Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH2:6][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([CH3:9])[CH3:8])(=O)=O.CC(NC(=O)OC(C)(C)C)(C)COC1C=CC=CC=1.[C:37]1([CH2:43]O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH3:8][C:7]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:9])[CH2:6][O:5][CH2:43][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: CC(C)(COc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(C)(COCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
1,1-Dimethylethyl {1,1-dimethyl-2-[(phenylmethyl)oxy]ethyl}carbamate (D275) was prepared from 2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylpropyl methanesulfonate (D273) in an analogous manner to 1,1-dimethylethyl [1,1-dimethyl-2-(phenyloxy)ethyl]carbamate (D274) using phenylmethanol instead of phenol.
Reaction SMILES: N1[CH:2]=[CH:3]N2C(N)=CC=CC=12.[NH2:11][C:12]1[N:17]=[C:16]([NH2:18])[CH:15]=[CH:14][N:13]=1>>[N:11]1[CH:2]=[CH:3][N:13]2[CH:14]=[CH:15][C:16]([NH2:18])=[N:17][C:12]=12
Reactant: Nc1cccc2nccn12
Reactant: Nc1ccnc(N)n1
Product: Nc1ccn2ccnc2n1

Procedure:
Intermediate 7 was prepared using methods analogous to those described for Intermediate 6 except 2,4-diaminopyrimidine was the starting material. MS (ESI+): calcd for C6H6N4 m/z 134.06, found 135.1 (M+H)+. 1H NMR (d4-methanol): 8.27 (d, J=7.2, 1H), 7.31 (d, J=1.8, 1H), 7.18 (d, J=1.8, 1H), 6.35 (d, J=7.2, 1H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl.O>CCOCC>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:26])=[O:25])=[CH:22][CH:23]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(-c2cc3ccccc3o2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)c2c(-c3ccccc3)oc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3.9 g.(0.02 mol.) of 2-phenylbenzofuran and 6.2 g. (0.03 mol.) of 4-methoxybenzenesulfonyl chloride in 50 ml. of methylene chloride was added 3.5 ml. (7.83 g., 0.03 mol.) of stannic chloride. The reaction mixture was stirred at ambient temperature for about 12 hours then poured into 150 ml. of water. The layers were separated and the organic phase was extracted once with 10% aqueous sodium bicarbonate solution, three times with water and once with a saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give a residue. Ether (ca. 35 ml.) was added to the residue and it was refluxed for 1 hour then filtered. The solid collected was recrystallized from benzene-hexane then chromatographed on a silica gel "dry column" with methylene chloride as eluant to give 3-(4-methoxyphenylsulfonyl)-2-phenylbenzofuran, m.p. 146°-148°.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24](=[O:51])[N:25]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)[C:26]#[C:27][Si](C(C)C)(C(C)C)C(C)C)([CH3:22])([CH3:21])[CH3:20].O>C1COCC1>[C:19]([O:23][C:24](=[O:51])[N:25]([C:26]#[CH:27])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:46][CH2:47][O:48][CH2:49][CH2:50]2)=[CH:41][CH:40]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)[Si](C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#CN(Cc1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
TBAF (2.18 g, 6.9 mmol) was added to a solution of (4-morpholin-4-yl-benzyl)-[(triisopropylsilanyl)-ethynyl]-carbamic acid t-butyl ester (1.42 g, 3 mmol) in THF (23 ml) at 0° C. The mixture was stirred for 1 hour at this temperature and was then warmed to RT. H2O (15 ml) was added and the organic phase was extracted with Et2O (3×15 ml) and dried over Na2SO4. The solvent was removed under reduced pressure and the desired compound was obtained after purification by column chromatography (PE/AcOEt:80/20 to 75/25). The title compound was obtained as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OC3C=CC=C(Cl)C=3)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=2)[C:7]=1[CH2:33][C:34]([O:36]CC)=[O:35])=[O:5])C.[OH-:39].[Na+].O.[ClH:42]>CCO>[C:34]([CH2:33][C:7]1[N:8]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[CH:25][CH:24]=2)[C:9]2[C:14]([C:6]=1[C:4]([OH:3])=[O:5])=[C:13]([O:39][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:42])[CH:10]=1)[CH:12]=[CH:11][CH:10]=2)([OH:36])=[O:35]
Reactant: Cl
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3cccc(Cl)c3)ccc2n1-c1ccc(OC(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(-n2c(CC(=O)O)c(C(=O)O)c3c(Oc4cccc(Cl)c4)cccc32)cc1

