Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH:14]=[O:15])[C:8]=2[CH:7]=[CH:6]1)[CH3:4]>CCO.C(Cl)Cl>[CH2:3]([N:5]1[C:13]2[C:8](=[C:9]([CH2:14][OH:15])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH3:4]
Reactant: CCn1ccc2c(C=O)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCn1ccc2c(CO)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
NaBH4 (49.8 mg, 1.32 mmol, Eq: 0.3) was added to a solution of 1-ethyl-1H-indole-4-carbaldehyde (800 mg, 4.39 mmol, Eq: 1.00) in EtOH (30 mL) and DCM (15 mL) at 0° C. and the mixture was warmed to RT and stirred overnight. The mixture concentrated to remove DCM and the resulting mixture diluted with NH4Cl, extracted with DCM and concentrated. The residue was purified by silica gel chromatography to give the title compound (700 mg, 91%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9](Br)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4].C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)CCC>>[CH3:1][O:2][C:3]([C:5]1[N:10]=[C:9]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:8]2[N:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:14][C:7]=2[C:6]=1[OH:21])=[O:4]
Reactant: COC(=O)c1nc(Br)c2nc(-c3ccccc3)oc2c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Product: COC(=O)c1nc(-c2ccc(F)cc2)c2nc(-c3ccccc3)oc2c1O

Procedure:
Prepared from 4-bromo-7-hydroxy-2-phenyl-oxazolo[4,5-c]pyridine-6-carboxylic acid methyl ester, example 3a, and tributyl(4-fluorophenyl)stannane under conditions analogous to example A-3b. MS: (+) m/z 364.9 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])=[CH:4]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN(C)CCOc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cn(S(=O)(=O)c2ccc(Br)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in mineral oil, 16.5 mmoles) was stirred with dimethyl formamide (ca 8 mL) in a ice-cooled, three necked round bottom flask. A solution of [2-(1H-indol-3-yloxy)ethyl]dimethylamine (15 mmole), in dimethyl formamide (ca 5 mL) was then added dropwise to this cooled suspention of sodium hydride. After the addtion was complete, the reaction mixture was allowed to attain the room temperature (25° C.). After about one hour of stirring at 25° C., a solution of 4-Bromobenzenesulfonyl chloride (18 mmole) was added dropwise to this solution. The reaction was further stirred at 25° C. for next 3-4 hours. After the completion of reaction (TLC), reaction mixture was poured on the ice cooled water and extracted by Ethyl acetate (3×20 mL). The combined organic extract was washed with water and brine, dried over sodium sulphate and the volatiles were evaporated under vacuume to get the product as a thick dark oil. The residue was purified by column chromatography, on silica gel; using hexane (100%) to triethylamine:ethyl acetate (2:98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (I) can be further purified by preparation of their acid addition salts. Melting range (° C.): Isolated as oil; Mass (m/z): 423, 425 (M+H)+; IR spectra (cm−1): 1150 (SO2); 1H-NMR (ppm): 2.40 (s, 6H); 2.83-2.88 (t, 2H, J=5.4 Hz); 4.11-4.16 (t, 2H, J=5.4 Hz); 6.87 (s, 1H); 7.19-7.38 (m, 3H); 7.50-7.67 (m, 4H); 7.95-7.99 (d, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[C:6]2=[N:5][C:4]=1[NH:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[N:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([F:13])([F:14])[F:15])[C:6]2=[N:5][C:4]=1[N:16]([CH2:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[C:34]([C:41]([F:44])([F:42])[F:43])[CH:35]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:2]
Reactant: CCc1c(NS(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccccc2)nc2c(C(F)(F)F)cccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of compound 13-E (0.060 g, 0.1 mmol) in DMF (3 mL) was added Na2CO3 (0.032 g, 0.3 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.028 g, 0.11 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 55 as a white solid (0.047 g, 87%); MS m/z (M+H+) 546.
Reaction SMILES: [C-:1]#[N:2].[K+].[I-].[Na+].[CH3:6][O:7][C:8]1[C:13]([CH2:14]Cl)=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1.O>CS(C)=O>[CH3:6][O:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:10][CH:11]=[CH:12][C:13]=1[CH2:14][C:1]#[N:2]
Reactant: COc1c(CCl)cccc1Oc1ccccc1C
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(CC#N)cccc1Oc1ccccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
Powdered potassium cyanide (12.50 g) and sodium iodide (28.80 g) were added to a solution of o-tolyl 2-methoxy-3-chloromethylphenyl ether (47.50 g) in dimethylsulfoxide (100 ml) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water 3 times, dried over magnesium sulfate and then evaporated to give only 2-[2-methoxy-3-(o-tolyloxy)phenyl]acetonitrile (44.0 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:21]#[N:22])([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1>>[C:21]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)#[N:22]
Reactant: CCOC(=O)C(C#N)(CCCBr)c1ccc(OC)c(OC)c1
Reactant: CNCCc1ccc(C(=O)OC)cc1
Product: CCOC(=O)C(C#N)(CCCN(C)CCc1ccc(C(=O)OC)cc1)c1ccc(OC)c(OC)c1

