Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][C:24](O)=[O:25])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[CH2:22][CH2:23][CH2:24][OH:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCn1c(=O)c(CCCO)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A mixture of 1.00 g of 3-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid, 20 ml of methanol and 0.5 ml of concentrated sulfuric acid was heated under reflux for a whole day and night. After cooling to room temperature, saturated sodium bicarbonate aqueous solution was added thereto and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate). The resulting compound was dissolved in 20 ml of THF and 500 mg of sodium borohydride was added thereto. While heating under reflux, 3 ml of methanol was added dropwise thereto, and the mixture was further heated under reflux for 3 hours. After cooling to room temperature, 1M hydrochloric acid was added and the whole was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from diisopropyl ether to obtain 497 mg of 4-(3-chlorophenyl)-1-ethyl-3-(3-hydroxypropyl)-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:18]([NH2:19])=[C:17]([Cl:20])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11]([F:14])([F:13])[F:12])[CH2:10][CH2:9]1)=[O:7].[C:21](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:22]>>[Cl:1][C:2]1[C:18]([N:19]=[C:21]=[S:22])=[C:17]([Cl:20])[CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([C:8]1([C:11]([F:13])([F:14])[F:12])[CH2:10][CH2:9]1)=[O:7]
Reactant: Nc1c(Cl)ccc(CNC(=O)C2(C(F)(F)F)CC2)c1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Product: O=C(NCc1ccc(Cl)c(N=C=S)c1Cl)C1(C(F)(F)F)CC1

Procedure:
The title compound is prepared from N-(2,4-dichloro-3-amino-benzyl)-1-trifluoromethyl-cyclopropane carboxamide (150 mg, 0.45 mmol) and 1,1′-thiocarbonyldi-2-pyridone (89 mg, 0.38 mmol) in analogy to step Af.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[CH2:21]([N:23]([CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>ClCCl>[CH2:30]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][C:27]([O-:29])=[O:28])[CH3:31].[CH3:19][N:2]([CH3:1])[CH2:3][CH:4]([OH:18])[CH:5]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCN(CC)CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)CC(O)C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)CCCC(=O)[O-]

Procedure:
A solution of 3-dimethylamino-1,1-diphenyl-propan-2-ol (2 55g) 4-diethylaminobutyric acid hydrochloride (1 95g.) and dicyclohexylcarbodiimide (2.1g.) in dichloromethane (50 ml) was stirred at room temperature for 5 days Dicyclohexylurea was filtered off and the filtrate concentrated. The residue was dissolved in dilute hydrochloric acid and ether. The acid extract was basified; isolation through ether in the normal manner gave an oil which was chromatographed as alumina (200g.). Elution with progressively graded mixtures of light petroleum and ether gave the 4-diethylaminobutyrate of 3-dimethylamino-1,1-diphenyl-propan-2-ol isolated as the dihydrochloride (41%) as a glass
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][N:12](C(=O)[C@@H]3CCCN3S(C3C=CC4C(=CC=CC=4)C=3)(=O)=O)[C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:13][NH:12][C:11]3[CH:34]=[CH:35][CH:36]=[CH:37][C:10]=3[S:9]2)=[CH:6][CH:7]=1
Reactant: O=C([C@@H]1CCCN1S(=O)(=O)c1ccc2ccccc2c1)N1C[C@@H](c2ccc(Cl)cc2)Sc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Clc1ccc([C@@H]2CNc3ccccc3S2)cc1
Temperature: 0 °C
Yield: 58.7 %

Procedure:
(R)-2-(4-Chlorophenyl)-4-[(S)-N-(2-naphthalenesulfonyl)prolyl]-3,4-dihydro-2H-1,4-benzothiazine (9.40 g, 0.017 mole) is suspended in ethanol-water (10:1, 188 ml), and thereto is added 86 % potassium hydroxide (11.2 g, 0.172 mole), and the mixture is refluxed for 30 minutes. The reaction mixture is poured into ice water and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed with water and saline, dried over sodium sulfate and distilled to remove the solvent. The residue is purified by silica gel column chromatography (CHCl3) and thereafter recrystallized from ethyl acetate-hexane twice to give (R)-(+)-2-(4-chlorophenyl)-3,4-dihydro-2H-1,4-benzothiazine (2.61 g, 58%).
Reaction SMILES: O1CCCC1.[C:6]([C:10]1[C:20]([F:21])=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][C:11]=1[F:22])([CH3:9])([CH3:8])[CH3:7].[Cl-].ClC1N(C)CC[NH+]1C.Cl.[NH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([CH3:47])[CH:37]=1)[CH3:35]>C(N(CC)CC)C>[C:6]([C:10]1[C:11]([F:22])=[CH:12][C:13]([O:14][CH2:15][C:16]([NH:33][C@@H:34]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[C:38]([CH3:47])[CH:37]=2)[CH3:35])=[O:18])=[CH:19][C:20]=1[F:21])([CH3:7])([CH3:8])[CH3:9]
Reactant: Cc1cc([C@@H](C)N)ccc1NS(C)(=O)=O
Reactant: CC(C)(C)c1c(F)cc(OCC(=O)O)cc1F
Agent: CN1CC[NH+](C)C1Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc([C@@H](C)NC(=O)COc2cc(F)c(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Reaction time: 2 h
Yield: 5.2 %