Procedure:
A mixture of 2-ethoxycarbonylmethyl-5-(3-chlorophenoxy)-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (0.10 g, 0.19 mmol); see step (b) above), NaOH (0.10 g, 2.50 mmol), H2O (2.5 mL) and EtOH (2.5 mL) was heated at reflux for 2 h, cooled and acidified with HCl (aq, conc). The solid was collected and dried to afford the title compound. Yield 0.06 g (66%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[ClH:14].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([C:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=2)[CH:20]=[CH:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[ClH:14].[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][CH2:2][N:26]1[CH2:25][CH:24]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:29])[F:30])[CH:18]=2)[CH2:28][CH2:27]1
Reactant: BrCCc1ccc2ccccc2c1
Reactant: FC(F)(F)c1cccc(C2=CCNCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(C2=CCN(CCc3ccc4ccccc4c3)CC2)c1
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of 6.25 g of 2-(2-bromoethyl)naphthalene, 7 g of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, 3.75 g of potassium carbonate and 100 ml of acetone is refluxed for 4 hours and the reaction mixture is then allowed to cool to room temperature. The salts formed are filtered off and discarded. The solvent is evaporated off and the residue is taken up with a solution of hydrochloric acid in ethanol to give 1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride, which is recrystallized from ethanol. Yield: 70% of theory, relative to the starting 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride. The product obtained is in the form of a fine white crystalline powder having an HPLC purity of 99.9%.
Reaction SMILES: FC1C=C(C=CC=1C1SC2C(N=1)=CC=C(C1(C3C=CC=CC=3)CC1)N=2)C=O.Cl.COC(C1CCNC1)=O.[F:38][C:39]1[CH:40]=[C:41]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([C:69]([O:71][CH3:72])=[O:70])[CH2:65]2)[CH:42]=[CH:43][C:44]=1[C:45]1[S:46][C:47]2[C:52]([N:53]=1)=[CH:51][CH:50]=[C:49]([C:54]1([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:56][CH2:55]1)[N:48]=2>>[F:38][C:39]1[CH:40]=[C:41]([CH2:63][N:64]2[CH2:68][CH2:67][C@@H:66]([C:69]([O:71][CH3:72])=[O:70])[CH2:65]2)[CH:42]=[CH:43][C:44]=1[C:45]1[S:46][C:47]2[C:52]([N:53]=1)=[CH:51][CH:50]=[C:49]([C:54]1([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:55][CH2:56]1)[N:48]=2.[F:38][C:39]1[CH:40]=[C:41]([CH2:63][N:64]2[CH2:68][CH2:67][C@H:66]([C:69]([O:71][CH3:72])=[O:70])[CH2:65]2)[CH:42]=[CH:43][C:44]=1[C:45]1[S:46][C:47]2[C:52]([N:53]=1)=[CH:51][CH:50]=[C:49]([C:54]1([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:55][CH2:56]1)[N:48]=2
Reactant: COC(=O)C1CCN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Agent: COC(=O)C1CCNC1
Agent: Cl
Agent: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Product: COC(=O)[C@@H]1CCN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1
Product: COC(=O)[C@H]1CCN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)-benzaldehyde (0.300 g, 0.801 mmol) and methylpyrrolidine-3-carboxylate hydrochloride (0.199 g, 1.20 mmol), according to Reference R and general procedure for reductive amination afforded the racemic mixture of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate. MS (ESI) m/z: Calculated: 487.2; Observed: 488.0 (M++1). The enantiomers of methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate were separated by SFC chromatography (Column: Chiralpak AS-H (21×250 mm, 5 um); A: Liquid CO2; B: Isopropanol (0.2% DEA); Isocratic: 56:44 (A:B); Flow rate: 70 mL/min; Outlet Pressure: 100 bar) to give (R)-methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate and (S)-methyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methyl)pyrrolidine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[S:11]3)=[CH:4][CH:3]=1.S(Cl)([Cl:23])(=O)=O.C(=O)([O-])O.[K+]>C(Cl)Cl>[Cl:23][C:15]1[N:14]2[C:10]([S:11][C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=32)=[N:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(-c2cn3c(n2)sc2ccccc23)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Clc1ccc(-c2nc3sc4ccccc4n3c2Cl)cc1
Reaction time: 0.17 h
Yield: 62.4 %

