Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)nc3)c2)=C(C)C1=O
Yield: 84.4 %

Procedure:
N-(6-Methoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.065 g, 0.135 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.114 mmol, 84%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([NH2:19])[CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:21]1[C:22](=[O:40])[N:23]([C:28]2[CH:29]=[C:30]([CH:35]=[C:36]([F:39])[C:37]=2[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([NH:19][C:21]2[C:22](=[O:40])[N:23]([C:28]3[CH:29]=[C:30]([CH:35]=[C:36]([F:39])[C:37]=3[CH3:38])[C:31]([O:33][CH3:34])=[O:32])[CH:24]=[C:25]([Br:27])[N:26]=2)[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(Br)c2=O)c1
Reactant: NC1(c2cc(F)ccc2OCc2ccccc2)CC1
Product: COC(=O)c1cc(F)c(C)c(-n2cc(Br)nc(NC3(c4cc(F)ccc4OCc4ccccc4)CC3)c2=O)c1

Procedure:
The subtitle compound was prepared from 1-(2-(benzyloxy)-5-fluorophenyl)cyclopropanamine (Example 278a) and methyl 3-(3,5-dibromo-2-oxopyrazin-1(2H)-yl)-5-fluoro-4-methylbenzoate (Example 252g) using a similar method to that described for Example 268d.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.[OH-].[NH4+:17].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [NH4+]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (1 g, 3.3 mmol, 90% pure) stirred at 0° C. in THF (15 ml) and DCM (5 ml) was treated with aqueous ammonium hydroxide (28%) by dropwise addition over 15 min. After stirring at 0° C. for 210 min, the mixture was acidified (pH=1) by addition of 1 N HCl (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to afford the title compound (503 mg, 60%) as a white solid which was carried forward without purification. LCMS (M−H)−=253.
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([C:17]([O:19]CC)=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4].[OH-].[Li+].Cl>O1CCCC1.O>[OH:1][C@H:2]([C:22]1[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=1)[C@@H:3]([NH:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[C:12]([C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[CH3:4]
Reactant: CCOC(=O)c1cccc2c(CCN[C@@H](C)[C@H](O)c3ccc(O)cc3)c[nH]c12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NCCc1c[nH]c2c(C(=O)O)cccc12)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of ethyl 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxy-phenyl)-1-(methyl) ethylamino]ethyl}-1H-indole-7-carboxylate (115 mg, 0.301 mmol) in tetrahydrofuran (10 mL) and water (5 mL) is added lithium hydroxide (36 mg, 1.51 mmol), and the mixture is stirred at room temperature for 15 hours. The pH value of the reaction solution is adjusted to pH 7 with 1N aqueous hydrochloric acid solution, and the solvent is distilled off. The residue is isolated by reversed phase column (octadecylsilyl, water→water-methanol=10:1→9:1→6:1) to give 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-(methyl)ethyl-amino]ethyl}-1H-indole-7-carboxylic acid (69.3 mg, 0.195 mmol, 65%).
Reaction SMILES: CO[C:3]1[C:4](=[O:12])[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[NH3:13]>CO>[NH2:13][C:3]1[C:4](=[O:12])[CH:5]=[CH:6][CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cccc(=O)c(OC)c1
Reactant: N
Solvent: CO
Product: COc1cccc(=O)c(N)c1
Temperature: 80 °C

Procedure:
A solution of 2,4-dimethoxy-2,4,6-cycloheptatrien-1-one [described above in(b),2.4 g] in methanol (70 ml) is cooled to -25° C. and saturated with ammonia gas. The solution is heated in a pressure bottle at 80° C. for 4 hours and cooled to -70° C. The pressure bottle is opened and the solvent is evaporated to give 2-amino-4-methoxy-2,4,6-cycloheptatrien-1-one.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([O:20]C)=O)[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28].[NH3:29]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[N:8]2[CH2:11][C:12]2[N:17]=[C:16]([C:18]([NH2:29])=[O:20])[CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COC(=O)c1cccc(Cn2c(-c3ccsc3)cc3cc(OC)c(F)cc32)n1
Reactant: N
Solvent: C1CCOC1
Product: COc1cc2cc(-c3ccsc3)n(Cc3cccc(C(N)=O)n3)c2cc1F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of methyl 6-[6-fluoro-5-methoxy-2-(thiophen-3-yl)indol-1-ylmethyl]pyridine-2-carboxylate (168 mg) and ammonia (about 7 mol/L methanol solution, 4.2 mL) was stirred at room temperature for 6 hours. The reaction mixture was diluted with tetrahydrofuran (4.2 mL), followed by stirring for 66 more hours. The reaction mixture was then concentrated under reduced pressure to obtain the title compound (166 mg). 1H-NMR (CDCl3) δ ppm: 3.94 (3H, s), 5.45 (2H, s), 5.51 (1H, br s), 6.61 (1H, d, J=0.4 Hz), 6.90-7.00 (2H, m). 7.15 (1H, dd, J=1.3, 5.0 Hz), 7.18 (1H, d, J=8.3 Hz), 7.24 (1H, dd, J=1.3, 2.9 Hz), 7.39 (1H, dd, J=2.9, 5.0 Hz), 7.65 (1H, br s), 7.75 (1H, t. J=7.8 Hz), 8.09 (1H, d, J=7.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[NH2:1][C:2]1[CH:13]=[CH:12][C:11]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])=[CH:10][C:3]=1[C:4]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:5]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)ccc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)c(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-N-methoxy-N-methylbenzamide (5.0 g, 16 mmol) in tetrahydrofuran (100 ml) was added dropwise 2.0 M solution (20 ml) of phenylmagnesium bromide in tetrahydrofuran at −78° C. The temperature of the reaction mixture was raised, and the mixture was stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column to give (2-amino-5-{[tert-butyl(dimethyl)silyl]oxy}-phenyl)(phenyl)methanone (3.4 g, yield 65%) as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33]Cl)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:35][CH3:36])=[C:28]([O:31][CH2:32][CH2:33][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCl
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCN1CCOCC1
Yield: 13.2 %

