Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:18][C:19]([C:21]1[CH:26]=[C:25](Cl)[CH:24]=[CH:23][N:22]=1)=[O:20])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([NH:18][C:19]([C:21]2[CH:26]=[C:25]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH:24]=[CH:23][N:22]=2)=[O:20])[C:3]([OH:28])=[O:2])=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Cl)ccn1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccnc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 46.4 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (80 mg, 0.20 mmol) was reacted with 4-methoxy phenylboronic acid (61 mg, 0.40 mmol) as described in general procedure D to afford the title compound (42 mg, 46%) as a light yellow solid. LC/MS (m/z): 453 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:21][CH:20]([OH:22])[CH2:19]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([O:32]CC2C=CC=CC=2)=[O:31])[CH2:29][CH2:28]1)=[O:26].CO.[H][H].[CH2:44]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45]>O1CCCC1.[Pd]>[CH2:44]([N:46]([CH2:49][CH3:50])[CH2:47][CH3:48])[CH3:45].[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([N:18]3[CH2:19][CH:20]([OH:22])[CH2:21]3)=[O:17])[CH:10]=2)[C:5]([F:23])=[CH:4][C:3]=1[NH:24][C:25]([C:27]1([C:30]([OH:32])=[O:31])[CH2:29][CH2:28]1)=[O:26]
Reactant: [H][H]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC(O)C1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)O)CC3)cc2F)ccn1)N1CC(O)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
Benzyl 1-[({2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylate (84.2 mg) was dissolved in tetrahydrofuran and methanol (1:1) (2 ml) under a nitrogen atmosphere. 10% palladium on carbon (33.2 mg) was added and the air in the reaction vessel was replaced by hydrogen, and the mixture was stirred at room temperature for 20 hours. The air in the reaction vessel was replaced by nitrogen, and triethylamine (0.0435 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was removed by filtration, and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound (75.3 mg, 88%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([CH:16]=[CH:17][C:18]#[N:19])(=[O:15])=[O:14])=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(S(=O)(=O)C=CC#N)cc1
Reaction time: 48 h

Procedure:
23 grams (0.2 mol) of methanesulfonyl chloride (CH3SO2Cl) are dissolved in 600 milliliters of chloroform, and 42 grams (0.2 mol) of 3-(4-aminobenzenesufonyl)acrylonitrile, prepared as described in copending application Ser. No. 228,410 filed Feb. 22, 1972, are added with stirring and cooling in an ice bath followed portionwise by a solution of 16 g (0.2 mol) of pyridine in 200 ml of pyridine. The reaction mixture is allowed to reach room temperature and is thereafter left at about 20° C for about 48 hours. The solution is filtered and then washed with water, a 5% solution of HCl in water, a 5% sodium bicarbonate solution in water, and water, in sequence.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:21])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2ccc(O)cc2N1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Temperature: 15 °C
Yield: 96.1 %