Procedure:
To a solution of 2 g of 2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole in 40 ml of methylene chloride was added a solution of 0.95 g of sulfuryl chloride in 5 ml of methylene chloride and after stirring for 10 minutes, 40 ml of an aqueous 10% potassium hydrogencarbonate solution was added to the mixture followed by stirring. The organic layer which formed was recovered, washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to form crystals, which were recrystallized from ethanol to provide 1.4 g of 3-chloro-2-(p-chlorophenyl)imidazo[2,1-b]benzothiazole.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:11][C:12]1([CH3:30])[O:16][N:15]=[C:14]([S:17][CH2:18][C:19]2[C:20]([C:26]([F:29])([F:28])[F:27])=[N:21][N:22]([CH3:25])[C:23]=2F)[CH2:13]1.O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:23]1[N:22]([CH3:25])[N:21]=[C:20]([C:26]([F:28])([F:27])[F:29])[C:19]=1[CH2:18][S:17][C:14]1[CH2:13][C:12]([CH3:30])([CH3:11])[O:16][N:15]=1
Reactant: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1F
Reactant: Oc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(C(F)(F)F)c(CSC2=NOC(C)(C)C2)c1Oc1ccccc1Cl
Reaction time: 1 h
Yield: 68.2 %

Procedure:
0.2 g (8.3 mmoles) of sodium hydride (purity: 60%) was added, with ice-cooling, to a solution of 0.44 g (3.4 mmoles) of 2-chlorophenol dissolved in 30 ml of N,N-dimethylformamide. The mixture was stirred for 1 hour. Thereto was added 0.7 g (2.2 mmoles) of 5,5-dimethyl-3-(5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline. The resulting mixture was stirred at 120 to 130° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.63 g (yield: 66.7%) of 3-(5-(2-chlorophenoxy)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-5,5-dimethyl-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].CC1C2[O:20]C3C(=CC=CC=3C)C(=O)C=2C=CC=1.[CH:24]1[C:37]2[CH2:36][C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([C:38]([OH:40])=[O:39])[C:30]=3[O:29][C:28]=2[C:27]([C:41]([OH:43])=[O:42])=[CH:26][CH:25]=1.C1(C(O)=O)C(C(O)=O)=CC=C2C=1CC1C(=CC=CC=1)O2>>[O:20]=[C:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([C:38]([OH:40])=[O:39])[C:30]=2[O:29][C:28]2[C:27]([C:41]([OH:43])=[O:42])=[CH:26][CH:25]=[CH:24][C:37]1=2
Reactant: Cc1cccc2c(=O)c3cccc(C)c3oc12
Reactant: O=C(O)c1cccc2c1Oc1c(cccc1C(=O)O)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=C(O)c1ccc2c(c1C(=O)O)Cc1ccccc1O2
Agent: [K+]
Product: O=C(O)c1cccc2c(=O)c3cccc(C(=O)O)c3oc12

Procedure:
9-Oxoxanthene-4,5-dicarboxylic acid which is prepared by potassium permanganate oxidation of the corresponding 4,5-dimethylxanthen-9-one [M. Schopff, Ber. 25, 3647 (1892)]49 is reduced to xanthene-4,5-dicarboxylic acid by a Wolff-Kishner reduction (N. Ishikawa, Yuki Gose: Kagaku Kyokai Shi 17, 553-6 (1959); CA 54:450]. The xanthene dicarboxylic acid derivative is converted to xanthene-4,5-dipiperidide by conventional procedures.
Reaction SMILES: [CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6](Cl)=[O:7])[CH2:2][CH2:3][CH3:4].[S:13]1[CH:17]=[CH:16][C:15]2[CH:18]([NH2:22])[CH2:19][CH2:20][CH2:21][C:14]1=2>>[CH2:1]([N:5]([CH2:9][CH2:10][CH2:11][CH3:12])[C:6]([NH:22][CH:18]1[C:15]2[CH:16]=[CH:17][S:13][C:14]=2[CH2:21][CH2:20][CH2:19]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)C(=O)Cl
Reactant: NC1CCCc2sccc21
Product: CCCCN(CCCC)C(=O)NC1CCCc2sccc21

