Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[NH2:34][C:35]1[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH:42]2[CH2:45][N:44]([CH3:46])[CH2:43]2)=[O:40])=[CH:37][C:36]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([O:29][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[CH:19][C:14]([C:15](=[O:16])[NH:17][CH3:18])=[CH:13][CH:12]=4)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=3[N:7]=[C:2]([NH:34][C:35]3[CH:48]=[CH:47][C:38]([C:39]([NH:41][CH:42]4[CH2:43][N:44]([CH3:46])[CH2:45]4)=[O:40])=[CH:37][C:36]=3[O:49][CH3:50])[N:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCC4)c23)cc1
Reactant: COc1cc(C(=O)NC2CN(C)C2)ccc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Nc4ccc(C(=O)NC5CN(C)C5)cc4OC)nc(OC4CCC4)c23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To a degassed mixture of 4-(2-chloro-4-cyclobutoxy-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), 4-amino-3-methoxy-N-(1-methylazetidin-3-yl)benzamide (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (10% MeOH in DCM) to afford the desired product (73% yield) as a yellow solid. MS (ESI) m/z 686.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[CH:17]=[C:18]([NH2:23])[C:19]([NH2:22])=[CH:20][CH:21]=4)=[CH:15][C:9]=3[N:8]=2)=[CH:3][CH:2]=1.[S:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[CH:26]=[C:25]1[CH:33]=O>CC(O)C.O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]5[NH:22][C:33]([C:25]6[S:24][C:28]7=[N:29][CH:30]=[CH:31][CH:32]=[C:27]7[CH:26]=6)=[N:23][C:18]=5[CH:17]=4)=[CH:15][C:9]=3[N:8]=2)=[CH:5][CH:6]=1
Reactant: Nc1ccc(-c2ccc3[nH]c(-c4ccncc4)nc3c2)cc1N
Reactant: O=Cc1cc2cccnc2s1
Solvent: O
Solvent: CC(C)O
Product: c1cnc2sc(-c3nc4cc(-c5ccc6[nH]c(-c7ccncc7)nc6c5)ccc4[nH]3)cc2c1
Temperature: 170 °C
Yield: 41.2 %

Procedure:
A mixture of 4-(2-(Pyridin-4-yl)-1H-benzo[d]imidazol-5-yl)benzene-1,2-diamine (intermediate A) (50 mg, 0.17 mmol), thieno[2,3-b]pyridine-2-carbaldehyde (33 mg, 0.20 mmol) and Na2S2O5 (38 mg. 0.20 mmol) in IPA-H2O (3:1, 8 mL) was heated under microwave radiation for 170° C. for 10 min. The mixture was absorbed onto silica and purified by column chromatography eluting with (95:5 EtOAc-MeOH to 85:15 EtOAc-MeOH) afforded the title compound as a yellow solid (30 mg, 0.07 mmol, 40%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:22][C:23]1[C:24]([CH3:35])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:28]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[C:24]([CH3:35])=[N:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1nc(-c2ccccc2)ncc1CBr
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)ncc1CN1CCN(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise over 30 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 3.05 g of 95% strength 5-bromomethyl-4-methyl-2-phenylpyrimidine (=11 mmol) and 80 ml of absolute 1,2-dimethoxyethane at 45° C. The mixture was stirred for a further 1 hour at 45° C. and 3 hours at 80° C., the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 water and neutralized to pH 6-7, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.7 g) was recrystallized from methanol. 2.35 g (65% of theory) of pure 4-(4-hydroxyphenyl)-1-(4 -methyl-2-phenylpyrimidin-5-ylmethyl)piperazine, melting point 201°-202° C., were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[N:8]([CH2:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]2=[O:18]
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(Cl)cc21
Solvent: CS(C)=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
2.86 g of 6,7-dichloro-1-ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid and 10 g of piperazine in 30 cm3 of dimethylsulphoxide were stirred and heated to 110° C. After two hours, the reaction was complete. After evaporation of the solvent under a good vacuum, the residue was taken up in 20 cm3 of water. The solid which precipitated was filtered off and recrystallised from 50 cm3 of a mixture of ethanol (1 volume) and methyl cellosolve (1 volume), which enabled an insoluble impurity, which was separated off by filtration of the hot solution to be removed. The crystals, which precipitated on cooling, were filtered off and recrystallised from the same solvent mixture. 1.2 g of 6-chloro-1-ethyl-4-oxo-7-piperazinyl-1,4-dihydro-quinoline-3-carboxylic acid were obtained; m.p. 228°-232° C.
Reaction SMILES: [N:1]([C:4](=[CH:10][C:11]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+]=[N-]>C1(C)C=CC=CC=1>[NH:1]1[C:23]2[C:11](=[CH:12][C:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:21]=3[CH:22]=2)[CH:10]=[C:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=Cc1ccc2c(c1)Cc1ccccc1-2)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc3c(cc2[nH]1)-c1ccccc1C3

