Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH:3]([C:7](Cl)=[O:8])[C:4](Cl)=[O:5])C.[NH2:10][C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1C(OC)=O.C(N(CC)CC)C>ClCCl>[CH3:16][C:15]1[C:11]2[NH:10][C:7](=[O:8])[CH2:3][C:4](=[O:5])[C:12]=2[S:13][CH:14]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: CCC(C(=O)Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1csc2c1NC(=O)CC2=O
Reaction time: 0.5 h
Yield: 48 %

Procedure:
Ethyl malonyl chloride (4.29 g, 28 mmol) was added to a solution of methyl 3-amino-4-methylthiophene-2-carboxylate (4 g, 23 mmol) and triethylamine (4.2 mL, 30 mmol) in dichloromethane (50 mL) and the resulting mixture was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. To the oily residue was added a freshly prepared ethanolic solution of sodium ethoxyde (0.5 g in 25 mL of EtOH) and the reaction mixture was heated at reflux overnight. The solvent was evaporated under reduced pressure and water (50 mL) was added to the residue, followed by sodium hydroxide (1.5 g). The resulting mixture was heated at reflux overnight, then was cooled and acidified by addition of an aqueous solution of hydrochloric acid (6 M). The solid formed was collected by filtration, washed with water and dried under reduced pressure to afford 2.0 g of 3-methyl-4H-thieno[3,2-b]pyridine-5,7-dione.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.[CH2:34]([N:38]1[C:42]2=[C:43](Cl)[N:44]=[N:45][CH:46]=[C:41]2[C:40]([CH3:48])=[C:39]1[CH3:49])[CH:35]=[CH:36][CH3:37]>O1CCCC1>[CH2:34]([N:38]1[C:42]2=[C:43]([O:13][CH2:12][C:11]3[CH:14]=[CH:15][C:8]([F:7])=[CH:9][CH:10]=3)[N:44]=[N:45][CH:46]=[C:41]2[C:40]([CH3:48])=[C:39]1[CH3:49])[CH:35]=[CH:36][CH3:37]
Reactant: OCc1ccc(F)cc1
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=CCn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.1 %

Procedure:
0.85 g (0.0076 mole) of potassium tert-butoxide was added to a solution of 0.48 g-(0.0038 mole) of 4-fluorobenzyl alcohol and 0.08 g (0.0003 mole) of 18-crown-6 in 30 ml of tetrahydrofuran and the mixture was stirred at room temperature for 10 minutes. 0.45 g (0.0019 mole) of 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine was then added to the mixture and stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 4:1 mixture of toluene and ethyl acetate as an eluent. An oily material thus obtained was crystallized in hexane to give 0.39 g of 1-(2-butenyl)-7-(4-fluorobenzyloxy)-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=13/87) as a pale brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([OH:23])=O)(=[O:19])=[O:18])=[CH:7]1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.ClC(Cl)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[O:23])(=[O:18])=[O:19])=[CH:7]1
Reactant: Nc1ccccn1
Reactant: O=C(O)CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: O=C(CS(=O)(=O)c1cn(Cc2cccc(Br)c2)c2cc(F)cc(F)c12)Nc1ccccn1

Procedure:
2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)acetic acid (30 mg, 0.68 mmol) from Step D, 2-amino-pyridine (13 mg, 0.135 mmol), PyClu (45 mg, 0.135 mmol), and DIEA (29 μL, 0.169 mmol) were added to dichloroethane (3 mL) and microwave irradiated at 110° C. for 30 minutes. The solvent was removed in vacuo and the remaining residue was purified on a Gilson reverse phase HPLC system with a Phenomenex, Luna 50×21.2 mm, 5 uM C18 column (5%-95% water:acetonitrile over 6 min) to yield the desired product. LCMS>99% 215 nm, RT=0.78 min, m/z=520 ([79Br]m+1), 522 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 10.89 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=4.0 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.66 (s, 1H) 7.59 (d, J=8.4 Hz, 2H), 7.38-7.34 (m, 2H), 5.61 (s, 2H), 4.64 (s, 2H), 2.16 (s, 3H). HRMS found 520.0142; calculated for C22H17N3O3SBrF2, 520.0142.