Procedure:
Similarly, diethyl-, dipropyl-, and dibutylcarbamoyl chloride are reacted with 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine to afford 1,1-diethyl-, 1,1-dipropyl-, and 1,1-dibutyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, respectively. Substitution of the above-mentioned carbamoyl chlorides with the corresponding thiocarbamoyl chlorides affords the corresponding thioureas.
Reaction SMILES: [CH:1]1([C@@H:6]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[NH:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][N:14]=[C:13]3I)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:46][C:42]4([CH2:45][O:44][CH2:43]4)[CH2:41]3)=[CH:36][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[CH2:45]1[C:42]2([CH2:46][N:40]([C:37]3[CH:38]=[CH:39][C:34]([C:13]4[C:12]5[C:16](=[CH:17][CH:18]=[C:10]([C:8]([NH:7][C@@H:6]([CH:1]6[CH2:5][CH2:4][CH2:3][CH2:2]6)[C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=6)=[O:9])[CH:11]=5)[NH:15][N:14]=4)=[CH:35][CH:36]=3)[CH2:41]2)[CH2:43][O:44]1
Reactant: O=C(N[C@H](c1ccccn1)C1CCCC1)c1ccc2[nH]nc(I)c2c1
Reactant: CC1(C)OB(c2ccc(N3CC4(COC4)C3)cc2)OC1(C)C
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: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H](c1ccccn1)C1CCCC1)c1ccc2[nH]nc(-c3ccc(N4CC5(COC5)C4)cc3)c2c1
Temperature: 130 °C

Procedure:
The title compound was synthesized according to General Method C2 by utilizing (S)—N-(cyclopentyl(pyridin-2-yl)methyl)-3-iodo-1H-indazole-5-carboxamide (135 mg, 0.30 mmol), 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-6-azaspiro[3.3]heptane (100 mg, 0.33 mmol), Pd(PPh3)4 (36 mg, 0.044 mmol) and 2 M aq Na2CO3 (0.3 mL) in PhMe/EtOH (14 mL, 1:1 mixture). The reaction mixture was heated under microwave irradiation at 130° C. for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with H2O (20 mL), dried (MgSO4) and concentrated under vacuum to give a crude product. Purification by flash chromatography (Biotage Isolera, 50 g HP-SIL, 60-100% EtOAc in hexanes then 0-20% DCM in MeOH) gave the product as a yellow solid. Further purification using reverse phase chromatography (Biotage Isolera, 50 g C18, 10-90% MeCN in H2O) followed by trituration with MeOH gave the title compound as a pale yellow solid (34 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (s, 1H), 8.88 (d, J=8.3 Hz, 1H), 8.34-8.63 (m, 2H), 7.80-7.93 (m, 3H), 7.75 (t, J=6.9 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.24 (t, J=5.3 Hz, 1H), 6.60 (d, J=8.5 Hz, 2H), 4.92 (t, J=9.0 Hz, 1H), 4.74 (s, 4H), 4.05 (s, 4H), 2.53-2.62 (m, 1H), 1.87 (s, 1H), 1.35-1.70 (m, 5H), 1.15-1.35 (m, 2H); MS ESI 494.4 [M+H]+, calcd for [C30H31N5O2+H]+ 494.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([NH2:7])=[O:6].[N:12]1[CH:17]=[CH:16][N:15]=[CH:14][C:13]=1[NH2:18]>>[Br:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:18][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][N:12]=2)[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: NC(=O)c1cc(Br)cc(Br)c1
Reactant: Nc1cnccn1
Product: NC(=O)c1cc(Br)cc(Nc2cnccn2)c1

Procedure:
3,5-Dibromo-benzamide and pyrazin-2-ylamine were coupled to give 3-bromo-5-(pyrazin-2-ylamino)-benzamide as described for Example 44. 3-Bromo-5-(pyrazin-2-ylamino)-benzamide was converted to 3-(1H-indol-4-yl)-5-(pyrazin-2-ylamino)-benzamide as described in Example 75. 1H NMR (400 MHz, CDCl3): δ 10.61 (s, 1H), 8.24 (t, J=1.8 Hz, 1H), 8.17-8.12 (m, 3H), 8.06 (s, 1H), 7.88 (s, 1H), 7.78 (t, J=1.5 Hz, 1H), 7.40 (dd, J=6.6, 2.1 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.21-7.16 (m, 2H), 6.74 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10](C2C=CC=CC=2)[C:11](=[O:13])[O-])[N:4]=1.[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[N+:21]=[N-:22].N12CCCCC1C=NCCC2.Cl>O1CCOCC1.O>[N:20]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][C:11]([NH:10][C:5]2[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=2)=[O:13])(=[O:30])=[O:31])=[CH:25][CH:24]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=Nc1ccc(S(N)(=O)=O)cc1
Reactant: COc1cc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccc(N=[N+]=[N-])cc2)n1
Reaction time: 3 h
Yield: 67 %