Procedure:
Ethyl 2-azido-3-fluoren-2-ylacrylate suspended in dry toluene was heated at reflux for 1 h, and the resulting solution was then evaporated to dryness in vacuo. The resulting mixture of ethyl 1,5-dihydroindino[2,1-f]indole-2-carboxylate and ethyl 1,10-dihydroindino[1,2-g]-indole-2-carboxylate was crystallised from ethanol, thus removing most of the [1,2 g] isomer and leaving the title compound (contained with approximately 30% of the [1,2-g]isomer) in the mother liquors which were evaporated to dryness. δH (CDCl3) 9.11 (1H, s, br, 1-NH), 7.82-7.76 (3H, m), 7.56-7.52 (1H, m), 7.37 (H, dd, J 1 and 7), 7.34-7.28 (1H, m), 7.25 (1H, dd, J 1 and 2), 4.45 (2H, q, OCH2CH3), 3.97 (2H, s, CH2) and 1.46 (3H, t, OCH2CH3).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[F:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28]Cl)[CH2:22][CH2:21]2)=[CH:17][CH:16]=1>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:28][CH2:27][CH2:26][N:23]3[CH2:24][CH2:25][N:20]([CH2:19][C:18]4[CH:17]=[CH:16][C:15]([F:14])=[CH:31][CH:30]=4)[CH2:21][CH2:22]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Reactant: Fc1ccc(CN2CCN(CCCCl)CC2)cc1
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCN(Cc4ccc(F)cc4)CC3)cc12

Procedure:
In a manner analogous to that described in Example 5, by the appropriate reaction of 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3-[4-(4-fluorobenzyl)-piperazin-1-yl]-propyl chloride, there is obtained 4-methyl-6-{3-[4-(4-fluorobenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline which, after recrystallization from ethanol, melts at 178°-180° C.
Reaction SMILES: [S:1]([C:5]1[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH2:20]>C(O)C>[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][NH:20][S:10]([C:8]1[S:9][C:5]([S:1]([NH2:2])(=[O:4])=[O:3])=[CH:6][CH:7]=1)(=[O:11])=[O:12]
Reactant: NCc1cccs1
Reactant: NS(=O)(=O)c1ccc(S(=O)(=O)Cl)s1
Solvent: CCO
Product: NS(=O)(=O)c1ccc(S(=O)(=O)NCc2cccs2)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
To a solution of 5-sulfamoyl-thiophene-2-sulfonyl chloride (0.80 g, 3.1 mmol) in ethanol (10 mL) at 0° C. was added 2-thiophenemethylamine (0.67 mL, 6.51 mmol) and this mixture stirred at room temperature for 18 hr. After evaporation of solvent the residue was dissolved in ethyl acetate (200 mL) and this solution was washed with saturated aqueous sodium bicarbonate (2×50 mL), dried (MgSO4), and evaporated to a crude material which was purified by column chromatography (silica, 5% methanol/methylene chloride) and recrystallization [methanol/methylene chloride (1:50)] to give the desired product (450 mg, 45%): mp 146°-148° C. Analysis: Calculated for C9H10 N2O4S4 : C, 31.94; H, 2.98; N, 8.28. Found: C, 32.00; H, 2.96; N, 8.29.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH:32]1([NH:35][C:4](=[O:5])[C:3]2[CH:8]=[CH:9][C:10]([O:12][C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:11][C:2]=2[OH:1])[CH2:34][CH2:33]1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O
Product: O=C(NC1CC1)c1ccc(OC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1O

