Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:16][C:15]=2[CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC1(C)CCC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1C
Product: CC1(C)CCC(c2cc(N3CCOCC3)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-[4-bromo-2-(4,4-dimethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (1 g, 2.22 mmol) prepared in Example (3e), morpholine (290 mg, 3.32 mmol), sodium t-butoxide (533 mg, 5.55 mmol), palladium(II) acetate (50 mg, 0.222 mmol), tri-t-butylphosphonium tetrafluoroborate (193 mg, 0.666 mmol) and xylene (10 mL) was stirred at an external temperature of 100° C. for 1 hour and 15 minutes under a nitrogen atmosphere.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]3[CH2:10][CH2:11][CH2:12][N:7]3[C:6]=2[CH:13]=1.[Br:14]Br.C(Cl)(Cl)Cl.CO.[K+].[Br-]>C(O)(=O)C.O.C(=O)(O)[O-].[Na+]>[Br:14][C:3]1[C:2]([CH3:1])=[CH:13][C:6]2[N:7]3[CH2:12][CH2:11][CH2:10][C:8]3=[N:9][C:5]=2[CH:4]=1
Reactant: Cc1ccc2nc3n(c2c1)CCC3
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc2c(cc1Br)nc1n2CCC1

Procedure:
To a solution of 1 q (5.81 mmol) of 22 in 30 mL of qlacial acetic acid, heated at 100°, was added 300 μl of bromine in 3 mL glacial acetic acid. After the addition, the reaction mixture was heated at 100°-110° C. for 4 hours. The cooled reaction mixture was diluted with I00 mL of water and neutralized with aqueous sodium bicarbonate. The product crystallized from solution as a light yellow solid. Yield upon drying the collected solid Was 1.37 g (88%). Recrystallization from chloroform/hexane afforded analytically pure 23: mp 167°-170° C.; TLC (chloroform/methanol, [90:10]), Rf =0.56, IR(KBr pellet), 2949, 2929, 1581, 1521, 1482, 1461, 1448, 1418, 1291, 872 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ71, and 7.43 (2 H, 2× s, aromatic protons), 4.04 (2 H, t, J~7 Hz, C(1) methylene), 2.91 (2 H, t, J~7 Hz), C(3) methylene), 2.59 (2 H, quintet, J~7 Hz, C(2) methylene), 2.39 (3 H, s, 7-methyl); mass spectrum (EI mode) m/z 250 and 252 (P+, 79Br and P+, 81Br), 171 (P+ -Br). Anal. Calcd for C11H11BrN2.0.25 H2O: C, 51.47; H, 4.31; N, 10.91. Found: C, 51.56; H, 4.24; N, 10.78.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[CH:4]=1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]2[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:9]=[C:5]2[CH:4]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: COc1ccnc(N)c1
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cc(OC)ccn12
Yield: 134.5 %

Procedure:
A mixture of 4-methoxy-2-aminopyridine (1.07 g, 8.6 mmol) and ethyl 2-chloroacetoacetate (5.4 g) in EtOH (50 mL) was refluxed for 24 h. The reaction mixture was then concentrated to half its volume, extracted with CH2Cl2, washed with brine and then water, and dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified on a silica gel column eluting with EtOAc and then MeOH/CH2Cl2 (1:9) to give ethyl 7-methoxy-2-methylimidazo[1,2-a]pyridine-3-carboxylate (2.71 g, 90%).
Reaction SMILES: [C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28][C:29]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([O:40]CC)=[O:39])[CH:33]=3)=[O:30])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+]>O1CCCC1.C(O)C>[C:1]1([CH3:44])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH2:13][CH:12]([NH:28][C:29](=[O:30])[NH:31][C:32]3[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:38]([OH:40])=[O:39])[C:11]2=[O:43])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C3CCCCC3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (0.26 g) was dissolved in a mixed solvent of tetrahydrofuran (5 ml) and ethanol (5 ml), aqueous lithium hydroxide monohydrate (0.18 g) solution (5 ml) was added, and the mixture was stirred at room temperature for 3 hour. The reaction mixture was concentrated under reduced pressure, the residue was weakly acidified with 1N hydrochloric acid, and extracted with chloroform. The organic layer was successively washed with water and saturated brine, the solvent was evaporated under reduced pressure, and diisoproryl ether was added to the residue for trituration, collected by filtration, to thereby obtain 0.20 g of the titled compound as yellow-white powder (Yield: 82%)
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)=O>N1C=CC=CC=1>[CH2:8]([NH:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: CC(C)=CC(=O)O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(CC(=O)O)NCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
3-Methylcrotonic acid (12.0 g) was dissolved in pyridine (40 ml), and benzyl amine (12.8 g) was added thereto, and the mixture was stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, and after acetone was added to the resulting suspension, crystals were collected by filtration and washed. The crystals were dried under reduced pressure to give 3-benzylamino-3-methylbutanoic acid (10.3 g, Y.:42%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH:22]([CH3:26])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:23]([CH3:24])[CH:22]([Cl:21])[CH3:26])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CC(=O)C(C)Cl
Product: CC(=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)C(C)Cl

