Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][CH2:21][C:22](O)=[S:23]>>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:22](=[S:23])[CH2:21][CH3:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCC(O)=S
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Product: CCC(=S)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 114 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and methylthioacetic acid. m.p.: 63-70° C. 1H-NMR (CDCl3) δ: 10.78 (1H, br s), 8.42 (1H, br s), 8.16 (1H, d, J=9.2 Hz), 7.86-7.79 (2H, m), 7.68-7.53 (3H, m), 7.31 (1H, d, J=1.8 Hz), 7.12 (1H, dd, J=9.2, 1.8 Hz), 3.39 (2H, s), 2.23 (3H, s)
Reaction SMILES: [C:1](/[N:3]=[C:4](\OC1C=CC=CC=1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2].C(#N)C.[NH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[C:1](/[N:3]=[C:4](\[N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)/[N:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=3[CH3:27])[CH2:15][CH2:14]2)=[O:12])[C@@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)#[N:2]
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)N2CCCCC2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1

Procedure:
To a stirred solution of methyl(3R,4S)-1-[(Z)-(cyanoimino)(phenoxy)methyl]-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-3-carboxylate (52 mg, 0.00010 mol) in acetonitrile (2.006 mL, 0.03840 mol) was added piperidine (0.200 mL, 0.00202 mol). The reaction mixture refluxed (oil bath at 85 deg). Upon completion reaction mixture concentrated in vacuum. The residue was purified by combiflash using 0-5% methanol/dichloromethane to give the product (53.3 mg, 98% in yield). MS (ESI): (M+H)+=506.
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:24])([CH3:23])[CH2:19][C:20]([OH:22])=[O:21])=[CH:5][CH:4]=1>C(O)(=O)C.Br>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=[C:9]2[CH2:17][C:18]([CH3:23])([CH3:24])[CH2:19][C:20]([OH:22])=[O:21])=[CH:25][CH:26]=1
Reactant: COc1ccc(Cn2c(CC(C)(C)CC(=O)O)nc3ccccc32)cc1
Agent: Br
Solvent: CC(=O)O
Product: CC(C)(CC(=O)O)Cc1nc2ccccc2n1Cc1ccc(O)cc1
Yield: 15.4 %

Procedure:
2.7 g of 4-[1-(4-methoxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid, prepared in Example 68, are dissolved in 40 ml of acetic acid and 40 ml of 48% hydrobromic acid. The mixture is refluxed for 3 hours and the solvents are evaporated off under vacuum. The residue is taken up with a 1N solution of sodium hydroxide so as to adjust the pH to 9-10, and the resulting aqueous phase is washed with ether and then acidified with sulfur dioxide to pH 5.5. The crystals obtained are filtered off, washed with water and then with ether and then chromatographed on silica gel in a 9:1 chloroform/methanol eluent to give 0.4 g of 4-[1-(4-hydroxybenzyl)benzimidazol-2-yl]-3,3-dimethylbutanoic acid in the form of crystals melting at 215°-216° C.
Reaction SMILES: CN(C)C=O.Cl[CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([O:20][C:21]3[C:22]([CH3:31])=[N:23][C:24]4[C:29]([CH:30]=3)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1>O>[CH3:33][O:32][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:10]=1[O:9][CH2:8][CH2:7][N:40]1[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH2:42][CH2:41]1)[N:17]=[CH:16][CH:15]=[C:14]2[O:20][C:21]1[C:22]([CH3:31])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(CCOc2cc3nccc(Oc4cc5ccccc5nc4C)c3cc2OC)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 7-(2-chloro-ethoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 353) (50 mg), potassium carbonate (53 mg), and ethyl piperidine-4-carboxylate (60 mg), and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (48 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO.[BH4-].[Na+]>C1COCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1N

Procedure:
1-[3-(Methyloxy)-4-nitrophenyl]-4-(methylsulfonyl)piperazine (1.09 g, 3.46 mmol) was suspended in 5 mL THF and 10 mL MeOH in a 100 mL round bottom flask. Nickle(II)chloride hexahydrate (0.247 g, 1.04 mmol) was added followed by slow addition of NaBH4 (0.392 g, 10.38 mmol). TLC analysis indicated reaction complete after addition of NaBH4. Reaction mixture was adsorbed on SiO2 and purified via column chromatography using a gradient of 0-10% MeOH in DCM. Fractions were combined and rotovapped to give the title compound of step B. (0.925 g, 3.24 mmol, 93%); MS (ESI): 285 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH:9]=[C:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1)=[O:4]>CO.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)=[CH:23][CH:24]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 101.6 %