Procedure:
Methyl 2-hydroxy-4-(trityloxy)benzoate (340 mg, 0.83 mmol) was dissolved in cyclopropylamine (3 mL) and left at room temperature for a week. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-20% ethyl acetate in petroleum ether) to give the subtitled compound (210 mg).
Reaction SMILES: [O:1]=[C:2]([CH3:8])[CH2:3][CH2:4][C:5](Cl)=[O:6].[CH3:9][NH:10][C:11]1[S:12][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][N:15]=1.[K+].[Br-]>ClC(Cl)C>[CH3:9][N:10]([C:11]1[S:12][C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][N:15]=1)[C:5](=[O:6])[CH2:4][CH2:3][C:2](=[O:1])[CH3:8]
Reactant: CNc1nnc(-c2cccnc2)s1
Reactant: CC(=O)CCC(=O)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CC(Cl)Cl
Product: CC(=O)CCC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-oxopentanoyl chloride (0.378 g, 2.8 mmol) was added to a suspension of N-methyl-5-(3-pyridyl)-1,3,4-thiadiazol-2-amine (0.3 g, 1.6 mmol) and 4-N,N-dimethylaminopyridine (0.229 g, 1.9 mmol) in dichloroethane (5 mL), stirred under nitrogen at room temperature for 30 minutes, refluxed for 14 hours, cooled, diluted with dichloroethane (50 mL) and washed with saturated aqueous sodium bicarbonate (70 mL). The aqueous layer was extracted with dichloroethane (30 mL) and the combined organic layers were dried over MgSO4, adsorbed on silica, applied to a Michel-Miller column and eluted with 9:1 ethyl acetate/hexane. The major fraction was collected and recrystallized from ethyl acetate/hexane to afford yellow needles. Yield 0.21 g (46%): mp 146-147° C.; IR (KBr, thin film) 1701, 1659 cm−1; 1HNMR (400 MHz, CDCl3) δ 9.13 (d, J=1.8 Hz, 1H), 8.69 (dd, J=4.8, 1.5 Hz, 1H), 8.28 (dt, J=6.2, 1.9 Hz, 1H), 7.42 (dd, J=8.0, 5.1 Hz, 1H), 3.90 (s, 3H), 2.96 (br, 4H), 2.29 (s, 3H); ESIMS m/z 291 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(CC)CC)C>C1COCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:12]#[C:11][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cn1cc(Br)cc(I)c1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(Br)cc(C#C[Si](C)(C)C)c1=O
Temperature: 60 °C
Yield: 82.8 %

Procedure:
A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (8.0 g, 25.48 mmol), ethynyltrimethylsilane (2.7 g, 27.52 mmol), CuI (485 mg, 2.55 mmol), Pd(PPh3)2Cl2 (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol) in dry THF (100 mL) was heated to 60° C. under an atmosphere of nitrogen for 2 h. The mixture was concentrated and the residue was purified by column chromatography on silica gel (PE: EA=5:1) to give the title compound (6 g, 82%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.61 (d, J=2.4 Hz, 1H), 7.42 (d, J=2.4 Hz, 1H), 3.54 (s, 3H), 0.25 (s, 9H). LCMS (M+H)+=285.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:15](Br)[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.ClCCl>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1cccc2c(O)ccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Temperature: 50 °C
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 4-hydroxy-8-nitroquinoline (200 mg) and allyl bromide (140 mg) in dimethylformamide (2 ml) was added potassium carbonate (290 mg) at 0° C., and the mixture was stirred for 6 hours at 50° C. The mixture was diluted with dichloromethane and washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved into hot ethyl acetate (2 ml), and the solution was stirred at ambient temperature. The resulting precipitate was collected by filtration to give 4-allyloxy-8-nitroquinoline (120 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH2:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1>O1CCOCC1.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>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:24]1[N:23]=[CH:22][N:21]=[C:20]([NH2:19])[CH:25]=1)[CH3:2]
Reactant: CCOc1ccccc1B(O)O
Reactant: Nc1cc(Cl)ncn1
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: [Na+]
Solvent: C1COCCO1
Product: CCOc1ccccc1-c1cc(N)ncn1
Yield: 96.9 %

Procedure:
To a solution of 2-ethoxyphenylboronic acid (II) (1.73 g, 10.4 mmol) in 30 ml of 1,4-dioxane 10 ml of saturated aqueous sodium carbonate solution were added. Argon gas was purged for 10 min at room temperature. 6-Chloro-pyrimidin-4-ylamine (I) (1.50 g, 11.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol) were added to the reaction mixture simultaneously and argon gas was bubbled in for another 5 min. The reaction mixture was heated to reflux for 12 hours. After completion of the reaction as indicated by TLC the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate and concentrated. The obtained crude residue was purified by column chromatography eluting with 15% ethyl acetate in dichloromethane to provide 6-(2-ethoxy-phenyl)-pyrimidin-4-ylamine (III) (2.17 g, 87.3%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[CH:13][NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[CH2:24][C:25]([Cl:27])=[O:26].O>O1CCOCC1.CCOCC>[Cl:27][C:25](=[O:26])[CH2:24][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[NH:14][CH:13]=1
Reactant: Fc1ccc(-c2ccc3cc[nH]c3c2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cl)Cc1c[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 20.5 %