Procedure:
The urea intermediate from Example 65A (200 mg, 0.38 mmol) and morpholine (0.099 mL, 1.14 mmol) in the manner described in Example 57B to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-ylthio)phenyl)urea as a colorless solid (29 mg, 13%). 1H NMR (300 MHz, DMSO-d6) δ 9.58 (brs, 1H), 9.02 (brs, 1H), 8.69 (s, 1H), 7.84 (s, 1H), 7.26-7.49 (m, 5H), 6.48 (s, 1H), 4.30-4.32 (m, 2H), 3.99 (s, 3H), 3.60-3.62 (m, 4H), 2.80 (m, 2H), 2.49-2.52 (m, 4H), 1.27 (s, 9H); LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][CH:21]=[C:20]([C:23](O)=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([O:30][C:31](=[O:40])[NH:32][C@H:33]1[CH2:34][CH2:35][C@@H:36]([NH:39][C:23]([C:20]2[C:16]3[N:17]=[CH:18][N:19]=[C:14]([C:7]4[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:15]=3[NH:22][CH:21]=2)=[O:24])[CH2:37][CH2:38]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)O)c[nH]c23)c1
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c[nH]c23)c1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A75) and cis-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N12CCN(CC1)CC2.Cl[C:25]1[CH:34]=[C:33]2[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]2[CH:35]2[CH2:37][CH2:36]2)=[CH:27][C:26]=1[F:42]>CS(C)=O>[CH2:1]([N:10]1[CH2:15][CH2:14][N:13]([C:25]2[CH:34]=[C:33]3[C:28]([C:29](=[O:41])[C:30]([C:38]([OH:40])=[O:39])=[CH:31][N:32]3[CH:35]3[CH2:37][CH2:36]3)=[CH:27][C:26]=2[F:42])[CH2:12][CH2:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C(=Cc1ccccc1)CN1CCNCC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Agent: C1CN2CCN1CC2
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(CC=Cc4ccccc4)CC3)c(F)cc2c1=O
Yield: 38 %

Procedure:
2.1 g (10 mmol) of 1-cinnamyl-piperazine and 2.2 g of 1,4-diazabicyclo[2.2.2]octane are added to 2.8 g (10 mmol) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 35 ml of dimethyl sulphoxide, and the mixture is heated at 140° for 5 hours. It is concentrated under a high vacuum, the residue is stirred with 50 ml of water and the pH is brought to 6 with 2N hydrochloric acid. The precipitate which has separated out is filtered off with suction, washed with water and boiled up with methanol. 1.7 g of 7-(4-cinnamyl-1-piperazinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 230°-234° (with decomposition) are obtained.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:33][CH:32]([OH:34])[CH2:31][CH:30]1[CH:35]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[O:36][CH:37]([C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)[C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:28]>>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH:37]([C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[O:36][CH:35]([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:30]2[CH2:31][CH:32]([OH:34])[CH2:33][N:29]2[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:39][CH:40]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: COc1ccc(C(OC(c2ccccc2)C2CC(O)CN2C(=O)CCCCCN)c2ccc(OC)cc2)cc1
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCCCC(=O)N1CC(O)CC1C(OC(c1ccc(OC)cc1)c1ccc(OC)cc1)c1ccccc1
Yield: 90 %