Procedure:
Step R1-1: To a suspension of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (200 g) in CHCl3 (2.0 L) was added pyridine (212 g) at room temperature over 10 minutes. Tf2O (344 g) was added to the mixture over 35 minutes, keeping the temperature below 10° C. After the mixture was allowed to warm to 15° C. over 1 hour, the reaction mixture was cooled to 0° C. and quenched by addition of water (2.0 L). The organic layer was separated, washed with aqueous saturated KHSO4 and water twice, dried over Na2SO4 and concentrated to obtain 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as a pale yellow solid (346 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][SH:5].[OH-].[Na+].Cl[C:9](Cl)=[CH:10][N+:11]([O-:13])=[O:12].Cl>CO.C(Cl)(Cl)Cl.O>[N+:11]([CH:10]=[C:9]1[NH:1][CH2:2][CH2:3][CH2:4][S:5]1)([O-:13])=[O:12]
Reactant: NCCCS
Reactant: O=[N+]([O-])C=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C=C1NCCCS1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
Into 40 ml of methanol were added 5.5 g of 1-amino-3-propanethiol and 2.4 g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 2.8 g of 2,2-dichloronitroethylene diluted in 10 ml of methanol was added dropwise slowly over 15 minutes, and the reaction was carried out for one hour. The reaction was exothermic and the liquid temperature was maintained at lower than 10° C. (about 8° C.) After the reaction, the reaction mixture was neutralized to pH 7 with 6 N aqueous hydrochloric acid, and then with addition of 30 ml of water, extraction with 50 ml of chloroform was repeated four times. The extracts were concentrated to give 2.24 g of tetrahydro-2-(nitromethylene)-1,3-thiazine (yield: 70.0%).
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:30]([C:33]2[N:34]=[CH:35][N:36]([CH3:38])[CH:37]=2)(=[O:32])=[O:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.O.O1CCOCC1.[ClH:47]>C(OCC)C>[CH3:38][N:36]1[CH:37]=[C:33]([S:30]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:32])[N:34]=[CH:35]1.[ClH:47]
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccc(-c3ncccn3)cc2)Cc2cccc(OCC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc(S(=O)(=O)N(Cc2ccc(-c3ncccn3)cc2)Cc2cccc(OCC(=O)O)c2)c1
Reaction time: 0.33 h

Procedure:
A solution of (3-(((1-methyl-1H-imidazole-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino)-methyl)-phenoxy)-acetic acid tert-butyl ester prepared of Example 10, Step B (0.094 g, 0.17 mmol) in 1N HCl in diethyl ether was stirred for 20 minutes as a precipitate formed. To the mixture was added 1 mL water and 1 mL dioxane and the reaction was stirred for 3 hours. The solvent was removed in vacuo, azeotroping with ethanol to yield the title compound as a solid (54 mg). 1H NMR (400 MHz, CD3OD) δ 9.09 (m, 2H), 8.95 (bs, 1H), 8.24 (d, 2H), 8.04 (s, 1H), 7.71 (s, 1H), 7.44 (d, 2H), 7.13 (m, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 6.69 (s, 1H), 4.61 (s, 2H), 4.54 (s, 2H), 4.46 (s, 2H), 3.92 (s, 3H); MS 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:10]1>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1.[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:19])[N:12]=[C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1
Reactant: COC(=O)C1=C(C)NC(c2ccccc2)=NC1c1ccc(Cl)cc1Cl
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc(Cl)cc1Cl
Product: Cc1nc(-c2ccccc2)nc(-c2ccc(Cl)cc2Cl)c1C(=O)O
Temperature: 95 °C
Yield: 23 %
Yield: 15 %

Procedure:
To a stirred solution of methyl 4-(2,4-dichlorophenyl)-6-methyl-2-phenyl-1,4-dihydropyrimidine-5-carboxylate (600 mg, 1.76 mmol) in PhCH3 (6 mL) was added MnO2 (227 mg, 2.64 mmol) and the reaction was heated to 95° C. for 14 hrs. The reaction was filtered through a pad of celite, concentrated under reduced pressure, and purified by flash chromatography (silica gel, 30% EtOAc/hexane) to give methyl 4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylate (150 mg, 23% for 2 steps) and 4-(2,4-dichlorophenyl)-6-methyl-2-phenylpyrimidine-5-carboxylic acid (100 mg, 15% for 2 steps).
Reaction SMILES: F[C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH2:20]([N:22](CC)CC)C.Cl.[CH3:28]N>C(O)(C)C>[Br:19][C:15]1[CH:14]=[C:13]([N:12]([C:8]2[C:9]3[CH:10]=[N:11][C:2]([NH:22][CH3:20])=[CH:3][C:4]=3[N:5]=[CH:6][N:7]=2)[CH3:28])[CH:18]=[CH:17][CH:16]=1
Reactant: CCN(CC)CC
Reactant: Fc1cc2ncnc(Nc3cccc(Br)c3)c2cn1
Reactant: CN
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc2ncnc(N(C)c3cccc(Br)c3)c2cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 21.6 %