Procedure:
A solution under N2 of 6-(4-fluorophenyl)indole (10.0 g, 47.4 mmol), prepared as described in WO 93/01813, in dioxane (36 mL) and pyridine (5.8 mL, 71.8 mmol) was heated to 60° C. and a solution of chloroacetyl chloride (5.7 mL, 71.1 mmol) in dioxane (12.5 mL) was added dropwise over 1 hour. The reaction mixture was stirred for 1 hour at 60° C., then cooled to ambient temperature and poured into a mixture of H2O (200 mL) and ether (50 mL). The resulting orange precipitate was filtered and dried. Recrystallization from ethanol, followed by rinsing with cold ether gave 1-chloro-2-[6-(4-fluorophenyl)indol-3-yl]ethanone (2.8 g) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.C1(=O)O[CH:21]=[CH:20]O1>O>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][CH:20]=[CH:21][N:16]=2)[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Reactant: O=c1occo1
Solvent: O
Product: Clc1cncc(Cl)c1N1CCC(c2ncco2)CC1
Temperature: 170 °C
Yield: 11.2 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (0.10 g, 0.36 mmol) in polyphosphoric acid (5 mL) at 80° C. was added vinylene carbonate (35 mg, 0.40 mmol). The mixture was heated at 170° C. for 4 hours, cooled to r.t. and poured into water (200 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL), a saturated solution of sodium hydrogen carbonate (50 mL), water (50 mL), brine (50 mL), dried (MgSO4) and concentrated under reduced pressure to furnish a colourless oil (12 mg). The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1 then hexane, EtOAc, 1:1) to furnish the title compound as a white solid (13 mg, 12%), LC-MS (ESI) Rt 2.66 min, m/z 298 (100%, W); m/z (ESI) C13H14Cl2N3O requires 298.0508 found [M+H]+ 298.0507.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:18][CH3:19])=[CH:22][CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ccc(S(=O)(=O)NCCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 4-ethoxyphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 14.7, 22.6, 28.9, 32.0, 42.6, 60.5, 63.2, 115.0, 126.6, 127.1, 128.2, 130.6, 138.4, 143.5 and 158.9.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[S:10].[OH-].[Li+].FC(F)(F)C(O)=O>O.C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[S:10]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC(N)=S)c1)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: NC(=S)Nc1cccc(C(=O)NCC(=O)NC(CC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Yield: 714.7 %

Procedure:
The compound of Example 113 (500 mg, 0.095 mmol) was dissolved in water/acetonitrile (1:1), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction mixture was stirred at 25° C., and monitored by HPLC. After complete hydrolysis (1-2 hours) trifluoroacetic acid was added until pH=2. The product was purified by reverse phase chromatography (water/acetonitrile) and lyophilized to result in a white solid (350 mg). MS and 1H-NMR were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1>CO.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.1 %

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)piperidin-4-ol (2.67 g, 11 mmol) in MeOH (100 mL) was added catalyst Pd/C (1.00 g). The reaction mixture was stirred at rt under H2 for 6 h, then filtered. The filtrate was concentrated in vacuo to give the crude product (2.50 g) for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]([CH2:26][CH3:27])([CH2:24][CH3:25])[C:19]([N:21]([CH3:23])[CH3:22])=[O:20]>>[CH3:23][N:21]([CH3:22])[C:19]([C:18]([NH:17][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([CH2:24][CH3:25])[CH2:26][CH3:27])=[O:20]
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: CCC(N)(CC)C(=O)N(C)C
Product: CCC(CC)(NC(=O)c1cccc(-c2cccc(Cl)c2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 2-amino-2-ethyl-N,N-dimethyl-butyramide as starting materials, MS (EI): 374.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([CH2:44][C:45]([N:47]2[CH2:51][CH2:50][CH2:49][CH2:48]2)=[O:46])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:41]3[CH2:40][CH2:39][N:38]([CH2:44][C:45]([N:47]4[CH2:48][CH2:49][CH2:50][CH2:51]4)=[O:46])[CH2:43][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CN1CCNCC1)N1CCCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C40H50N5O3Cl2 [(M+H)+] 718.3285, observed 718.3286.