Procedure:
Using the above described procedure, stearic acid 101e (2.84 g, 10 mmol) was coupled with the amine 100 and after work-up and column purification the pure amide was isolated as a foam (7.17 g, 90%). 1H NMR (DMSO-d6, 400 MHz) δ=7.76-7.65 (m, 1H), 7.34-7.10 (m, 9H), 6.90-6.79 (m, 4H), 4.96 (d, J=3.90 Hz, 0.7H), 4.88 (d, J=3.90 Hz, 0.3H), 4.40-4.05 (m, 2H), 3.71 (s, 6H), 3.59-3.42 (m, 1H), 3.34-3.13 (m, 2H), 3.10-2.87 (m, 3H), 2.20-1.80 (m, 6H), 1.50-1.08 (m, 36H), 0.83 (t, J=6.1 Hz, 3H). 13C NMR (DMSO-d6, 400 MHz) δ=171.83, 170.92, 170.82, 162.29, 158.10, 157.97, 145.08, 144.74, 135.86, 135.42, 135.47, 129.59, 129.54, 127.84, 127.76, 127.57, 126.56, 113.18, 113.09, 85.78, 85.10, 68.57, 67.44, 65.19, 63.32, 54.97, 40.12, 38.21, 36.29, 35.77, 35.42, 34.16, 31.30, 30.75, 29.04, 28.78, 28.72, 28.65, 26.18, 25.33, 24.14, 22.10, 13.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[C:21]4[C:17]([C:18]5[CH2:27][CH2:26][NH:25][CH2:24][C:19]=5[N:20]4[CH3:23])=[CH:16][CH:15]=3)[C:10](=[O:28])[CH:9]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.C=O.[C:33](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:22]=[C:21]4[C:17]([C:18]5[CH2:27][CH2:26][N:25]([CH3:33])[CH2:24][C:19]=5[N:20]4[CH3:23])=[CH:16][CH:15]=3)[C:10](=[O:28])[CH:9]=2)=[C:4]([O:29][CH3:30])[CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CNCC4)c(=O)c1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CN(C)CC4)c(=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 88.7 %

Procedure:
4-(4-Chloro-2-methoxyphenyl)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one (83 mg, 0.20 mmol) and 37% aqueous formaldehyde (24 μL, 0.30 mmol) were dissolved in 1:1 MeOH/CH2Cl2 (1.4 mL) and stirred at room temperature for 45 min. Sodium triacetoxyborohydride (84 mg, 0.40 mmol) was added, and the reaction was stirred at ambient temperature for 30 min. The reaction mixture was neutralized with saturated NaHCO3 solution and extracted with CH2Cl2 (3×25 mL). The combined organics were washed with brine (25 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography (12 g ISCO (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 95:5 to 10:90 over 20 column volumes, hold for 10 column volumes) provided the title compound (77 mg, 89%) as a yellow film: 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J=8.0 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.35-7.34 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.07-7.03 (m, 2H), 7.00-6.99 (m, 1H), 6.81-6.80 (m, 1H), 6.43-6.42 (m, 1H), 3.87 (s, 3H), 3.66-3.65 (m, 2H), 3.48 (s, 3H), 2.87-2.86 (m, 2H), 2.81-2.80 (m, 2H), 2.58 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][S:10]([OH:13])(=O)=[O:11]>>[CH3:1][C:2]1[C:7]([S:10]([Cl:9])(=[O:13])=[O:11])=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:13])=[O:11]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc(C)cc1
Product: Cc1cc(S(=O)(=O)Cl)c(C)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
1,4-Dimethylbenzene (10.6 g, 0.1 mol) was added dropwise to chlorosulfonic acid (60 g, 0.51 mol ) at room temperature with stirring. After the addition was complete, the reaction mixture was heated to ˜100C for 1 hr, cooled to room temperature and poured onto ice-water-1,2-dichloromethane mixture with stirring. The organic layer was separated, washed with water (2×), dried over anhydrous MgSO4 and the solvent evaporated to give 2,5-dimethyl-1,3-benzenedisulfonyl chloride, 26 g (86%) as a viscous liquid that solidified on standing, mp 24-27° C. Reported 25-27C. (C. M. Suter, Organic Chemistry of Sulfur Compounds, Chapter 3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2Cl.[CH3:13][O-:14].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:14][CH3:13]
Reactant: C[O-]
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: [Na+]
Solvent: CO
Product: COc1ccnc2ccc(Br)cc12
Temperature: 120 °C
Yield: 90.7 %

