Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH:28]([C:25]2[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[C:21]4[C:13]([C:11]5[CH:10]=[N:9][N:8]([CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH:12]=5)=[CH:14][NH:15][C:16]4=[N:17][CH:18]=3)=[CH:27][CH:26]=2)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccccn6)c5)c4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)nc1
Yield: 11.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (110 mg, 0.205 mmol) was deprotected in TFA/DCM (5/5 ml). This afforded 10 mg (11.1% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.73 (s, 1H), 8.68-8.67 (d, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.16-8.11 (t, 1H), 8.01 (s, 1H), 7.81 (s, 1H), 7.75-7.72 (d, 2H), 7.66-7.61 (t, 1H), 7.49-7.42 (m, 3H), 5.68 (s, 2H), 3.55-3.51 (d, 2H), 3.21-3.13 (m, 2H), 3.03-2.95 (m, 1H), 2.14-1.90 (m, 4H). MS: m/z=434.9 (M+1), HPLC: 92.12% in method A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].[C:13]1(C)C=CC=C[CH:14]=1>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:13]([CH3:14])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: CC(C)(O)c1cc(Br)ccc1N
Reactant: Cc1ccccc1
Product: CC1Nc2ccc(Br)cc2C(C)(C)O1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of 2-(2-amino-5-bromophenyl)propan-2-ol (27 g, 125 mmol) in anhydrous toluene was added at ambient temperature under a blanket of nitrogen acetylaldehyde (10.5 mL, 187 mmol). After 10 minutes, the mixture was passed through a pad of silica gel and filtrate was concentrated to yield 6-bromo-2,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazine as off-white solid (25 g, 78%): 1H-NMR (DMSO-d6) δ 7.22 (d, 1H, J=2.2 Hz), 7.08 (dd, 1H, J=8.6, 2.3 Hz), 6.51 (d, 1H, J=8.6 Hz), 6.36 (s, 1H), 4.72 (m, 1H), 1.45 (s, 3H), 1.40 (s, 3H), 1.25 (d, 3H, J=5.5 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:31])([F:30])[CH:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C1C=CC=CN=1)C.[Cl-]>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:29][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:19]([F:18])([F:30])[F:31])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC(O)C(F)(F)F
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Agent: CN(C)c1ccccn1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a solution of 4-benzyloxybenzoic acid chloride (1.23 g) in methylene chloride (10 ml) was slowly added under ice cooling a solution of optically active 1,1,1-trifluoro-2-decanol (0.96 g), dimethylaminopyridine (0.55 g) and triethylamine (0.48 g) in methylane chloride (20 ml). The mixture was left to stand until it reached room temperature and allowed to react overnight. The mixture was poured in ice water and extracted with methylene chloride. The extracted layer was washed with dilute aqueous hydrochloric acid solution, water, 1N aqueous sodium carbonate solution and water in this order, and was dried over anhydrous magnesium sulfate. After the solution was distilled to remove the solvent, the crude product thus obtained was purified by toluene-silica-gel column chromatography and recrystallized from ethanol to obtain the titled compound (1.84 g).
Reaction SMILES: [OH-].[Na+].[NH:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[NH2:4].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[CH3:16]>O>[C:18]1(/[C:15](=[N:4]/[NH:3][C:5]2[CH:10]=[CH:9][C:8]([S:11]([OH:14])(=[O:12])=[O:13])=[CH:7][CH:6]=2)/[CH3:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccccc1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C/C(=N\Nc1ccc(S(=O)(=O)O)cc1)c1ccccc1
Temperature: 100 °C
Yield: 23.4 %