Procedure:
A mixture of 7-fluoro-4-(3-bromoanilino)pyrido[4,3-d]pyrimidine (100 mg, 0.31 mmole), triethylamine (4.4 mL, 32 mmole) and methylamine hydrochloride (2.12 g, 32 mmole) in isopropanol (30 mL) contained in a steel bomb is stirred at 100° C. (oil bath) for 5 h. The resulting mixture is concentrated under vacuum, basified with aqueous Na2CO3, diluted with water and extracted with EtOAc (3×100 mL). Chromatography of this extract on silica gel (1-2% MeOH/CH2Cl2) gives 4-[N-(3-bromophenyl)-N-methylamino]-7-methylaminopyrido[4,3-d]pyrimidine (23 mg, 21%) as a pale yellow solid. 1H NMR (DMSO) δ 8.14 (1H, s), 7.79 (1H, s), 7.30 (1H, t, J=8.0 Hz), 7.20 (1H, ddd, J 7.9, 1.8, 0.8 Hz), 7.03 (1H, brq, J=4.9 Hz), 7.01 (1H, t, J=1.9 Hz), 6.82 (1H, ddd, J=7.8, 1.8, 0.9 Hz), 6.25 (1H, s), 3.40 (3H, s), 2.73 (3H, d, J=4.9 Hz).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]([CH3:29])[S:25](Cl)(=[O:27])=[O:26]>CN(C1C=CN=CC=1)C.C(#N)C>[CH:1]1([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][C:15]([NH:17][S:25]([N:24]([CH3:29])[CH3:23])(=[O:27])=[O:26])=[CH:16][C:11]=3[N:10]=[C:9]2[C:18]([CH3:21])([CH3:22])[CH2:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCC(C)(C)c1nc2cc(N)ccc2n1CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCC(C)(C)c1nc2cc(NS(=O)(=O)N(C)C)ccc2n1CC1CCCCC1
Yield: 76.8 %

Procedure:
DMAP (80.1 mg, 0.65 mmol) was added to a solution of 1-(cyclohexylmethyl)-2-(1,1-dimethylpropyl)-1H-benzimidazol-5-amine (69.5 mg, 0.18 mmol) (for preparation, see the following steps B, C, D, E and F) in acetonitrile (10 mL) at 0° C., followed by addition of dimethylsulfamoyl chloride (22 uL, 28.7 mg, 0.20 mmol). The resulting mixture was heated at reflux for 20 h and then quenched with MeOH (2 mL). After evaporation of the solvent, the residue was dissolved in EtOAc (100 mL) and washed with NaCl aqueous solution (10 mL) and dried over Na2SO4. After filtration and evaporation, the residue was purified by MPLC (hexanes/EtOAc 1:1 as eluent on silica gel) to give the title compound as a white solid (56.2 mg, 76%), which was converted to a white solid as a TFA salt. 1H NMR (400 MHz, CD3OD): δ 0.84 (t, J=7.52 Hz, 3H), 1.24 (m, 5H), 1.64 (m, 2H), 1.66 (s, 6 μl), 1.71 (m, 1H), 1.78 (m, 2H), 2.01 (q, J=7.55 Hz, 2H), 2.11 (m, 1H), 2.82 (s, 6H), 4.44 (d, J=7.81 Hz, 2H), 7.37 (dd, J=8.98, 2.15 Hz, 1H), 7.69 (d, J=2.15 Hz, 1H), 7.84 (d, J=8.98 Hz, 1H); MS (ESI) (M+H)+: 407.3; Anal. Calcd for C21H34N4O2S+1.0 TFA+0.2 H2O: C, 52.70; H, 6.81; N, 10.69. Found: C, 52.70; H, 6.66; N, 10.45.
Reaction SMILES: C(N([CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1)CC)C.C([Cl:41])(=O)OCC.C(Cl)Cl>CC(O)C>[Cl:41][CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1
Reactant: CCN(CC)Cc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Reactant: CCOC(=O)Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.0 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one and 5.1 mL of ethyl chlorocarbonate were added to 60 mL of methylene chloride. This was then stirred for 3 hours at room temperature, and 140 mL of 2-propanol was added dropwise into the reaction mixture over a period of 30 minutes. The result was stirred for 2 hours at 5-15° C. and solids were filtered to obtain 16.6 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one in the form of a pale yellowish-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@@H:10]([N:12]=[N+]=[N-])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:22])[C@@H:7]1[CH2:11][C@@H:10]([NH2:12])[CH2:9][N:8]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C