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17]([O:19]C(C)(C)C)=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:24][NH:25][C:26]([CH2:31][S:32][CH3:33])([CH2:29][OH:30])[CH2:27][OH:28])=[CH:11]1)C1C=CC=CC=1.Cl>CO>[OH:28][CH2:27][C:26]([NH:25][CH2:24][C:12]1[C:13]2[N:14]=[CH:15][NH:16][C:17](=[O:19])[C:18]=2[NH:10][CH:11]=1)([CH2:31][S:32][CH3:33])[CH2:29][OH:30]
Reactant: CSCC(CO)(CO)NCc1cn(COCc2ccccc2)c2c(OC(C)(C)C)ncnc12
Agent: Cl
Solvent: CO
Product: CSCC(CO)(CO)NCc1c[nH]c2c(=O)[nH]cnc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
A solution of 2-((5-(benzyloxymethyl)-4-tert-butoxy-5H-pyrrolo[3,2-d]pyrimidin-7-yl)methylamino)-2-(methylthiomethyl)propane-1,3-diol (200 mg, 0.421 mmol) in methanol (1 mL) was added to a solution of concentrated hydrochloric acid (2 mL) in methanol (5 mL) and the reaction was heated at 100° C. for 3 h. The contents of the flask were concentrated under reduced pressure, redissolved in methanol (5 mL) and Amberlyst 21 resin (˜1 g) was added. After stirring for 1 h at ambient temperature the resin was removed by filtration, the filtrate concentrated under reduced pressure and then redissolved in 7 M methanolic ammonia (5 mL) and stirred for 30 min. TLC(CH2Cl2:7 M methanolic ammonia, 4:1, visualised with Erlichs) indicated the reaction was complete so the solution was concentrated under reduced pressure and the residue dry-loaded on to a silica column. Purification by flash column chromatography (CH2Cl2:7 M methanolic ammonia, 3:1, visualised with Erlichs) gave 7-((1,3-dihydroxy-2-(methylthiomethyl)propan-2-ylamino)methyl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (62.0 mg, 49%) as a white foam. 1H NMR (D2O, drop of DCl) δ 8.91 (1H), 7.79 (1H), 4.43 (2H), 3.84 (d, J=12.7 Hz, 2H), 3.79 (d, J=12.7 Hz, 2H), 2.92 (s, 2H), 2.13 (s, 3H). 13C NMR (D2O, drop of DCl): δ 152.8, 145.2, 133.3, 131.8, 118.5, 103.5, 67.4, 59.2, 35.4, 33.5, 17.0. +ESMS Found 299.1185 (M+Fr) C12H19N4O3S requires 299.1178.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[CH2:14][CH3:15])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[OH:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[C:26]([O:25][C:23]([NH:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([N:13]([CH2:14][CH3:15])[C:4]2[C:5]([CH3:12])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)[CH:3]=2)[CH2:17][CH2:18]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccc(O)cc1
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: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(O)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
To a stirred solution of methyl 5-bromo-3-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-2-methylbenzoate (10 g, 21.3 mmol, see, e.g., WO2012142504) and (4-hydroxyphenyl)boronic acid (3.5 g, 25.3 mmol) in a mixture of dioxane (225 mL) and water (75 mL), Na2CO3 (8.01 g, 75.5 mmol) was added and the solution was purged with argon for 30 min. Then Pd(PPh3)4 (2.4 g, 2.07 mmol) was added and argon was purged again for another 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with ethyl acetate. Combined organic layer was dried over sodium sulfate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (8.9 g, 87% yield).