Procedure:
To a tetrahydrofuran (THF) (3.0 ml) solution of (4-tert-butyl-3,5-difluorophenoxy)acetic acid (166 mg, 0.68 mmol) was added 2-chloro-1,3-dimethylimidazolinium chloride (CDI) (110 mg, 0.68 mmol) at room temperature and the mixture was stirred for 2 hours, followed by the addition of triethylamine (0.5 ml) and N-{4-[(1R)-1-aminoethyl]-2-methylphenyl}methanesulfonamide hydrochloride (180 mg, 0.68 mmol) with stirring for 10 hours. The reaction was partitioned with water and dichloromethane and the organic layer was separated and dried over sodium sulfate. Then filtration and evaporation under reduced pressure gave the crude residue which was purified by silica gel column chromatography, eluting with dichloromethane/methanol from 5:1 to 5:2, to furnish 1 16mg (38%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15]>[Fe].C(O)(=O)C>[NH2:12][C:4]1[C:3]([OH:15])=[C:2]([Cl:1])[CH:10]=[C:9]([Cl:11])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c(Cl)cc(Cl)c(O)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1c(O)c(Cl)cc(Cl)c1C(=O)O
Temperature: 80 °C
Yield: 94.3 %

Procedure:
A mixture of 4,6-dichloro-3-hydroxy-2-nitrobenzoic 1-6 (700 mg, 2.78 mmol), Fe powder (400 mg, 7.16 mmol) and glacial acetic acid (13 mL) was heated at 80° C. for 50 min, cooled and the solids filtered off. The filtrate was concentrated to a brown solid. Purification by flash chromatography eluting with 1% AcOH/EtOAc to 3% AcOH/EtOAc afforded 2-amino-4,6-dichloro-3-hydroxybenzoic acid (1-8) as a light brown solid (582 mg, 94%). 1H NMR (d6-DMSO, 400 MHz) δ. 6.68 (s, 1H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[CH2:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:21]=[C:20]2[C:33]1[N:34]=[N:35][N:36]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[O:45])=[CH:40][CH:39]=2)[CH:37]=1.[N:52]1[NH:53][C:54](=[O:58])[CH:55]=[CH:56][CH:57]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl>[N:46]1([C:44]([C:41]2[CH:42]=[CH:43][C:38]([N:36]3[CH:37]=[C:33]([C:20]4[C:19]5[C:23](=[CH:24][CH:25]=[C:17]([CH2:16][N:53]6[C:54](=[O:58])[CH:55]=[CH:56][CH:57]=[N:52]6)[CH:18]=5)[N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:21]=4)[N:34]=[N:35]3)=[CH:39][CH:40]=2)=[O:45])[CH2:47][CH2:48][O:49][CH2:50][CH2:51]1
Reactant: O=c1cccn[nH]1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(CO)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1nc(-c2cn(-c3ccc(C(=O)N4CCOCC4)cc3)nn2)c2cc(Cn3ncccc3=O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIAD (0.30 mL; 1.54 mmol; 2.3 eq.) was added dropwise over 1 min to a solution of tert-butyl 5-(hydroxymethyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazole-1-carboxylate (340 mg; 0.67 mmol; 1.0 eq.), 3(2H)-pyridazinone (100 mg; 1.04 mmol; 1.5 eq.) and triphenylphosphine (354 mg; 1.35 mmol; 2.0 eq.) in DCM (15 mL). The reaction mixture was stirred for 4 h at RT then poured into HCl (0.1N solution) and extracted with DCM. Combine organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (gradient 20:80 to 90:10, MeOH pure) to give the title compound as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.52 (s, 1H), 8.19 (d, J=8.6 Hz, 2H), 8.13 (d, J=8.7 Hz, 1H), 7.98 (dd, J=1.6, 3.9 Hz, 1H), 7.77-7.61 (m, 3H), 7.45 (dd, J=3.9 Hz, 1H), 7.01 (dd, J=9.5 Hz, 1.6, 1H), 5.46 (s, 2H), 3.76-3.35 (m, 8H), 1.69 (s, 9H). HPLC (Condition A): Rt 3.74 min (purity 91.1%). MS (ESI−): 483.4.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:34]=[CH:33][C:6]2=[N:7][N:8]([C:10]3[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])([CH3:25])[CH3:24])[C:21]=3[OH:22])[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])[N:9]=[C:5]2[CH:4]=1.Cl>[OH-].[Na+]>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:34]=[CH:33][C:6]2=[N:7][N:8]([C:10]3[CH:11]=[C:12]([CH:19]=[C:20]([C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])([CH3:25])[CH3:24])[C:21]=3[OH:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[N:9]=[C:5]2[CH:4]=1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(C(F)(F)F)cc3n2)c(O)c(C(C)(C)c2ccccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(c1ccccc1F)c1cc(CCC(=O)O)cc(-n2nc3ccc(C(F)(F)F)cc3n2)c1O