Procedure:
A solution of tert-butyl 4-(4-methoxycarbonylbenzylidene)piperidine-1-carboxylate (6 g, 18 mmol) in methanol (150 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium-carbon (containing 50% water, 1 g) at room temperature for 5 hours. The catalyst was filtered off, and the filtrate was condensed under reduced pressure. The residue was purified by flash column chromatography (silica gel 90 g, ethyl acetate/hexane=1/10) to give the title compound as a pale yellow oil (6.1 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[O:3]1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33](OS(C)(=O)=O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN1C(=O)CCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([O:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([B:4]3[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]3)[CH:10]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (10.0 g, 45.4 mmol, 1.0 equiv) in NMP (100 ml) was added Cs2CO3 (44.4 g), 136.3 mmol, 3.0 equiv) and 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (19.0 g, 68.2 mmol, 1.5 equiv). The reaction mixture was heated to 80° C. and monitored until complete. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed successively with 2N KOH, water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The target molecule was purified by column chromatography (SiO2), eluted with 5→30% EtOAc-petrol to afford a colourless liquid (9.5 g) that crystallised on standing. 1H NMR (400 MHz, CDCl3): 7.42 (1H, d), 7.37 (1H, d), 7.31 (1H, t), 7.03 (1H, dd), 4.61-4.49 (1H, m), 3.76-3.62 (2H, m), 3.47-3.32 (2H, m), 1.99-1.86 (2H, m), 1.86-1.70 (2H, m), 1.49 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1([CH2:32][C:33](=[O:36])[O:34]C)[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]CC)=[O:28])[CH2:23][CH2:22]2)=[O:20])[CH2:6]1.C1COCC1.[OH-].[Na+].Cl>CO>[C:33]([CH2:32][C:5]1([CH2:4][C:3]([OH:37])=[O:2])[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:11]=2[CH2:17][CH2:18][C:19]([N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:20])[CH2:6]1)([OH:36])=[O:34]
Reactant: CCOC(=O)C1CCN(C(=O)CCc2ccc(O)cc2C2=NOC(CC(=O)OC)(CC(=O)OC)C2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CC1(CC(=O)O)CC(c2cc(O)ccc2CCC(=O)N2CCC(C(=O)O)CC2)=NO1
Yield: 98 %

Procedure:
A mixture of ethyl 1-(3-(2-(5,5-bis(2-methoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-hydroxyphenyl)propanoyl)piperidine-4-carboxylate (760 mg), THF (8 mL), methanol (8 mL), and a 1 M aqueous sodium hydroxide solution (8 mL) was stirred at room temperature for 2 hours. The reaction mixture was rendered acidic using 6 M hydrochloric acid at 0 C, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (664 mg).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH:12]1[C:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24](Cl)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1.[C:29]([O-:32])([O-])=O.[K+].[K+].CN(C=O)C>O.CCOCC>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:14]1[CH:15]=[CH:16][C:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:32][C:29]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=3)=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(Oc2cccc(C(F)(F)F)c2)cc1)c1ccc(Oc2cccc(C(F)(F)F)c2)cc1