Reaction SMILES: C1(S(C2CCCNC2)(=O)=O)C=CC=CC=1.C(Cl)(Cl)=O.[C:20]1([S:26]([CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([C:35](Cl)=[O:36])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH2:38]([NH:40][CH2:41][CH2:42][NH2:43])[CH3:39]>>[CH2:38]([NH:40][CH2:41][CH2:42][NH:43][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:29]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:28])=[O:27])[CH2:30]1)=[O:36])[CH3:39]
Reactant: O=C(Cl)N1CCCC(S(=O)(=O)c2ccccc2)C1
Reactant: CCNCCN
Agent: O=C(Cl)Cl
Agent: O=S(=O)(c1ccccc1)C1CCCNC1
Product: CCNCCNC(=O)N1CCCC(S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound is prepared by reacting 3-(phenylsulfonyl)piperidine with phosgene and reacting the resulting 3-(phenylsulfonyl)piperidine-1-carbonylchloride with N-ethylethylenediamine.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1.[CH3:18][N:19]1[C:24](=[O:25])[C:23]2[CH:26]=[C:27]([CH:29]=[O:30])[S:28][C:22]=2[N:21]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:20]1=[O:35].C(=O)([O-])O.[Na+]>O1CCCC1>[OH:30][CH:29]([C:27]1[S:28][C:22]2[N:21]([CH2:31][CH:32]([CH3:33])[CH3:34])[C:20](=[O:35])[N:19]([CH3:18])[C:24](=[O:25])[C:23]=2[CH:26]=1)[C:10]1[S:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C=O)sc21
Reactant: c1ccc2scnc2c1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cc(C(O)c3nc4ccccc4s3)sc21
Temperature: 25 °C
Yield: 33.2 %

Procedure:
Lithium diisopropylamide (2.25 mmol) was added to a solution of benzothiazole (230 mg) in tetrahydrofuran (10 ml) at −78° C. After 5 minutes 1,2,3,4-tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxothieno[2,3-d]pyrimidine-6-carboxaldehyde (300 mg) was added and the reaction mixture kept at −78° C. After a further 30 minutes saturated sodium hydrogen carbonate solution was added and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and evaporated. Purification by chromatography eluting with isohexane:ethyl acetate (2:1 to 1:2) gave the title compound as an oil (150 mg).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].C1(C)C=CC=CC=1>O>[CH3:2][C:1]1[O:16][C:11]([C:12]([F:13])([F:14])[F:15])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(CC(=O)C(F)(F)F)C(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(F)(F)F)oc1C
Yield: 57.6 %

Procedure:
To a mixture of ethyl 2-acetyl-5,5,5-trifluoro-4-oxopentanoate (1.37 g) and toluene (5 mL) was added TsOH monohydrate (0.109 g) at room temperature, and the mixture was refluxed with azeotropic removal of water by Dean-Stark apparatus for 14 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (0.730 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5](Br)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:13]2[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=2)=[CH:4][N:3]=1
Reactant: Nc1cnc(Br)cn1
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1cnc(-c2ccc(O)cc2)cn1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2-amino-5-bromopyrazine (366 mg) in dimethoxyethane (20 mL) was added 4-hydroxyphenylboronic acid (320 mL), 1.5N sodium carbonate aqueous solution (2.5 mL) and tetrakis (triphenylphosphine) palladium (0) (54 mg). The mixture was stirred at 80° C. for 3 hours. To the reaction mixture was added water (20 mL) and the whole was extracted with ethyl acetate (50 mL×3). The extract was washed with saturated saline solution, then dried over anhydrous Na2SO4. The removal of the solvent provided crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (305 mg).