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be reacted with 3-chloro-2-butanone to give 7-chloro-2-[(2-chloro-1-methylpropylidene) hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].C(N(CC)CC)C.[NH2:20][C:21]1[CH:42]=[CH:41][C:24]([C:25]([N:27]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[CH2:31][N:30]3[CH:38]=[CH:39][CH:40]=[C:29]3[CH2:28]2)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH:40]1[CH:39]=[CH:38][N:30]2[CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N:27]([C:25]([C:24]3[CH:23]=[CH:22][C:21]([NH:20][C:6](=[O:7])[C:5]4[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=4[O:3][CH2:1][CH3:2])=[CH:42][CH:41]=3)=[O:26])[CH2:28][C:29]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: CCOc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reaction time: 0.05 h
Yield: 119.6 %

Procedure:
To a stirred solution of 0.362 g of 2-ethoxybenzoyl chloride 5 ml of methylene chloride is added 0.346 g of triethylamine at 0C. After stirring for 3 minutes, 0.500 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 72 hours at room temperature. The reaction mixture is diluted with 45 ml of methylene chloride and washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.890 g of solid which is crystallized from ethyl acetate to give 0.540 g of the desired product as a white solid, m.p. 160-176° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8])=[CH:2]1.FC(F)(F)C(O)=O>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][C:3](/[C:6](=[CH:14]\[C:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=3[Cl:24])[N:17]([S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]=2[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8])=[CH:2]1
Reactant: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(/C=C(/C(=O)O)c2ccsc2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.75 h

Procedure:
Combine (E)-2-(thien-3-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester and trifluoroacetic acid (10 mL). After 45 min, evaporate in vacuo to obtain a residue. Dissolve the residue in ethyl acetate and extract with water. Evaporate the organic layer in vacuo to obtain a residue. Triturate with pentane containing a small amount of ether to give a solid. Recrystallize the solid from cyclohexane/ethyl acetate, filter, and dry to give the title compound: mp 197-200° C. (dec); 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.95 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.27 (d, 2H, J=8.5 Hz), 7.25 (d, 1H, J=1.7 Hz), 7.08 (d, 1H, J=2.8 Hz), 7.08 (d, 1H, J=3.6 Hz), 6.81 (dd, 1H, J=3.6, 2.8 Hz), 4.22 (q, 2H, J=7.2 Hz), 2.40 (s, 3H), 1.28 (t, 3H, J=7.2 Hz); 1H NMR (DMSO-d6) δ 13.07 (br s, 1H), 7.88 (d, 1H, J=1.7 Hz), 7.74 (d, 2H, J=8.4 Hz), 7.66 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, H, J=8.4 Hz), 7.27 (dd, 1H, J=5.0, 2.9 Hz), 7.09 (dd, 1H, J=2.9, 1.2 Hz), 6.63 (dd, 1H, J=5.0, 1.2 Hz), 4.11 (q, 2H, J=7.1 Hz), 2.36 (s, 3H), 1.14 (t, 3H, J=7.1 Hz). Elemental Analysis calculated for C25H19Cl2NO6S2: C, 53.20; H, 3.39; N, 2.48. Found: C, 52.80; H, 3.19; N, 2.29.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][NH2:22].[CH3:23][O:24][CH2:25][CH2:26][CH:27]=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)/[C:6]([CH3:18])=[C:5]2[CH2:19][CH2:20][O:21][N:22]=[CH:27][CH2:26][CH2:25][O:24][CH3:23]
Reactant: COCCC=O
Reactant: CC1=C(CCON)c2cc(F)ccc2/C1=C\c1ccncc1
Product: COCCC=NOCCC1=C(C)/C(=C/c2ccncc2)c2ccc(F)cc21

Procedure:
The title compound is prepared by reaction of O-2-[Z-5-fluoro-2-methyl-1-(4-pyridyl)methylene-1H-inden-3-yl]ethyl hydroxylamine with 3-methoxypropanal by the method of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:28])=[O:27]>C(N(C(C)C)C(C)C)C>[OH:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)(=[O:28])=[O:27]
Reactant: O=S(=O)(CCCCCCl)NCCO
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1)NCCO
Yield: 94 %