Procedure:
A solution of 2.9 g of N-(4-methoxy-6-methylpyrimidin-2-yl)phenylcarbamate in 10 ml of dioxan is added dropwise at 20°-25° C. to a solution of 2 g of 4-azidophenylsulfonamide and 1.6 ml of 1,5-diazabicyclo(5,4,0)-undec-5-ene in 20 ml of dioxan and the mixture is stirred for 3 hours at the same temperature. The reaction mixture is then taken up in 200 ml of water and the aqueous mixture is then acidified with hydrochloric acid to pH 2. The precipitated product is isolated, washed with ethyl acetate and dried, affording N-(4-azidophenylsulfonyl)-N'-(4-methoxy-6-methylpyrimidin-2-yl)urea in 67% yield in the form of greenish crystals with a melting point of 192° C.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:13]([O:15][C:16](=[O:19])[CH2:17]I)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][C:8]1[C:7]2[C:11](=[CH:12][C:4]([NH2:1])=[CH:5][CH:6]=2)[NH:10][CH:9]=1)[CH3:14]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CI
Product: CCOC(=O)Cc1c[nH]c2cc(N)ccc12

Procedure:
(6-Amino-1H-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesized following the general scheme above starting from 6-nitroindole and iodo-acetic acid ethyl ester. Overall yield (24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[S:11](Cl)(Cl)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2=[N:9][S:11][N:10]=[C:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(F)c(Br)cc1N
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1cc2nsnc2cc1Br
Yield: 76 %

Procedure:
4-Bromo-5-fluorobenzene-1,2-diamine (500 mg, 2.4 mmol) was dissolved in 20 mL chloroform, treated in portions with thionyl chloride (580 mg, 4.9 mmol) and heated to reflux for 20 h. After cooling the mixture was diluted with 60 mL ethyl acetate, washed with 15 mL water, 15 mL saturated NaCl, dried (Na2SO4) and concentrated under vacuum. The material was chromatographed on silica with a 0-30% ethyl acetate-hexane gradient to give the title compound as a white solid (425 mg, 76%): mp 79-82° C.; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=6.7 Hz, 1H), 7.72 (d, J=8.3 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −102.91; EIMS m/z 232.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[N+:20]([O-])=O)[NH:16][C:15](=[O:23])[CH2:14][CH2:13]2)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1>[Pd].CO>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[NH:9][C:10]3=[CH:11][C:12]4[CH2:13][CH2:14][C:15](=[O:23])[NH:16][C:17]=4[CH:18]=[C:19]3[N:20]=2)=[CH:3][CH:4]=1
Reactant: O=C1CCc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc2N1
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc3[nH]c(-c4ccncc4)nc3cc2N1
Reaction time: 24 h

Procedure:
2.4 g. (7.7 mmole) 6-isonicotinoylamino-7-nitro-1,2,3,4-tetrahydroquinolin-2-one were hydrogenated in 100 ml. methanol in the presence of 0.4 g. 10% palladium on charcoal. After filtering off the catalyst and evaporating the filtrate, the residue was boiled for 24 hours with 80 ml. ethanol and 15 ml. concentrated hydrochloric acid. The evaporation residue was treated with water and ammonia, filtered off with suction and recrystallized from methanol to give 1.3 g. (62% of theory) of the title compound; m.p. above 300° C.
Reaction SMILES: C(N[C:5]1[C:10](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)(=O)C.[Cl-].[NH4+:28].[CH2:29]([OH:31])[CH3:30]>[Fe].O>[C:29]([NH:28][C:7]1[N:6]=[CH:5][C:10](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]([NH:19][C:20]3[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)Nc1ncccc1/C=C/c1cccc(Nc2ncccc2N)c1
Reactant: CCO
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: CC(=O)Nc1ccc(/C=C/c2cccc(Nc3ncccc3N)c2)cn1

Procedure:
A mixture of 2-[3-[(E)-2-(2-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine (1.86 g), iron powder (1.39 g) and ammonium chloride (0.26 g), ethanol (20 ml) and water (6 ml) was stirred under reflux for an hour. The reaction was filtered, concentrated and extracted with chloroform. The extracts were washed with saturated sodium bicarbonate solution, dried and evaporated to afford 2-[3-[(E)-2-(6-acetamido-3-pyridyl)vinyl]phenylamino]-3-aminopyridine as dark purple crystals (1.59 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:18])=[O:19]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Br)c1
Yield: 81 %

Procedure:
2,5-Dimethyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give off-white crystals, m.p. 102-104° C., yield 81%.