Reaction SMILES: C([O:5][C:6]([C:8]1[S:12][C:11]([O:13][C:14]2[CH:15]=[C:16]([CH3:30])[C:17]3[CH:21]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][B:19]([OH:28])[C:18]=3[CH:29]=2)=[N:10][CH:9]=1)=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:26]([O:25][C:23]([CH2:22][CH:21]1[O:20][B:19]([OH:28])[C:18]2[CH:29]=[C:14]([O:13][C:11]3[S:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9][N:10]=3)[CH:15]=[C:16]([CH3:30])[C:17]1=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=O)OC(C)(C)C)s3)cc(C)c21
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ncc(C(=O)O)s3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
2-(3-Ethoxycarbonylmethyl-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yloxy)-thiazole-5-carboxylic acid tert-butyl ester (3.3 g, 7.6 mmol) was treated with TFA (40 mL) and stirred at room temperature for overnight. The reaction mixture was concentrated and purified by column chromatography (silica, DCM/MeOH=20:1) affording the title compound (2.5 g, 87%) as a white foam. 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.45 (d, 1H), 7.19 (d, 1H), 5.67 (dd, 1H), 4.20 (q, 2H), 3.12 (dd, 1H), 2.43 (m, 1H), 2.39 (s, 3H), 1.56 (s, 9H), 1.24 (t, 3H). MS found: (M+H)+: 378.05.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:10]2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:13]1[CH:11]2[CH2:12][NH:8][CH2:9][CH:10]2[CH2:15][N:14]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a solution of tert-butyl 5-benzylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (2.50 g) in MeOH (100 mL) was added a catalytic amount of Pd(OH)2. The suspension was stirred under H2 overnight and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 7:1 (v/v) DCM/MeOH) to give the compound as oil (1.60 g, 90.00%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:23]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C)C=O>[CH2:1]([C:8]1[C:13]([I:23])=[CH:12][CH:11]=[C:10]([N:14]2[CH2:18][CH2:17][C:16]3([O:19][CH2:20][CH2:21][O:22]3)[CH2:15]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: c1ccc(Cc2cccc(N3CCC4(C3)OCCO4)n2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccc(N2CCC3(C2)OCCO3)nc1Cc1ccccc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of 6.6 g of 2-benzyl-6-(3,3-ethylenedioxypyrrolidin-1-yl)pyridine and 60 ml of N,N-dimethylformamide was stirred in advance in an ice bath. 5.5 g of N-iodosuccinimide was added thereto and the resultant mixture was stirred as it was at room temperature overnight. To the reaction mixture was added 10 ml of a 1 M aqueous solution of sodium thiosulfate and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography with 5–10% ethyl acetate/hexane, to give 6.7 g of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([CH2:26][C:27](OC)=[O:28])[CH2:20][CH2:19]2)(=[O:14])[CH3:13]>C(OCC)(=O)C>[OH:28][CH2:27][CH2:26][C:21]1[CH2:20][CH2:19][C:18]2[CH:17]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[CH:25]=[CH:24][C:23]=2[CH:22]=1
Reactant: COC(=O)CC1=Cc2ccc(NC(C)=O)cc2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(c1)CCC(CCO)=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
Lithium aluminum hydride (242 mg, 6.38 mmol) was added to a tetrahydrofuran solution (16 ml) of methyl [6-(acetylamino)-3,4-dihydro-2-naphthalenyl]acetate (827 mg, 3.19 mmol) obtained in Reference Example 101 under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The residue was powdered with isopropyl ether, to give the titled compound (364 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH:19]=[O:20])=[CH:7]2.[BH4-].[Na+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])[C:8]([CH2:19][OH:20])=[CH:7]2
Reactant: Cc1ccccc1-c1nc2c(C)cccc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc2c(C)cccc2cc1CO

Procedure:
Prepared according to Procedure B using 8-methyl-2-o-tolylquinoline-3-carbaldehyde (1.28 g, 4.9 mmol) and solid NaBH4 (278 mg, 1.5 eq) in THF (10 mL). After purification, (8-methyl-2-o-tolylquinolin-3-yl)methanol was obtained as white solid.
Reaction SMILES: [Br:1][C:2]1[C:20]([F:21])=[CH:19][C:5]([C:6]([C:8](=[CH:14][NH:15][CH:16]2[CH2:18][CH2:17]2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[C:4](F)[C:3]=1[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:23])=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:21]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Br)c(C)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(Br)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
In 175 ml of dimethyl sulfoxide was dissolved 35.0 g of ethyl 2-(4-bromo-2,5-difluoro-3-methylbenzoyl)-3-cyclopropylaminoacrylate, and 27.4 g of potassium carbonate was added to the solution, after which the resulting mixture was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature, and 1,000 ml of water was then added thereto, after which the crystals formed were collected by filtration, to obtain 30.0 g of colorless, crystalline ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[I:12][C:13]1[CH:14]=[C:15]([C:22]([N:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:16]=[C:17]([CH:21]=1)C(O)=O.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:5]([O:4][C:2](=[O:3])[C:17]1[CH:21]=[C:13]([I:12])[CH:14]=[C:15]([C:22]([N:24]([CH3:28])[CH2:25][CH2:26][CH3:27])=[O:23])[CH:16]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCCN(C)C(=O)c1cc(I)cc(C(=O)O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OCc2ccccc2)c1
Reaction time: 40 h
Yield: 32.9 %

Procedure:
Add benzyl chloroformate (5.96 mL, 41.77 mmol) to a solution of 5-iodo-N-methyl-N-propyl-isophthalamic acid (14.5 g, 41.77 mmol), triethylamine (6.4 mL, 45.95 mmol) and 4-dimethylaminopyridine (2.55 g, 20.88 mmol) in dichloromethane (125 mL) at 0° C. and at room temperature for 40 h. Wash the solution twice with a saturated aqueous solution of NaHCO3, 5% aqueous solution of potassium hydrogen sulfate, saturated aqueous sodium chloride, dry (magnesium sulfate), and concentrate. Dissolve the crude in dichloromethane, wash with a 0.5 N NaOH solution, H2O, saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound (6 g, 33%).