Procedure:
All apparatus is rigorously dried and flushed with nitrogen before use. The reaction is performed in a 250 mL 3-necked flask equipped with a mechanical stirrer, a reflux condenser topped with a nitrogen inlet tube, and a stopper. The flask is charged with 3-trifluoromethyl-phenol (11.29 g, 69.7 mmol), 4,4'-dichlorodiphenyl sulfone (10.00 g, 34.8 mmol), K2CO3 (15.00 g, 109 mmol) and DMF (125 mL). The reacting mixture is stirred and heated at reflux for 12 hours. The mixture is analyzed by gas chromatography, which showed that almost no starting materials remained. The reaction mixture is diluted with water, and the aqueous layer is removed to leave an oil. This oil is diluted with ether and washed with 5% NaOH to remove any acidic species. It is then washed with brine, dried with MgSO4, and the solvent removed on the rotary evaporator to leave a white crystalline solid. This solid is purified by column chromatography on flash grade silica gel using a 1:1 mixture of CH 2 Cl2 /Hexane as eluent. Further purification is accomplished by recrystallization of the white solid from ethanol to give white, diamond-shaped crystals (11.08 g, 59%), m.p. 96.5-97.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11][O:12][CH2:13]Cl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:11][O:12][CH3:13])([OH:8])[CH2:4][CH:3]=1
Reactant: COCCl
Reactant: Oc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1(O)C=CC(Br)=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Commercially available 4-bromophenol (17.3 g) was dissolved in N,N-dimethylformamide (90 ml), to which sodium hydride (2.64 g) was added while cooled in ice. After stirring at room temperature overnight, chloromethyl methyl ether (8.35 ml) was added, and the admixture was stirred for a further 1 hour. The reaction mixture was partitioned between water and ethyl acetate, and the ethyl acetate layer was dried with anhydrous magnesium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was purified by column chromatography on silica gel eluting with hexane/acetone to obtain 18.25 g of the title compound (yield: 84%).
Reaction SMILES: N1C=CC=CC=1C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([OH:28])=[CH:25]2)=[CH:20][CH:19]=1.Br[C:30]1[C:31]([NH2:36])=[N:32][CH:33]=[CH:34][CH:35]=1>[Cu]I.O.CS(C)=O>[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([O:28][C:30]3[C:31]([NH2:36])=[N:32][CH:33]=[CH:34][CH:35]=3)=[CH:25]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(O)cc2c1
Reactant: Nc1ncccc1Br
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccn1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc2ccc(Oc3cccnc3N)cc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
A mixture of picoline acid (0.427 g), tripotassium phosphate (11.04 g), copper (I) iodide (0.660 g), 7-methoxynaphthalen-2-ol (6.04 g), 3-bromopyridin-2-amine (3 g) and DMSO(50 mL) was stirred under a nitrogen atmosphere at 140° C. overnight. Water was added, and the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and basic silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.667 g) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[CH3:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[N:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[CH3:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:16]3[CH:17]=[N:18][CH:19]=[C:14]([CH3:13])[CH:15]=3)=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:12]
Reactant: Cc1cncc(B(O)O)c1
Reactant: CN1C(=O)Cc2cc(Br)ccc21
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: COCCOC
Solvent: ClCCl
Product: Cc1cncc(-c2ccc3c(c2)CC(=O)N3C)c1
Temperature: 100 °C

Procedure:
To 5-bromo-1-methyl-1,3-dihydro-indol-2-one (CAS#20870-90-0, 80 mg, 0.35 mmol) was added 5-methyl-3-pyridinyl boronic acid (CAS#173999-18-3, 55 mg, 0.39 mmol), in 1,2-dimethoxyethane (2.7 mL) and 2 M aqueous sodium carbonate (0.45 mL, 0.9 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (195 mg, 0.018 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethanol-dichloromethane, 0 to 6%) to afford 1-methyl-5-(5-methyl-pyridin-3-yl)-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 239.1181 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 2.42 (s, 3H), 3.27 (s, 3H), 3.61 (s, 2H), 6.93 (d, J=8.1 Hz, 1H), 7.45-7.58 (m, 2H), 7.67 (s, 1H), 8.42 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:34])([F:33])[C:25]1[C:29]([CH2:30][CH2:31][OH:32])=[CH:28][NH:27][N:26]=1.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:30][C:29]1[C:25]([C:24]([F:34])([F:33])[F:23])=[N:26][N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[CH:28]=1
Reactant: OCCc1c[nH]nc1C(F)(F)F
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(CCO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (45 mg, 0.17 mmol) was dissolved in DCM (5 mL) and thionyl chloride (99 mg, 0.83 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) and added to a solution of 2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)ethanol (30 mg, 0.17 mmol) in DMF (2 mL) which had been treated with sodium hydride (8 mg, 0.33 mmol) for 15 min. The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by preparative basic HPLC gave (R)—N-(5-((4-(2-hydroxyethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (13.6 mg, 0.032 mmol, 18.9%). MS (ESI): m/z [M+H]+ 432.5
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[CH:5][CH:4]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:26][N+:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[NH2:35].N12CCCN=C1CCCCC2>C(O)C>[F:33][C:31]1[C:30]([F:34])=[CH:29][C:28]2[N:27]([N:26]=[C:9]([C:8]3[CH:7]=[N:6][CH:5]=[CH:4][C:3]=3[C:2]([F:12])([F:11])[F:1])[N:35]=2)[CH:32]=1
Reactant: Nc1cc(F)c(F)c[n+]1N
Reactant: O=Cc1cnccc1C(F)(F)F
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Fc1cc2nc(-c3cnccc3C(F)(F)F)nn2cc1F