Procedure:
1-[Bis(4-fluorophenyl)methyl]piperazine (576.7 mg, 2.00 mmol) and N-(2-hydroxyethyl)-5-chloropentanesulfonamide (459.5 mg, 2.00 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 6 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-(2-hydroxyethyl)-5-[4-[bis(4-fluorophenyl)methyl]-1- piperaziny]pentanesulfonamide (905.6 mg) as a pale yellow oil (94.0%).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([NH2:11])[CH2:3][CH2:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:1][CH2:2][CH2:3]1)([O-:14])=[O:13]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: NC1CCOc2ccccc21
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=NC2CCOc3ccccc32)c1

Procedure:
An 80 g, (0.54 mole) portion of 4-chromanamine, and 650 ml of ethanol were placed in a 2-l, 3-necked flask, equipped with a stirrer and reflux condenser fitted with a drying tube. The slurry was treated with 85 g (0.56 mole) portion of m-nitrobenzaldehyde using rapid mechanical stirring. The reaction mixture was refluxed for 5 hrs., cooled 1 hr. and filtered. The yellow crystalline solid was washed with 100 ml of ethanol, ether, and dried, m.p. 117°-118°. Yield: 115 g (76%).
Reaction SMILES: [C:1]([CH:6]([C:18](O)=[O:19])[NH:7]C(OCC1C=CC=CC=1)=O)([O:3][CH2:4][CH3:5])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:27][C:28]1[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:29]=1[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O.Br>C(O)(=O)C.C(Cl)Cl.CN(C)C=O>[CH2:4]([O:3][C:1]([CH:6]1[N:7]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[NH:27][C:18]1=[O:19])=[O:2])[CH3:5]
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1cc(Cl)ccc1C(=O)c1ccccc1
Agent: Br
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1N=C(c2ccccc2)c2ccc(Cl)cc2NC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 45.0 g. of 2-carbethoxy-N-(benzyloxycarbonyl)glycine in 120 ml. of dry methylene chloride, cooled to -20° C., is treated portionwise with 30 g. of phosphorus pentachloride and stirred for 30 minutes at -20° C. to -10° C. To the now clear solution, there is added at the same temperature a solution of 27.7 g. of 2-amino-4-chlorobenzophenone and 1 ml. of dimethylformamide in 120 ml. of dry methylene chloride. The mixture is concentrated under reduced pressure at 40°-45° C. The residue in partitioned between methylene chloride and 10% aqueous soda solution and the methylene chloride phase is dried over sodium sulfate and evaporated to dryness. There is obtained a reddish-colored resin of crude 2'-benzoyl-2-[(benzyloxycarbonyl)amino]-2-carbethoxy-5'-chloroacetanilide, which is then immediately reacted with 130 ml. of a 33% solution of hydrobromic acid in glacial acetic acid. After stirring at room temperature for 90 minutes, the obtained solution is concentrated at 45° C. and the oily residue partitioned between water and ether. The aqueous solution is made weakly alkaline with solid sodium bicarbonate while cooling with ice. The separated base is extracted with methylene chloride and the extracts are dried over sodium sulfate and evaporated to dryness. The resulting oil is dissolved in a mixture of 180 ml. of toluene and 180 ml. of glacial acetic acid and heated at 80° C. for 90 minutes. The solution is concentrated to an oil and is crystallized from ether so that there is obtained 8-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester, having a melting point of 214°-217° C. (decomposition). Recrystallization from acetonitrile does not increase the melting point.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[S:25]([C:22]1[CH:21]=[CH:20][C:19]([C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=3)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=2[CH3:18])=[CH:24][CH:23]=1)(=[O:26])=[O:27]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3ccc(F)cc3F)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.6 %

Procedure:
Lithium hydroxide monohydrate (0.01 g, 0.23 mmol) was added to a stirred solution of {4-[4-(2,4-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.028 g, 0.057 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(2,4-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.02 g, 74%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (br. S, 1 H) 8.23 (q, J=7.60 Hz, 1 H) 8.12 (d, J=7.82 Hz, 2 H) 8.01 (dd, J=9.40, 6.20 Hz, 1H) 7.91 (s, 1 H) 7.63 (t, J=9.40 Hz, 1 H) 7.56 (d, J=8.31 Hz, 2 H) 7.45 (t, J=8.60 Hz, 1 H) 7.39 (td, J=9.00, 2.60 Hz, 1 H) 6.64 (dd, J=11.00, 2.40 Hz, 1 H) 3.84 (s, 2 H) 2.04 (s, 3 H). MS calcd. for C25H16F3O4S [(M−H)−] 469, obsd. 469.3.
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3.B(Br)(Br)Br.N#N>C(Cl)Cl>[NH2:15][C:13]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][C:5]=2[N:14]=1
Reactant: COc1ccc2c(c1)nc(N)c1ncccc12
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: Nc1nc2cc(O)ccc2c2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methoxybenzo[f][1,7]naphthyridin-5-amine (from Example 10) (1.0 eq.) in DCM (0.04 M) was added BBr3 (2.5 eq.) dropwise under N2 at −20° C. The reaction was allowed to warm to ambient temperature over 30 minutes. The reaction was then stirred overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% MeOH/DCM to give 5-aminobenzo[f][1,7]naphthyridin-8-ol as a yellow solid: 1H NMR (acetone-d6): δ 8.90 (dd, 1H), 8.83 (dd, 1H), 8.32 (d, 1H), 7.83 (dd, 1H), 7.11 (br s, 2H), 7.10 (d, 1H), 6.96 (dd, 1H), 5.86 (br s, 1H). LRMS [M+H]=212.1.
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])=[C:8]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)#[N:3]>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[C:31]1[NH:30][C:7]2[C:8]([CH:10]=1)=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C