Reaction SMILES: C([O:5][C:6]([C:8]1[N:12]([CH2:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)[N:11]=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH:9]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:31][C:26]1[CH:25]=[C:24]([C:10]2[CH:9]=[C:8]([C:6]([OH:7])=[O:5])[N:12]([CH2:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=3)[N:11]=2)[CH:29]=[CH:28][C:27]=1[Cl:30]
Reactant: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2nc(-c3ccc(Cl)c(Cl)c3)cc2C(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the intermediate from step E (551 mg, 1.19 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring at room temperature for 4 hours the reaction mixture was concentrated in vacuo and azeotroped with toluene (3×). A white solid obtained. This material was used in the next step without any further purification. LC-MS: 2.38 min; (M+H)=406.0.
Reaction SMILES: Cl[C:2]1C=CC(C2C3C(=O)N(C)C=CC=3C3C(C)=NOC=3CN=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]3[NH:46][C:45](=[O:47])[CH:44]=[CH:43][C:34]=3[C:35]3[C:41]([CH3:42])=[N:40][O:39][C:36]=3[CH2:37][N:38]=2)=[CH:28][CH:27]=1.ClC1C=CC(C2C3C(=O)NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[C:33]3[N:46]([CH3:2])[C:45](=[O:47])[CH:44]=[CH:43][C:34]=3[C:35]3[C:41]([CH3:42])=[N:40][O:39][C:36]=3[CH2:37][N:38]=2)=[CH:28][CH:27]=1
Reactant: Cc1noc2c1-c1ccc(=O)[nH]c1C(c1ccc(Cl)cc1)=NC2
Reactant: Cc1noc2c1-c1ccn(C)c(=O)c1C(c1ccc(Cl)cc1)=NC2
Agent: Cc1noc2c1-c1cc[nH]c(=O)c1C(c1ccc(Cl)cc1)=NC2
Product: Cc1noc2c1-c1ccc(=O)n(C)c1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-1,8-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one was followed, except that 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepin-8(7H)-one was used as starting material instead of 6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7(8H)-one. LC/MS m/z 340 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=9.56 Hz, 1H), 7.48 (d, J=8.93 Hz, 2H), 7.35 (d, J=8.52 Hz, 2H), 6.82 (d, J=9.35 Hz, 1H), 5.32 (d, J=12.46 Hz, 1H), 4.15 (d, J=12.7 Hz, 1H), 2.95 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([O-:3])=[O:2].Cl.[CH3:22]O>>[CH3:22][O:19][C:18](=[O:20])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:12][CH:13]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of [4-(2-nitro-phenylamino)-phenyl]-acetic acid (1.0 g, 3.68 mmol) and HCl conc. (0.4 mL) in MeOH (20 mL) is stirred and refluxed for 1 h, allowed to cool to rt, and concentrated in vacuo. The residue is diluted with CH2Cl2, washed with an aqueous saturated solution of NaHCO3, H2O, and brine, then dried (Na2SO4), filtered and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 4:1) of the crude product affords the title compound as a red oil: ES-MS: 287.0 [M+H]+; single peak at tR=5.01 min (System 1); Rf=0.20 (Hexane/EtOAc, 4:1).