Procedure:
Reaction of 1c with 2b produced 3p. MS found M+H=483. The oxalate salt of 3p was recrystallized from ethyl acetate; mp 75-77° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[CH2:8]([NH:7][C:4]1[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[NH:6][N:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#Cc1c(NCc2ccccc2)n[nH]c1N
Reactant: CCOC(OCC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=Nc1[nH]nc(NCc2ccccc2)c1C#N
Temperature: 25 °C

Procedure:
Under a N2 atmosphere, a suspension of 74.3 g (348 mmol) of 5-amino-3-benzylamino-1H-pyrazole-4-carbonitrile in 1.0 liter of toluene is boiled under reflux for 2 hours with 70.1 ml (95%; 409 mmol) of N,N-dimethylformamide diethyl acetal. Cooling to RT, filtering with suction and washing with diethyl ether yield N'-(3-benzylamino-4-cyano-1H-pyrazol-5-yl)-N,N-dimethylformamidine; m.p. 197-200° C.; TLC: Rf =0.50 (ethyl acetate).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][C:7]=1[C:8]#[N:9])#[N:2].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Cl.O>CN(C)C=O>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16][N:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]#[N:9])[N:6]=[CH:5]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: N#Cc1nc[nH]c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ncn(Cc2ccc(Cl)c(Cl)c2)c1C#N
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
4,5-Dicyanoimidazole (93 g, described by Woodward, U.S. Pat. No. 2534331 (1950)) was dissolved in dry dimethylformamide (500 ml) with stirring. Sodium hydride (20 g) was added to the solution in portions at such a rate that the temperature after the addition was 90° C. When effervescence had ceased the solution was heated on a steam bath for 15 minutes and then allowed to cool to 60° C. 3,4-Dichlorobenzyl chloride (230 g, described by Beilstein & Kuhlberg, Ann., 146, 326 (1867)) was added over 30 minutes to the solution, which was heated on a steam bath for 6 hours and then at 150° C. for 10 minutes. The cooled reaction mixture was poured into water (2 liters) and a brown solid was filtered off and washed with water. The damp solid was recrystallised from ethanol (1 liter) to give 1-(3,4-dichlorobenzyl)-4,5-dicyanoimidazole, m.p. 132°-134° C., (114 g) as off-white crystals.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([O:41]C)=[O:40])=[C:11]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:29][CH2:28]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH3:46])(=[O:45])=[O:44])[CH3:4].[K]>CO.O>[CH2:3]([O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:39]([OH:41])=[O:40])=[C:11]([CH2:26][N:27]3[CH2:28][CH2:29][CH:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:31][CH2:32]3)[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=3)=[N:13]2)=[CH:8][C:7]=1[S:43]([CH3:46])(=[O:45])=[O:44])[CH3:4]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(C)(=O)=O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 106.2 %