Procedure:
A solution (4R)-1-(tert-butyloxycarbonyl)-4-azido-L-proline tert-butyl ester (191 mg, 0.611 mmol) in 90% ethanol (15 mL) was hydrogenated in the presence of 10% palladium-on-charcoal (40 mg) under a balloon atmosphere of hydrogen gas for one hour. The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. The title compound was obtained as a colorless oil after drying under high vacuum; yield 177 mg.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][CH2:24][CH2:25]I)[CH:21]=2)[C:16]([C:29]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=2)=[CH:15]1.O>C(#N)C.C(OCC)(=O)C>[CH3:13][N:14]1[C:22]2[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([O:23][CH2:24][CH2:25][N:7]3[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)[CH:21]=2)[C:16]([C:29]2[N:37]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[CH:30]=2)=[CH:15]1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCN1CCOCC1
Temperature: 60 °C

Procedure:
0.11 g of potassium carbonate and 0.14 ml of morpholine are added to a solution of 0.24 g of 2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 24 ml of acetonitrile, under an inert argon atmosphere at a temperature in the region of 20° C. The reaction medium is heated at 60° C. for 24 hours. After cooling, the reaction medium is concentrated under reduced pressure. The oil obtained is taken up with 10 ml of water and 10 ml of ethyl acetate. After separation by settling out, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified by flash-pack chromatography (silica, 30/70 by volume ethyl acetate/cyclohexane as eluents). The fractions containing the product are concentrated under reduced pressure. 0.24 g of 2-[1-methyl-5-methoxy-6-(2-morpholin-4-ylethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is thus obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]([NH:28][OH:29])=[NH:27])[N:8]=[CH:7]3.[O-2].[Mg+2].[CH:34]1([C:37](Cl)=O)[CH2:36][CH2:35]1>O1CCOCC1>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[O:24][CH3:25])[C:13](=[O:14])[C:4]=2[CH:3]=1)=[C:9]([C:26]1[N:27]=[C:37]([CH:34]2[CH2:36][CH2:35]2)[O:29][N:28]=1)[N:8]=[CH:7]3
Reactant: O=C(Cl)C1CC1
Reactant: COc1ccc(CN2Cc3c(C(=N)NO)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Product: COc1ccc(CN2Cc3c(-c4noc(C5CC5)n4)ncn3-c3ccc(Cl)cc3C2=O)c(OC)c1
Yield: 37.8 %

Procedure:
8-Chloro-5-(2,4-dimethoxy-benzyl)-N-hydroxy-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxamidine (1.9 g, 4.3 mmol), magnesiumoxide (0.156 g, 3.9 mmol), and cyclopropanecarbonyl chloride (0.5 mL, 5.3 mmol) were refluxed in dioxane overnight. Dioxane was evaporated and the residue dissolved in DMF (20 mL) and refluxed for 1 h. DMF was evaporated and the residue extracted with CH2Cl2 and water. The product crystallized upon concentration of the organic layer and dilution with ethyl acetate. One obtained a white solid (0.8 g, 39%). mp 198-205° C. m/z 492 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].[I-].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (3 g) obtained in Example 59 was suspended in dimethyl sulfoxide (120 ml), and potassium carbonate (2.6 g) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and i-propyl bromoacetate (1.4 ml) and potassium iodide (1 grain) were added in succession to the mixture. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (500 ml), and the crystals precipitated were recovered by filtration. The crude crystals were purified by silica gel flash column chromatography (eluent: methylene chloride containing 1% methanol) to obtain the title compound (2.0 g, 51%).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>>[CH2:16]([NH:18][C:19](=[O:20])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([S:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:17]
Reactant: CCC(C)Sc1ccc(OCCO)cc1
Reactant: CCN=C=O
Product: CCNC(=O)OCCOc1ccc(SC(C)CC)cc1