Procedure:
4-(trifluoromethyl)nicotinaldehyde was added to a solution of 1,2-diamino-4,5-difluoropyridinium 2,4,6-trimethylbenzenesulfonate (47-4; 0.2 g, 0.000579 mol) in ethanol (20 mL) while stirring, followed by the addition of 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction mixture was stirred for 12 h at RT. It was then concentrated under vacuum, diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The collected organic parts were concentrated under vacuum to afford the crude product, which was purified by silica gel column chromatography to afford the title compounds. 1H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 9.09-9.06 (m, 1H), 9.03-9.02 (d, J=4 Hz, 1H), 7.99-7.77 (d, J=8 Hz, 1H), 7.61-7.55 (m, 1H). HPLC purity-99.13%, MS (M+1): 301.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH3:2]>C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:2]
Reactant: CCc1ccccc1C=CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCc1ccccc1CCC(=O)O

Procedure:
3-(2-Ethyl-phenyl)-acrylic acid (17.00 g, 96.48 mmol) in THF was mixed with Pd/C (1.50 g) and hydrogenated at 50 psi for 6 hours. The resulting mixture was filtered through a pad of celite and the filtrate was concentrated to give 3-(2-ethyl-phenyl)-propionic acid. The acid was reacted with SOCl2 (5.00 mL, 68.55 mmol) and AlCl3 (6.70 g, 50.25 mmol) according to the protocols as outlined in general procedure D to give the title compound.
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([N:5]1[CH2:6][CH2:7][N:2]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]3)=[O:9])[CH2:3][CH2:4]1)=[O:26]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(Cl)c1)N1CCN(C(=O)c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 Gram of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride, 0.72 g of m-chlorobenzoylchloride and 1.4 ml of triethylamine were suspended in 15 ml of dichloromethane and the suspension was stirred at a room temperature for 2 hours. Crystals formed in the reaction mixture were collected by filtration and recrystallized from dimethylformamide to obtain 1.07 g of 6-[4-(3-chlorobenzoyl)-1-piperazinylcarbonyl]-carbostyril. Colorless powdery crystals. Melting point: over 300° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:12](=O)/[CH:13]=[CH:14]/[CH3:15].[OH-].[Na+].[C:19](=O)(O)[O-].[Na+]>Cl.CO.C(OCC)(=O)C.CCOCC>[CH3:12][C:13]1[CH:14]=[CH:15][C:7]2[C:2](=[CH:3][C:4]([CH2:8][C:9]([O:11][CH3:19])=[O:10])=[CH:5][CH:6]=2)[N:1]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: C/C=C/C=O
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2ccc(C)nc2c1
Temperature: 25 °C

Procedure:
2-(3-aminophenyl)acetic acid (11.0 g, 72.8 mmol) was dissolved in 6 N HCl (200 mL) and heated to reflux. (E)-but-2-enal (11.9 mL, 146 mmol) was added dropwise over 10 minutes. The reaction was heated at reflux for 2 hours. After cooling to ambient temperature, the reaction mixture was basified with sodium hydroxide to pH˜12 and ether (100 mL) was added. The aqueous layer was separated, acidified with saturated potassium hydrogen sulfate to pH˜3-4, extracted with 3:1 CHCl3:IPA (3×300 mL), dried (sodium sulfate) and concentrated to give a solid. The solid was dissolved in MeOH (200 mL). The residue was suspended in ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated. The residue obtained was purified by flash chromatography (5:1 DCM:ethyl acetate) to give methyl 2-(2-methylquinolin-7-yl)acetate as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[C:6]([Cl:8])[N:7]=1.[H-].[Na+].I[CH3:15]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][N:9]([CH3:15])[C:5]2=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1nc(Br)cc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(Br)nc(Cl)c21
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
A solution of 5-bromo-7-chloro-1H-pyrrolo[2,3-c]pyridine (Aldrich, 0.86 g, 3.72 mmol) in tetrahydrofuran (37.2 mL) was treated with sodium hydride (0.297 g, 7.43 mmol) at ambient temperature, stirred for 15 minutes, treated with iodomethane (0.348 mL, 5.57 mmol), stirred for 1 hour at ambient temperature and quenched with saturated aqueous ammonium chloride. The mixture was partitioned with ethyl acetate and the organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. Purification by chromatography (silica gel, 0-40% ethyl acetate in heptanes) afforded the title compound (0.75 g, 82%).