Procedure:
The title compound is prepared by refluxing the compound prepared in Example 50 in aqueous sodium hydroxide solution followed by neutralization with aqueous hydrochloric acid.
Reaction SMILES: N(OC(C)(C)C)=O.[N-:8]=[N+:9]=[N-:10].[Na+].[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:30])([F:29])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1N.O>FC(F)(F)C(O)=O>[Cl:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([C:21]2[C:25]([Cl:26])=[C:24]([C:27]([F:29])([F:30])[F:28])[N:23]([CH3:31])[N:22]=2)=[CH:16][C:14]=1[N:8]=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(-c2cc(N=[N+]=[N-])c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reaction time: 2 h

Procedure:
0.46 g (4.5 mmol) of tert-butyl nitrite and 0.3 g (4.5 mmol) of sodium azide were added to a solution of 1 g (3 mmol) of 2-chloro-5-(4-chloro-1-methyl-5-trifluoromethyl-1H-pyrazol-3-yl)-4-fluoroaniline in 20 ml of trifluoroacetic acid. The mixture was subsequently stirred for 2 hours and then admixed with 50 ml of water. The resulting product was extracted from the aqueous phase using 100 ml of methyl tert-butyl ether. The extract was washed with 10% strength aqueous sodium hydroxide solution, then dried over magnesium sulfate and finally concentrated. The crude product was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1:1). Yield: 0.7 g; 1H NMR (400 MHz; in (CD3)2SO): δ[ppm]=4.10 (s,3H), 7.53 (d,1H), 7.77 (d,1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([CH3:19])[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(N(CC)CC)C.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([F:37])[CH:36]=1)[C:31](Cl)=[O:32]>C(Cl)Cl>[CH3:19][C@H:10]([C:7]1[CH:8]=[CH:9][C:4]([NH:1][C:31]([C:30]2[CH:29]=[C:28]([F:27])[CH:36]=[C:35]([F:37])[CH:34]=2)=[O:32])=[CH:5][CH:6]=1)[CH2:11][NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)S(=O)(=O)NC[C@H](C)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC[C@H](C)c1ccc(NC(=O)c2cc(F)cc(F)c2)cc1
Reaction time: 0.17 h
Yield: 80.9 %

Procedure:
A 500 mL three necked round bottom flask equipped with a magnetic stirrer, thermometer, addition funnel and a positive nitrogen was charged with [(2R)-2-(4-nitrophenyl)propyl][(methylethyl)sulfonyl]amine (12.02 g, 46.85 mmol) and methylene chloride (200.0 mL). To this solution was added triethylamine (6.53 mL, 46.85 mmol) all at once. The solution was stirred for 10 minutes then added dropwise, neat 3,5difluorobenzoyl chloride (5.9 mL, 46.85 mmol) over a period of 20 minutes. The reaction exothermed to reflux by the end of addition. Stirred to room temperature over the weekend for convenience. Quenched reaction with 1 N HCl (100.0 mL) and separated lower organic layer. Washed the organic layer with 25% brine (70.0 mL) and dried with anhydrous magnesium sulfate. Filtered precipitates and concentrated filtrate to a tan oil (20.0 g). To this oil was added 1:1 ethyl acetate/hexane (125.0 mL) with stirring. A massive off white precipitate formed. The precipitate was then filtered and the cake washed with 1:1 ethyl acetate/hexane (50.0 mL). Precipitate was then dried in a house vacuum oven at 40° C. to provide N-[4-((1R)-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl](3,5-difluorophenyl)carboxamide (15.02 g, 80.9%); 1H NMR (CDCl3, 300 MHz) δ 1.26-1.27 (d, 6H), 1.29-1.30 (d, 2H), 2.92 (m, 1H), 3.10 (m, 1H), 3.20 (1H), 3.3-3.4 (m, 1H), 7.0 (triplet, 1H), 7.20 (d, 2H), 7.40 (d, 2H), 7.60 (m, 2H), 8.19 (s, 1H); 13C NMR (CDCl3, 300 MHz) δ 17.19, 17.30, 19.75, 41.03, 50.99, 54.15, 107.68, 107.86, 108.08, 111.12, 111.33, 121.81, 128.59, 136.97, 138.77, 140.51, 162.62, 162.71, 164.12, 164.61, 164.71.
Reaction SMILES: C([NH:9][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:11](=[O:13])[CH3:12])(=O)C1C=CC=CC=1.[ClH:27]>>[ClH:27].[NH2:9][CH:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)C(CCCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Agent: Cl
Product: CC(=O)C(N)CCCCNC(=O)c1ccccc1
Yield: 34.2 %