Procedure:
Potassium hydroxide (1.36 g, 2.42 mmol) was added to a solution of methyl 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.54 g, 2.423 mmol) in methanol (60 mL) and water (20 mL). The reaction mixture was heated to reflux overnight. The mixture was cooled to room temperature, diluted with water, and concentrated in vacuo to remove methanol. The solid precipitate was collected by filtration, washed with cold water, and dried to afford 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (1.6 g, >99% yield) as the potassium salt. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.92 (d, J=7.53 Hz, 1H), 7.79 (d, J=7.78 Hz, 1H), 7.68 (t, J=7.78 Hz, 1H), 7.52 (s, 1H), 4.34 (q, J=6.94 Hz, 2H), 3.49-3.55 (m, 4H), 3.44 (s, 2H), 3.17 (s, 3H), 2.53 (br. s., 2H), 2.31-2.38 (m, 4H), 1.93-2.02 (m, 1H), 1.85 (t, J=11.29 Hz, 2H), 1.52 (d, J=11.04 Hz, 2H), 1.46 (t, J=7.03 Hz, 3H), 0.94-1.07 (m, 2H); MS (m/z) 622.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=O)=[CH:2]1.COC1C=CC(/C=[C:27]2/[C:28]([NH:30][C:31]([S:33]/2)=[NH:32])=[O:29])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[NH2:32][C:31]1[S:33]/[C:27](=[CH:10]\[C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)/[C:28](=[O:29])[N:30]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC1=NC(=O)/C(=C/c2c[nH]c3ncccc23)S1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
The suspension of 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (example 1b, 200 mg, 1.4 mmol), pseudothiohydantoin (159 mg, 1.4 mmol), and sodium acetate (459 mg, 5.6 mmol) in acetic acid (2 mL) was stirred under reflux for 12 h. After cooling to room temperature, water was added. The solid was collected by filtration, washed with water and dried to obtain 2-amino-5-[1-(1H-pyrrolo[2,3-b]pyridin-3-yl)-meth-(Z)-ylidene]-thiazol-4-one (280 mg, 82%) as a slight yellow solid. LC-MS m/e 245 (MH+).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:12]=1[O:13][CH:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1.[N:26]1[N:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]2=[C:28]([C:35]([OH:37])=O)[CH:27]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:25][C:23]1[CH:22]=[CH:21][C:12]([O:13][CH:14]2[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]2)=[C:11]([NH:10][C:35]([C:28]2[CH:27]=[N:26][N:30]3[CH:29]=[CH:34][CH:33]=[N:32][C:31]=23)=[O:37])[CH:24]=1
Reactant: Nc1cc(Cl)ccc1OC1CCC(O)CC1
Reactant: O=C(O)c1cnn2cnccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1cc(Cl)ccc1OC1CCC(O)CC1)c1cnn2cccnc12
Temperature: 80 °C
Yield: 37.2 %

Procedure:
Diisopropylethylamine (0.35 mL, 2.01 mmol) was added at room temperature to a suspension of 4-(2-amino-4-chloro-phenoxy)-cyclohexanol (127 mg, 0.525 mmol), pyrazolo[1,5-c]pyrimidine-3-carboxylic acid (85 mg, 0.521 mmol) and HBTU (0.21 g, 0.55 mmol) in anhydrous acetonitrile (15 mL) and the resulting solution was heated at 80° C. overnight. The resulting mixture was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%). The aqueous layer was extracted 3 times with ethyl acetate and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The brown oily residue was purified on a silica gel plug and by flash chromatography (DCM/MeOH/NH4OH) to give a pale yellow solid which was washed with dichloromethane and methanol to give 75 mg (38% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-chloro-2-(4-hydroxy-cyclohexyloxy)-phenyl]-amide as a white powder. MS=387 [M+H]+.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18][C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)(=O)C.[ClH:33]>CO>[ClH:33].[ClH:33].[NH2:4][C:5]1[CH:6]=[C:7]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[N:18][C:17]3[CH:29]=[CH:30][CH:31]=[N:32][C:16]2=3)[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1
Reactant: COC(=O)c1cc(NC(C)=O)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-n2c(=O)c(Cc3cccnc3)nc3cccnc32)c1

Procedure:
A mixture of 4-(3-acetylamino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (847 mg) and hydrochloric acid (35%, 1 ml) in methanol (10 ml) was stirred under reflux for 2 hours. After cooling, the resultant precipitate was collected and washed with methanol to give 4-(3-amino-5-methoxycarbonylphenyl)-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine.dihydrochloride (612 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCCCCC.CS(C)=O>[C:12]1([S:18]([N:3]2[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cnc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=S(=O)(c1ccccc1)n1ccc2ncccc21
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
Sodium hydride (60% in mineral oil, 203 mg, 5.08 mmol) was washed twice with hexane, and the residue suspended in DMSO (5 ml). 1H-Pyrrolo[3,2-b]pyridine (500 mg, 4.24 mmol) was added and the reaction stirred for 15 minutes. Benzenesulphonyl chloride (749 mg, 4.42 mmol) was added rapidly and the reaction stirred for 0.5 h. After quenching with water the product was extracted into EtOAc, dried (Na2SO4) and concentrated in vacuo. Chromatography (EtOAc, silica) yielded the title compound as a white crystalline solid (903 mg, 83%). δH (d6-DMSO) 8.48 (1H, dd, J 0.8, 3.8 Hz), 8.31 (1H, m), 8.15 (1H, d, J 3.8 Hz), 8.04 (2H, m), 7.72 (1H, m,), 7.61 (2H, m,), 7.36 (1H, dd, J 4.7, 8.4 Hz), 6.98 (1H, dd, J 0.8, 3.8 Hz). LCMS (ES+) RT 3.056 minutes, 259 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Cu][C:14]#[N:15]>CN(C=O)C.C(OCC)(=O)C>[C:14]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:15]
Reactant: N#C[Cu]
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Yield: 65 %