Procedure:
Sodium hydroxide (400 mg, 10 mmol) in 10 mL of water was added to a solution of 4-hydrazino-benzenesulfonic acid (1.88 g, 10 mmol) in 20 mL of water. Acetophenone (1.32 g, 11 mmol) was then added, and the mixture was heated to 100° C. overnight. The resulting mixture was then cooled and washed with ether. The pH of the aqueous solution was then adjusted to 4 with conc. HCl. Water was removed under vacuum, and methanol was added. The solution was filtered and concentrated to give product (680 mg) as a yellow solid (MS: (M+H)+=291.15).
Reaction SMILES: [CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2].[OH-].[Na+].O.Cl>C(O)C>[CH:1]([NH:3][C:4]1[N:9]=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=[O:2]
Reactant: CCOC(=O)Cc1cccc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=CNc1cccc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a solution of ethyl 2-(6-formamidopyridin-2-yl)acetate (4.4 g.) in ethanol (44 ml.) was added 2 N sodium hydroxide solution [solvent:water (1 part)+ethanol (4 parts] (15.9 ml.) at 18° to 20° C. over 30 minutes, and then the solution was stirred at room temperature for one hour. After 1 N hydrochloric acid (31.7 ml.) was added to the solution, the solution was concentrated under reduced pressure. The residue was extracted with hot ethyl acetate (500 ml.) and the extract was concentrated under reduced pressure. The residue was washed with ethyl acetate to give 2-(6-formamidopyridin-2-yl)acetic acid (2.5 g.), mp 125° to 126° C. (dec.).
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:36]([F:37])=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][C:29]=2[F:38])[CH2:24][CH:23]1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:45].O1CCOCC1>>[ClH:45].[F:37][C:36]1[CH:35]=[C:31]([CH:30]=[C:29]([F:38])[C:28]=1[N:25]1[CH2:26][CH2:27][CH:22]([CH2:21][NH:8][C@@H:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:23]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:24]1)[C:32]([OH:34])=[O:33]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2c(F)cc(C(=O)O)cc2F)CC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2c(F)cc(C(=O)O)cc2F)CC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 230 mg of 4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid was added 1.5 mL of a 4 M hydrogen chloride/1,4-dioxane solution at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was solidified by isopropanol and diisopropyl ether, and then collected by filtration. The obtained solid was purified by silica gel column chromatography (methanol-chloroform), and a 4 M hydrogen chloride/1,4-dioxane solution was then added thereto. The mixture was concentrated under reduced pressure, and the obtained individual product was washed with isopropanol to obtain 140 mg of 3,5-difluoro-4-[4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]benzoic acid hydrochloride.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>O1CCOCC1.O>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[N:5]=1
Reactant: C1COCCN1
Reactant: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Solvent: O
Solvent: C1COCCO1
Product: FC(F)(F)Oc1ccc(Nc2nc(Cl)nc(N3CCOCC3)n2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a stirred solution of (4,6-dichloro-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIII) (5.0 g, 15.3 mmol) in dioxane (25 mL) was added i-Pr2(Et)N (2.37 g, 18.3 mmol) and morpholine (1.60 g, 18.3 mmol), and the resulting mixture heated at 85° C. for 12 hours. The reaction mixture was cooled to ambient temperature, diluted with water and stirred for 1 h. The white precipitate was filtered and dried under vacuum to give (4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-(4-trifluoromethoxyphenyl)amine (XIV) (5.63 g, 98% yield): GC/MS m/z 375 (M+); 1H NMR (CDCl3) δ 7.55 (d, J=3.7 Hz, 2H), 7.51 (bs, 1H), 7.25 (d, J=2.2 Hz, 2H), 3.74-3.87 (m, 8H).
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:18]1[N:19]=[C:20]2[C:25](=[C:26]3[C:31]=1[CH:30]=[CH:29][CH:28]=[CH:27]3)[CH:24]=[CH:23][CH:22]=[CH:21]2.CC(C)([O-])C.[Na+]>CN1C(=O)CCC1>[C:4]([O:3][C:1]([N:8]1[CH2:15][C@H:14]([O:16][C:18]2[N:19]=[C:20]3[C:25](=[C:26]4[C:31]=2[CH:30]=[CH:29][CH:28]=[CH:27]4)[CH:24]=[CH:23][CH:22]=[CH:21]3)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: Clc1nc2ccccc2c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2nc3ccccc3c3ccccc23)C[C@H]1C(=O)O

Procedure:
(2S,4R)—N-Boc-4-hydroxyproline can be reacted with 6-chlorophenanthridine in NMP, in the presence of sodium t-butoxide, to produce (2S,4R)-1-(tert-butoxycarbonyl)-4-(phenanthridin-6-yloxy)pyrrolidine-2-carboxylic acid. Methyl tertiary butyl ether (MTBE) and water can then be added. The aqueous layer is separated, washed, and then HCl is added, followed by extraction with MTBE. The extracted product can be mixed with diisopropylethylamine (DIPEA) and HATU (CAS #148893-10-1), and then reacted with (1R,2S)-ethyl-1-amino-2-vinylcyclopropanecarboxylate tosylate salt in dimethylformide (DMF) and toluene. The reaction produces (2S,4R)-tert-butyl 2-((1R,2S)-1-(ethoxycarbonyl)-2-vinylcyclopropylcarbamoyl)-4-(phenanthridin-6-yloxy)pyrrolidine-1-carboxylate, which can be extracted with MTBE and washed with HCl, further extracted, washed, dried, and dissolved in 2-propanol.
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:17](=[O:19])[CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:41][C:42]([CH3:44])=[O:43].Cl>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:17](=[O:19])[CH2:18][C:42]([OH:43])([CH3:44])[CH3:41])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(O)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CCO2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a cold (-78° C.) solution of 1-(8-tert-butyl-4,4-dimethyl-2,3-dihydrobenzopyran-6-yl)1-ethanone (0.35 g, 1.36 mmol) in CH2Cl2 (3.0 mL) is added TMSOTf (0.32 mL, 1.63 mmol, 1.2 equiv) and (i-Pr)2NEt (0.28 mL, 1.63 mmol, 1.2 equiv) dropwise. The resulting red mixture is stirred at -78° C. for 30 min, and then allowed to warm to room temperature over 1 h. The resulting pale red solution is recooled to -78° C. and acetone (0.12 mL, 1.63 mmol, 1.2 equiv) and TiCl4 (0.15 mL, 1.36 mmol, 1.0 equiv) are added dropwise. The resulting deep red solution is allowed to warm to room temperature over 3.5 h and 0.5N HCl is added and the mixture is stirred for 30 min. The reaction mixture is diluted with hexanes and washed with water and brine. The aqueous layers are extracted with hexanes; the combined organic layers are dried (MgSO4), filtered and concentrated. The residue is purified by flash column chromatography on silica (hexanes, hexanes/EtOAc; 10/1) to give the title compound (0.30 g, 70%) as a pale yellow solid which is recrystallized using pentane.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7](=[CH:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:15])[CH2:13][CH3:14])[CH3:8]>C1(C)C=CC=CC=1>[CH3:6][C:7]1([CH3:8])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:9]1
Reactant: CCC(=O)C(CC=C(C)C)c1ccccc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 0 °C
Yield: 69.4 %