Procedure:
Following the procedure of Example 2, 2-[4-(1-methylpropylthio)phenoxy]ethanol (2.16 g, 10.0 mmol) is reacted with ethyl isocyanate (1.5 ml, 18.0 mmol) to give O-2-[4-(1-methylpropylthio)phenoxy]ethyl N-ethylcarbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].[H][H]>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C1OCCN1c1ccc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOC2=O)c(Cl)c1

Procedure:
A mixture of 24.1 g of 1B and 0.5 g of 10% palladium-on-charcoal catalyst in 150 ml of tetrahydrofuran was treated with hydrogen in a Parr shaker. The mixture then was filtered to give 3-(4-amino-2-chlorophenyl)-2-oxazolidinone (1C) in solution in the tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]1([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC(C)([O-])C.[Na+]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: N#Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Yield: 100.6 %

Procedure:
According to the general procedure A, 4-chlorobenzonitrile (76 mg, 0.55 mmol) reacted with diphenylamine (85 mg, 0.50 mmol) using 1 mol % of catalyst and sodium tert-butoxide (72 mg, 0.75 mmol) at 45° C. for 21 h to give the title compound (136 mg, 96%) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.43 (d, 2H, J=8.8 Hz, Ar—H), 7.35 (m, 4H), 7.17 (m, 6H), 6.97 (d, 2H, J=8.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.56, 145.93, 133.16, 129.75, 126.14, 125.11, 119.69, 119.67, 102.46. GC/MS(EI): m/z 270 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[C:24]([NH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[NH:10][C:9](=[O:11])[C@@H:8]([CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[NH:7][C:6]1=[O:23])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc(C[C@H]2NC(=O)[C@@H](CCCN)NC2=O)c2ccccc21
Solvent: c1ccncc1
Product: CC(=O)NCCC[C@H]1NC(=O)[C@@H](Cc2cn(C)c3ccccc23)NC1=O
Temperature: 100 °C
Yield: 88.2 %

Procedure:
A mixture of (3R,6R)-3-(3-aminopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (0.1 g) and acetic anhydride (0.08 g) in pyridine (1.0 ml) was heated at 100° C. for 1 hour. After the mixture was cooled to ambient temperature, the precipitated solid was collected by filtration and washed with pyridine (2 ml) and ethanol (5 ml) to give (3R,6R)-3-(3-acetamidopropyl)-6-(1-methylindol-3-ylmethyl)piperazine-2,5-dione (0.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.N1C=CC=CC=1.[Br:24]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][C:9]([Br:24])=[CH:8]2
Reactant: BrBr
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1c(F)cc2ncc(Br)cc2c1F
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To a mixture of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (35.3 g, 148.9 mmol) and pyridine (24 mL, 298 mmol) in 300 mL of carbon tetrachloride was added bromine (15.3 mL, 298 mmol) in a dropwise fashion. The mixture was heated to reflux for 2 hrs before being cooled to ambient temperature. The liquid in the flask was decanted and washed with NaHCO3 and water. The dark solid on the bottom of the flask was treated with NaHCO3 and dichloromethane. The combined organic layers were washed with water, dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography eluting with petroleum ether/ethyl acetate (40/1˜3/1) to return 31.5 g (67% yield) of the title compound as white crystalline solid. 1H NMR (DMSO-d6): δ 8.92 (d, 1H), 8.50 (d, 1H), 7.57˜7.61 (m, 1H), 3.91 (s, 2H), 3.75 (s, 3H).