Procedure:
To a solution of (3-bromo-4-fluoro-phenyl)-acetic acid (10 g, 42.9 mmol) in DMF (65 mL) was added copper (I) cyanide (7.7 g, 85.8 mmol) and heated at 130° C. for 24 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The organic layer was washed with water (5×50 mL), brine (50 mL), dried over sodium filtered and concentrated under reduced pressure. The crude material was re-crystallized from diethyl ether and hexane to afford the title compound as a yellow solid in 65% yield, 5 g.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:25][C:15]2[NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.O>CN(C=O)C>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:25][C:15]2[N:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: BrCc1ccccn1
Reactant: N#Cc1ccc2[nH]c3c(c2c1)CC(N1C(=O)c2ccccc2C1=O)C3
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Heat a mixture of 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (5 g, 15.3 mmol) in DMF (25 ml) to 40° C. Add cesium carbonate (10.4 g, 32.4 mmol) and 2-bromomethylpyridine hydrobromide (4.05 g, 16 mmol). Stir the mixture at 40° C. for 24 h. Add the mixture to water (250 mL) and stir for 1 h. Filter the solids and dry the collected material under vacuum. Add the solid to ethanol (25 mL) and reflux for 30 min. Cool the mixture to 22° C. and filter. Dry the solid under vacuum to constant weight to provide 4.8 g (75%) of the title compound. MS (m/z): 419 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][N:32]=[C:31]1[C:35](Cl)=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:35]([C:31]4[S:30][CH:34]=[CH:33][N:32]=4)=[O:36])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1nccs1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2nccs2)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 20 mg, 50 μmol) and 1,3-thiazole-2carbonyl chloride (23 mg, 150 μmol). Yield 25 mg (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.C(OC(=O)C)(=O)C.[S:32](=O)(=[O:35])([OH:34])[OH:33]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:5]2[S:32]([OH:35])(=[O:34])=[O:33]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1c(S(=O)(=O)O)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 5-chloro-1-(phenylsulfonyl)-1H-indole-2-carboxylate (5.56 g, 15.3 mmol) in 50 mL of dichloromethane at 0° C. was added acetic anhydride (7.23 mL, 76.6 mmol), followed by dropwise addition of concentrated sulfuric acid. The solution was warmed to room temperature, stirred for 3 hours, and partitioned between 0.5 L of EtOAc and 0.5 L of 3N HCl solution. The organic phase was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The product was reconcentrated from benzene in vacuo to give the titled product as a yellow solid. Proton NMR for the product was consistent with the titled compound of the formula C17H14ClNO7S2.0.5 CH3CO2H. ESI+MS: 444.0 [M+H+, 466.0 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[OH:10].[Br:11]Br>ClCCl>[Br:11][C:6]1[CH:5]=[C:4]([F:9])[C:3]([OH:10])=[C:2]([F:1])[C:7]=1[F:8]
Reactant: Oc1c(F)ccc(F)c1F
Reactant: BrBr
Solvent: ClCCl
Product: Oc1c(F)cc(Br)c(F)c1F
Reaction time: 168 h

Procedure:
10 g (0.0678 mol) of 2,3,6-trifluorophenol (prepared according to Examples 1a and 1b) are dissolved in 50 ml of dichloromethane, and this solution is admixed at 20° C. with 13 g (0.0811 mol) of bromine. After mixing by shaking, the mixture is left standing for 7 days.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([CH2:45][CH2:46][CH2:47][N:48]4[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(CCCN2CCCCC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClCCl
Product: COc1cc(CCCN2CCCCC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 120 °C
Yield: 35 %

Procedure:
5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (120 mg, 0.24 mmol), 2-(methyloxy)-4-[3-(1-piperidinyl)propyl]aniline (Example 139, step D) (55 mg, 0.22 mmol), and p-toluenesulfonic acid (111 mg, 0.59 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 120° C. for 40 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (54 mg, 0.077 mmol, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.77 (s, 1H), 9.36 (s, 1H), 8.49 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.76 (s, 1H), 7.68 (s, 1H), 7.63 (s, 1H), 7.34-7.45 (m, J=17.58 Hz, 2H), 7.27 (s, 1H), 7.12-7.21 (m, 2H), 6.91-6.98 (m, 2H), 6.74 (s, 1H), 6.59 (s, 1H), 3.97 (s, 3H), 3.81 (s, 3H), 2.51-2.59 (m, 2H), 2.19-2.31 (m, 6H), 1.67-1.77 (m, 2H), 1.42-1.50 (m, 4H), 1.30-1.39 (m, 2H). MS (ESI): 704 [M+H]+.