Procedure:
To a solution of 6-bromo-4-chloro-quinoline (12.12 g, 50 mmol) in methanol (200 mL) was added sodium methoxide (13.50 g, 250 mmol) at room temperature. Then, the reaction mixture was heated to 120° C. for 15 h in a sealed reaction flask. After cooling to room temperature, the methanol was removed under the vacuum and the residue was diluted with water. Then, the solids were collected by filtration and washed with water. After drying in air, 10.8 g (90.8% yield) of 6-bromo-4-methoxy-quinoline was isolated as a white solid which can be crystallized from acetonitrile: EI-HRMS m/e calcd for C10H8BrNO (M+) 236.9789, found 236.9784.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([N:39]=[C:40]=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]>C1COCC1>[Cl:31][C:32]1[CH:33]=[C:34]([NH:39][C:40]([NH:2][CH2:3][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[C:6](=[O:23])[N:7]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:8]([CH3:14])=[N:9]3)=[O:41])[CH:35]=[CH:36][C:37]=1[CH3:38]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)NCc2cccc3nc(C)n(C4CCC(=O)NC4=O)c(=O)c23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.51 g, 1.5 mmol) and triethylamine (0.30 mL, 2.1 mmol) in THF (15 mL) at 5˜10° C., was added 3-chloro-4-methyl phenyl isocyanate (0.27 mL, 1.9 mmol). Then the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(3-chloro-4-methyl-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-urea as an off-white solid (520 mg, 73% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.58 min (99.1%); mp, 250-252° C.; 1HNMR (DMSO-d6)2.17-2.22 (m, 4H, CHH, ArCH3), 2.59-2.93 (m, 6H, CHCH2, CH3), 4.71 (d, J=6 Hz, 2H, CH2NH), 5.27 (dd, J=6, 11 Hz, 1H, CH), 6.64 (t, J=6 Hz, 1H, CH2NH), 7.06-7.78 (m, 6H, Ar), 8.88 (s, 1H, NH), 11.04 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.69, 20.70, 23.31, 30.62, 42.31, 56.52, 116.24, 117.46, 117.81, 125.78, 126.28, 127.24, 130.98, 132.96, 133.99, 139.66, 141.30, 148.49, 154.76, 154.88, 161.02, 169.49, 172.65. LCMS MH=468, 470; Anal Calcd For C23H22N5O4Cl+0.2H2O: C, 58.59; H, 4.79; N, 14.85; Cl, 7.52. Found: C, 58.42; H, 4.55; N, 14.57; Cl, 7.83.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:11]([C:13]2[CH:14]=[C:15]([Cl:22])[CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][CH:42]1[CH2:44][CH2:43]1>C(#N)C>[C:1]([C:5]1[CH:33]=[CH:32][C:8]([CH2:9][N:10]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:41][CH:42]3[CH2:44][CH2:43]3)[CH:26]=2)[C:11]([C:13]2[CH:14]=[C:15]([Cl:22])[CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(O)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OCC3CC3)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
122 mg of 5-chloro-1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(3-hydroxy-phenyl)-ethyl]-amide (0.25 mmol) and 52 mg potassium carbonate (0.375 mmol) were suspended in 5 ml acetonitrile and treated with 0.027 ml bromomethyl-cyclopropane (0.275 mmol). The mixture was stirred for 24 h in an oil-bath heated to 80° C. After cooling down, the mixture was poured on water/EtOAc, and after separation the aqueous phase was extracted with EtOAc. The combined organic phases were then washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silicagel, heptane/EtOAc 9:1) leading to 66 mg of 5-chloro-1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-[2-(3-cyclopropylmethoxy-phenyl)-ethyl]-amide as a colorless viscous oil. MS (ISP) 515.5 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]2[CH2:11][C:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=3)([CH2:7]2)[C:5]1=[O:21])([CH3:3])[CH3:2].C(OCC)(=O)C.CCCCCC>C(OCC)(=O)C.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]23[CH2:7][CH:8]([CH2:11]2)[C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[O:21])=[CH:17][CH:16]=1
Reactant: CC(C)N1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C2CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 1a, 2.3 g of 3-isopropyl-1-(4-nitrophenyl)-3-azabicyclo[-3.1.1]-heptane-2,4-dione are dissolved in 50 ml of ethyl acetate, hydrogenated in the presence of 0.25 g of 5% palladium-on-carbon and worked up. Melting point 191°-201° (from ethyl acetate/hexane).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]([O-])(=O)[CH3:14].[K+].O>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([NH:3][C:4]2[CH:9]=[CH:8][C:13]([CH3:14])=[CH:6][CH:5]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(Nc2nc(Cl)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 144.8 %

Procedure:
A mixture of 2,4-dichloroquinazoline (5.8 g, 0.029 mol), p-tolyamine (3.5 g, 0.032 mol), and potassium acetate (3.72 g, 0.038 mol) in THF/water (66 ml/30 ml) was stirred at room temperature for 16 h. Water (66 ml) was added to the mixture, and a precipitate was formed. The precipitate was washed with water, filtered, and dried under high vacuum to afford (2-chloro-quinazolin-4-yl)-p-tolyl-amine (5.65 g, 0.021 mol, 70%). m.p.: 198-199° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 7.21 (d, J=7.8 Hz, 2H), 7.50 (d, J=7.2 Hz, 3H), 7.83 (t, J=8.5 Hz, 2H), 8.50 (t, J=8.0 Hz, 1H).