Procedure:
36 g of 85% phosphoric acid, 36 g of polyphosphoric acid, 175 ml of toluene and 72 g of 2-methyl-5-phenyl-oct-2-en-6-one are heated together at 100° C. for 2 hours under a nitrogen atmosphere and while stirring. The mixture is left to cool, 250 ml of ice/water are added, the aqueous phase is separated and the organic phase is subjected to a steam distillation. The distillate is separated from the water and distilled in vacuo. There are obtained 50 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 70%. Odour: see (3).
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:4]=[C:5]1[CH2:8][CH:7]([C:9]([O:11][CH2:2][CH3:3])=[O:10])[CH2:6]1
Reactant: CCI
Reactant: C=C1CC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1CC(C(=O)OCC)C1
Reaction time: 16 h

Procedure:
Iodoethane (7.5 mL, 93.0 mol) was added at rt to a mixture of 3-methylenecyclobutanecarboxylic acid (10.0 g, 80.0 mmol) and cesium carbonate (56.0 g, 170.0 mmol) in anhydrous N,N-dimethylformamide (500.00 mL) under an atmosphere of nitrogen. The reaction was stirred for 16 hr then partitioned between diethyl ether (1 L) and brine (1 L). The aqueous layer was extracted with diethyl ether (3×500 mL) and the combined organic phases washed with water (2×1L), dried over sodium sulfate, filtered and concentrated in vacuo to yield desired product 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (t, 3H), 2.71-3.27 (m, 5H), 4.15 (q, J=7.07 Hz, 2H) and 4.53-4.96 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:1]([NH:4][C:5]1[CH:27]=[CH:26][C:8]([O:9][C:10]2[C:18]([S:19](=[O:21])(=[O:22])[NH:20][C:28](=[O:30])[CH3:29])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[N+:23]([O-:25])=[O:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Product: CC(=O)Nc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1

Procedure:
The starting material is prepared as follows: The mixture of 12.5 g of 4-(4-acetamidophenoxy)-3-nitro-5-sulfamoylbenzoic acid and 125 ml of acetic anhydride is refluxed for 2 hours under nitrogen and evaporated under reduced pressure. The residue is taken up in 125 ml of 2N aqueous sodium hydroxide and 25 ml of water, the solution washed with diethyl ether, filtered and the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from 33 and 50% aqueous ethanol, to yield the 4-(4-acetamidophenoxy)-3-nitro-5-acetylsulfamoylbenzoic acid decomposing at about 240°. The solution of 10.5 g thereof in 100 ml of water and 22 ml of 2N aqueous sodium hydroxide is hydrogenated over 2.5 g of 10% palladium on charcoal until the theoretical amount of hydrogen has been absorbed. The mixture is filtered, the filtrate acidified with concentrated hydrochloric acid and the precipitate recrystallized from aqeuous ethanol, to yield the 4-(4-acetamidophenoxy)-3-amino-5 -acetylsulfamoylbenzoic acid melting at 305°-306° with decomposition.
Reaction SMILES: [CH:1]([NH:4][CH3:5])([CH3:3])[CH3:2].N[CH2:7][C@@H:8]1CC[CH2:10][N:9]1CC>>[CH3:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:7][CH2:8][NH:9][CH3:10]
Reactant: CCN1CCC[C@H]1CN
Reactant: CNC(C)C
Product: CNCCN(C)C(C)C