Procedure:
3,7-Dibenzamidoheptan-2-one (91.11 g, 0.258 mol) was hydrolysed in a sealed tube with concentrated HCl for 3 hours at 160° (oil bath). The solution was extracted with ether and evaporated to dryness to give 3-amino-7-benzamidoheptan-2-one hydrochloride (25.01 g, 34.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH3:14][CH:15]([S:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)[CH3:16]>>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:19][C:18]([S:17][CH:15]([CH3:16])[CH3:14])([CH3:22])[CH3:21]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: CC(C)SC(C)(C)C=O
Product: CC(C)SC(C)(C)CNc1ccccc1NCC(C)(C)S
Yield: 28.2 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.515 g, 2.65×10-3 mol) and 0.786 g (5.31×10-3 mol, 200 M %) 2-(1-methylethylthio)-2-methylpropanal were reacted by the method of Example 2 to give 2-(2-mercapto-2-methylpropylamino)-1-[2-(1-methylethylthio)-2-methylpropylamino]benzene 0.244 g (28% yield) as a colorless oil after purification by radial chromatography on a 2 mm silica gel plate eluting with 100 ml 100% petroleum ether and 200 ml 5% diethyl ether/petroleum ether.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][N:6]([C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:25]=3[O:32][CH3:33])=[CH:20][CH:19]=2)[CH:10]=1)[CH3:7])C.[OH-].[Li+]>C1COCC1>[F:31][C:27]1[C:28]([F:30])=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=3[F:15])[C:8]([N:6]([CH2:5][C:4]([OH:35])=[O:3])[CH3:7])=[O:34])=[CH:23][CH:22]=2)=[C:25]([O:32][CH3:33])[CH:26]=1
Reactant: CCOC(=O)CN(C)C(=O)c1ccc(F)c(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cc(C(=O)N(C)CC(=O)O)ccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.9 %

Procedure:
{[3-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoyl]-methyl-amino}-acetic acid ethyl ester (0.29 g, 0.59 mmol) was dissolved in THF (25 mL) and lithium hydroxide solution (0.5N, 2 mL) was added. The mixture was stirred at room temperature for 2 hrs. Solvents were evaporated and the residue was treated with dilute hydrochloric acid and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Solvent was evaporated and the residue was dissolved in acetonitrile (1 mL) and diluted with water (8 mL). The mixture was lyophilized to give a fluffy solid as {[3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-4-fluoro-benzoyl]-methyl-amino}-acetic acid (0.26 g, 96%). HRMS (ES) calculated for C24H20F3NO5, 482.1186; found m/z 482.1185 [M+Na]+; 1H-NMR (DMSO-d6) δ ppm 12.86 (br s, 1H), 7.29-7.69 (m, 6H), 7.24 (dd, J=13.0, 7.2 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 5.19 and 5.23 (s, 2H, rotamer), 3.97 and 4.14 (s, 2H, rotamer), 3.76 (s, 3H), 2.94 and 2.95 (s, 3H, rotamer).
Reaction SMILES: Cl.[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]=[C:24]([C:28]([OH:30])=[O:29])[CH2:23]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:31](O)(=O)C.N1CCC(CC(OC)=O)C1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C(O)(=O)C(C(C(O)=O)O)O>CC(CC(C)C)=O.C(OCC)(=O)C.O.C1COCC1.CCCCCCC>[CH3:31][O:30][C:28](=[O:29])[CH2:24][CH:25]1[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[CH:2][C:12]=3[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]2=3)[CH2:23]1
Reactant: CC(=O)O
Reactant: O=C(O)C1=CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Agent: COC(=O)CC1CCNC1
Agent: Cl
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(=O)CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Yield: 50 %