Procedure:
({5-Cyano-2-[(trifluoroacetypamino]phenyl}methyl)(triphenyl)phosphonium chloride (Intermediate 32, 50.41 g, 95 mmol) was heated in DMF (180 mL) at 140° C. for 7 h. The mixture was cooled to room temperature and the solvents were evaporated. This residue was combined with the corresponding residue from another experiment (wherein Intermediate 32, 7.9 g, 15.05 mmol was heated in DMF (50 mL) at 155° C. for 2 h). The combined residues were azeotroped with toluene (100 mL×2). The resulting residue was treated with diethyl ether (500 mL) and the precipitate filtered and washed with diethyl ether (100 mL). The filtrate was evaporated and the resulting orange oil (˜60 g) was dissolved in DCM (200 mL) and stirred at room temperature. Iso-hexane was added until the cloudyness remained (˜400 mL) and the mixtured stirred for 3 days. No precipitate was observed so the mixture was evaporated and chromatographed (Biotage 75L, eluting with DCM) to give the title compound as a colourless solid (21.7 g);
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.[OH-].[Na+].S(OC)(O[CH3:17])(=O)=O>CCOCC.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:17])[CH:6]=[C:5]([OH:10])[N:4]=1
Reactant: COS(=O)(=O)OC
Reactant: COc1nc(O)cc(O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: COc1cc(O)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
142 g (1 mol) of 2-methoxy-4,6-dihydroxypyrimidine are added while stirring to 500 cc of sodium hydroxide solution 2N and the mixture is stirred at 50° for 1 hour. Subsequently it is cooled to room temperature and 139 g (1.1 mol) of dimethyl sulphate are added dropwise while stirring; by the addition of sodium hydroxide solution 2N the pH value is kept at between 8.0 and 8.2. The mixture is stirred at 50° for a further 2 hours, cooled to room temperature and extracted with chloroform. After drying the chloroform phase over sodium sulphate the solvent is decanted in a vacuum. A white powder is obtained. After decomposition with ether/chloroform (1:1), the substance has a M.P. of 197°-201°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]=1[C:19]([O:21]CC)=[O:20])[CH3:3]>CCO>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:7](=[O:18])[C:6]=1[C:19]([OH:21])=[O:20])[CH3:3]
Reactant: CCOC(=O)c1c(OCC)ccn(-c2ccc(F)cc2)c1=O
Agent: Cl
Solvent: CCO
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)O
Temperature: 62 °C
Reaction time: 0.33 h
Yield: 76.1 %

Procedure:
At room temperature, 2.75 N HCl (7.7 L) was added to a solution of crude ethyl 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.1 kg) in EtOH (3.85 L). The mixture was heated for 10 hrs to 60-64° C. Next, the mixture was cooled to 50-54° C. and methanol was removed by vacuum distillation. The mixture was cooled to 20-25° C. and the pH was adjusted to 8.0 to 8.5 by addition of 30% sodium carbonate solution (8.5 L). The phases were separated and the aqueous layer was washed three times with DCM (4 L). Next, charcoal (0.7 kg) was charged to the aqueous layer and the layer was filtered through a celite bed. To the filtrate was added 1.5 N HCl until the pH had reached 2.0. The resulted slurry was stirred for 20 min at room temperature. The solids were filtered off, washed with water (15 L) and dried under vacuum at 50-55° C. until the loss on drying was less than 5 wt %. The crude product was suspended in ethyl acetate (5 L) and slurried for 15 min at 40° C. After cooling to room temperature, the solids were filtered off, washed with ethyl acetate (1 L) and dried at 40-45° C. under vacuum for 10 hrs to yield 4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.76 kg; 58% yield for Steps 6 and 7).