Procedure:
By using N-isopropylmethylamine (844.7 mg) as a starting material, the title compound (58 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [N:1]1[N:10]2[C:4]([CH2:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1>ClCCl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:6]2[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9][N:10]3[N:1]=[CH:2][CH:3]=[C:4]3[CH2:5]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1nccc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1Cc2ccnn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
To a solution of 10 mmol of 5,10-dihydro-4H-pyrazolo [5,1-c][1,4]benzodiazepine and 1.5 g of triethylamine in 20 ml of dichloromethane is added a solution of 2.11 g of 6-chloropyridine-3-carbonyl chloride in 5 ml of dichloromethane. The mixture is stirred for 3 hours at room temperature diluted with 20 ml of dichloromethane and washed with 30 ml of 1N NaOH. The organic layer is washed twice with 20 ml of 1N NaOH, dried (Na2SO4) and the solvent removed. The residue is triturated with ether to give 3 g of solid.
Reaction SMILES: [CH:1]1([C:7]2[S:18][C:10]3[N:11]=[C:12]([CH3:17])[N:13]=[C:14]([CH2:15]O)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:20].S(Cl)(Cl)=O>CN(C=O)C>[Cl:20][CH2:15][C:14]1[C:9]2[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[S:18][C:10]=2[N:11]=[C:12]([CH3:17])[N:13]=1
Reactant: ClCCl
Reactant: Cc1nc(CO)c2cc(C3CCCCC3)sc2n1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Cc1nc(CCl)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methanol (1.28 g) and DCM (20 mL) were added thionyl chloride (1 mL) and DMF (50 μL), followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and dried. To the residue was added EtOAc. The organic layer was washed sequentially with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to obtain 4-(chloromethyl)-6-cyclohexyl-2-methylthieno[2,3-d]pyrimidine (663 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>C(Cl)Cl>[C:13]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])(=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: C=C(C)C(=O)Cl
Reactant: CS(=O)(=O)Nc1ccccc1O
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccccc1NS(C)(=O)=O
Reaction time: 2 h

Procedure:
To a solution of 10.12 g (0.10 mol) of triethylamie, 18.72 g (0.10 mol) of N-(2-hydroxyphenyl)methanesulfonamide and 300 ml of methylene chloride cooled to 0° C. was added a solution of 10.45 g (0.10 mol) of methacryloyl chloride in 100 ml of methylene chloride over a 15-minute period. After stirring 2 hours at reduced temperature, the solution was washed three times with water, dried over magnesium sulfate and concentrated to an oil. On cooling and scratching, the oil crystallized. Recrystallization from 1:1 benzene:hexane gave a white solid which was collected, washed with 1:1 benzene:hexane, and dried at room temperature in vacuo. The yield of N-(2-methacryloyloxyphenyl)methanesulfonamide was 10.4 g (40.7 percent); m.p.=88° to 90° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (60 mg, 0.16 mmol), 5-aminovaleric acid (909 mg, 7.8 mmol), and NaOMe solution (12 mL, 6.2 mmol) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 24 mg of the title compound as a pale yellow solid. MS: (+) m/z 472.34 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][C@@H:13]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29]Cl)[C:24]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:18]([O:17][C:16](=[O:21])[NH:15][C@@H:13]1[CH2:12][C:7]2[N:8]([CH2:29][C:25]3[C:24]([O:31][CH3:32])=[C:23]([Cl:22])[CH:28]=[CH:27][N:26]=3)[C:9]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[CH2:14]1)([CH3:19])[CH3:20]
Reactant: COc1c(Cl)ccnc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)ccnc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of (S)-isopropyl 7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamate (680 mg, 2.40 mmol) and 4-chloro-2-(chloromethyl)-3-methoxypyridine (553 mg, 2.88 mmol) in dimethylformamide (5 mL) is added cesium carbonate (1.17 g, 3.60 mmol) and the mixture stirred at room temperature overnight. The reaction mixture is diluted with water and the beige solid is filtered. It is rinsed with water and then dried in a vacuum oven at 50° C. for 48 h to obtain a gray solid (970 mg, 92%). LC-ES/MS m/z 439.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[N:5]=[C:6]2[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]2[CH:16]=1.Cl>CO>[Br:3][C:4]1[N:5]=[C:6]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]2[CH:16]=1
Reactant: COC(=O)C1CCn2cc(Br)nc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCn2cc(Br)nc2C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A 1 N sodium hydroxide aqueous solution (23 ml) was added to a methanol (23 ml) solution of the methyl 2-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-7-carboxylate (6.3 g) obtained in (Example 2.7) <Step 2>, and the obtained mixture was then stirred at 40° C. for 1 hour. Thereafter, 1 N hydrochloric acid (23 ml) was added to the reaction solution, and the generated solid was then collected by filtration, followed by washing with water (20 ml). The obtained solid was subjected to azeotropy with toluene, and was then dried under reduced pressure, so as to obtain the title compound (3.5 g) in the form of a beige solid.