Procedure:
A mixture of 2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethylchloride (1.5 g, 4.9 mmol, prepared as described in Example 15), methyl 3-pyrrolidineacetate acetate (2.0 g, 9.8 mmol), potassium carbonate (2.4 g, 17 mmol) and potassium iodide (0.16 g) in methylisobutyl ketone (30 ml) was heated at reflux temperature for 48 h. The reaction mixture was allowed to cool and water (40 ml) was added. The phases were separated and from the organic phase the solvent was evaporated in vacuo to give an oily residue. This residue was dissolved in a mixture of ethyl acetate (25 ml) and water (25 ml) and pH was adjusted to 4 with a 34% aqueous tartaric acid solution. The phases were separated and the organic phase was discarded. Ethyl acetate (25 ml) was added to the aqueous phase and pH was adjusted to approx. 9 with a 2 M aqueous sodium hydroxide solution. The phases were separated and from the organic phase the solvent was evaporated in vacuo to give an oily residue which was submitted to column chromatography on silica gel (180 ml) using a mixture of THF and n-heptane (1:1) as eluent. Collecting the proper fraction afforded 1.0 g of N-(2-(2 -(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-pyrrolidineacetic acid methyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[O:11])[CH:10]=1)=[O:4].S(Cl)([Cl:25])(=O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[C:13]=2[F:21])[CH2:8][C:9](=[O:11])[C:10]=1[Cl:25])=[O:4]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)C1=CC(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Solvent: ClCCl
Product: COC(=O)C1=C(Cl)C(=O)CC(c2ccc(Cl)c(OC)c2F)N1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
6-(4-Chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (16; 483 mg, 1.54 mmol) was slurried in CH2Cl2 (10 mL) and cooled in an ice bath. A solution of SO2Cl2 (209 mg, 1.55 mmol) in CH2Cl2 (5 mL) was added dropwise. After 30 min, the reaction solution was quenched with 10% aqueous sodium bisulfite solution. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, H2O and brine and then dried (MgSO4). The solution was evaporated to a yellow oil which was crystallized from cold methanol to give 3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-4-oxo-1,4,5,6-tetrahydropyridine-2-carboxylic acid methyl ester (33; 0.437 g, 81%) as a light yellow solid: mp 127-129° C.; 1H NMR (300 MHz, CDCl3) δ 7.20 (dd, JF-H=1.5 Hz, JH-H=8.1 Hz, 1H, aromatic), 7.10 (dd, JF-H=6.9 Hz, JH-H=8.1 Hz, 1H, aromatic), 5.82 (br s, 1H, NH), 5.10 (t, J=9.3 Hz, 1H, H6), 3.98 (d, JF-H=1.5 Hz, 3H, OCH3), 3.97 (s, 3H, CO2CH3), 2.88 (d, J=9 Hz, 2H, H5); ESIMS m/z 347.9 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1.[OH-].[K+].O>CCO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH:18]([CH3:25])[CH2:19][C:20]([OH:22])=[O:21])=[C:8]2[CH3:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)c(C(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 75 %

Procedure:
To a suspension of the ester from Step 4 (5.13 g, 11.5 mmol) in 50 mL of EtOH was added 8N KOH (5 mL, 40 mmol) and 5 mL water. The mixture was heated to 60° C. for 1 h, then cooled and concentrated. The residue was partitioned between 1M HCl and EtOAc. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated. Crystallization from CH2Cl2/ hexanes gave 3.59 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:28])[C:8]([C:23]([O:25]CC)=[O:24])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([F:21])=[CH:16][C:15]=2[CH3:22])=[CH:5][C:4]=1[F:29]>>[NH2:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7](=[O:28])[C:8]([C:23]([OH:25])=[O:24])=[CH:9][N:10]2[C:14]2[CH:19]=[C:18]([NH2:20])[C:17]([F:21])=[CH:16][C:15]=2[CH3:22])=[CH:5][C:4]=1[F:29]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2C)c2c(C)c(N)c(F)cc2c1=O
Agent: Cl
Product: Cc1cc(F)c(N)cc1-n1cc(C(=O)O)c(=O)c2cc(F)c(N)c(C)c21
Reaction time: 3 h
Yield: 19.7 %

Procedure:
12N Hydrochloric acid (2 ml) was added to ethyl 7-amino-1-(5-amino-4-fluoro-2-methylphenyl)-6-fluoro-8-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (230 mg), and the mixture was stirred for 3 hours while heating under reflux. After the reaction mixture was allowed to cool, solids deposited were collected by filtration. The solids were washed with water, ethanol and diethyl ether in that order and dried to obtain the title compound (42 mg) as a pale yellow powder.