g, 30.0 mmol) was stirred in DMF (15 mL) at 80° C. for 16 hours. The reaction mixture was poured into water and extracted with EtOAc (3×). The organics were combined, washed with water (3×), brine, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (5 to 30% EtOAc in hexanes) gave the desired product (0.7 g, 40%) as a white solid. ESI-MS m/z calc. 179.3. found 180.3 (M+1)+. Retention time: 0.74 minutes (3 min run).