Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:21]2[O:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:18]([CH3:28])[C:17](=[O:29])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCO)cccc2c1=O
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)oc2c(C(=O)NCCCCl)cccc2c1=O
Reaction time: 1.5 h

Procedure:
A solution of 1.1 ml of thionyl chloride in 2 ml of chloroform was added to a boiling solution of 3.37 g of Intermediate XXXVI in 20 ml of chloroform. After stirring for 90 minutes under reflux, the solvent was removed in vacuo and the residue was crystallized from acetonitrile to give 3 g of pure title compound, m.p. (188) 193°-194° C.
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:17]#[N:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2].OO.C(=O)([O-])[O-:22].[K+].[K+]>CS(C)=O>[C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:18])=[O:22])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C#N
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 282.3 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 5-(sec-butylamino)-4-cyano-2-methylbenzoate (300 mg, 1.22 mmol) in DMSO (1.5 mL) was added 30% hydrogen peroxide solution (258 μL, 8.96 mmol) and potassium carbonate (56 mg, 0.402 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h, at which time it was concentrated in vacuo. The residue was purified by flash chromatography (100% hexanes to 10% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoate (300 mg, 93%) as yellow crystals. MS (EI) for C14H20N2O3: 265 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: CCS(=O)(=O)Nc1ccccc1Br
Product: CCS(=O)(=O)Nc1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 34 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and N-(2-bromophenyl)ethanesulfonamide. MS (ESI): mass calcd. for C18H17FN4O2S, 372.11; m/z found, 372.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.43-8.36 (m, 1H), 8.04 (d, J=1.0, 1H), 7.93 (m, 1H), 7.46-7.28 (m, 6H), 6.72 (s, 2H), 2.91 (q, J=7.4, 2H), 1.07 (t, J=7.3, 3H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][C:34]([OH:36])=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:27]=2[CH2:32][CH2:33][C:34]3=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)CCc1ccccc1Cc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1CCc2c(Cc3ccc(Cl)cc3)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To stirred polyphosphoric acid, prepared from 100 g. of phosphorus pentoxide and 70 ml. of phosphoric acid, 5.0 g. of 3-[o-(p-chlorobenzyl)phenyl]propionic acid is added. The mixture is stirred at 110°-120°C for 2 hours. Upon addition of ice-water, yellow crystals separate out. These crystals are collected by filtration, washed with water and dried. The crystals are purified by column chromatography (silica gel; eluted with a 40 : 1 mixture of benzene and ethyl acetate. The described procedure gives 4-(p-chlorobenzyl)indan-1-one as crystals melting at 87°-88°C.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:12](OC)(=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[SH:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]2[S:15][C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[C:12](=[O:20])[N:9]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccccc1S
Reactant: CC(=O)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cc1
Yield: 1.8 %

Procedure:
A mixture of 4-acetylbenzonitrile (2.00 g, 14 mmol), methyl thiosalicylate (4.63 g, 28 mmol), triethylamine (2.79 g, 28 mmol) and toluene (10 ml) was heated and refluxed for 72 hours under a nitrogen flow. The reaction solution was concentrated under reduced pressure and the residue was applied to column chromatography using silica gel (100 g). Fractions eluted with hexane-ethyl acetate (3:1, v/v) were concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the title compound (0.07 g, 2%) as crystals.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][C@H:5]([CH2:7][OH:8])[N:4]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[C:3]1=[O:21].FC1(F)C[C@H](CO)N(CCCCCCC(OC)=O)C1=O>>[F:22][C:2]1([F:1])[CH2:6][C@H:5]([CH:7]=[O:8])[N:4]([CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:13]=2)[C:3]1=[O:21]
Reactant: COC(=O)c1ccc(CCCN2C(=O)C(F)(F)C[C@@H]2CO)s1
Agent: COC(=O)CCCCCCN1C(=O)C(F)(F)C[C@@H]1CO
Product: COC(=O)c1ccc(CCCN2C(=O)C(F)(F)C[C@@H]2C=O)s1

Procedure:
(R)-Methyl 5-(3-(3,3-difluoro-5-formyl-2-oxopyrrolidin-1-yl)propyl)thiophene-2-carboxylate was prepared from 12f using the oxidation procedure (Step K) described for the preparation of intermediate 13a from intermediate 12a to afford the title intermediate (80 mg) as a pale yellow oil; TLC Rf 0.60 (solvent system: 7:93 v/v methanol-dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][C:9]=2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C#N)c2)c(-c2cccc(Cl)c2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cc(C(=O)O)sc2-c2cccc(Cl)c2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
182 mg (0.50 mmol) of the compound from Example 17A are provided in 2 ml of dioxane, and 4.4 ml (8.80 mmol) of a 2N aqueous lithium hydroxide solution are added. The mixture is stirred at 50° C. for 2 hours and subsequently concentrated. The residue is diluted with water, a concentrated aqueous HCl solution is added until an acidic pH is obtained and the mixture is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by preparative HPLC (RP18 column; eluent: acetonitrile/water gradient). 159 mg (95% of theory) of the title compound are obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([O:23]CC)=[O:22])=[CH:8]1>S(=O)(=O)(O)O.C(O)(=O)C.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([F:18])[C:15]=2[F:17])[C:10](=[O:20])[C:9]([C:21]([OH:23])=[O:22])=[CH:8]1
Reactant: CCOC(=O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cn(Cc2nccs2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.3 %

Procedure:
A mixture of 6.0 g of ethyl(2,3,4,5-tetrafluorobenzoyl)acetate, 5.8 g of ethyl orthoformate and 6.3 g of acetic anhydride was refluxed for 2 hours. After distillation under reduced pressure, the residue was dissolved in 50 ml of ethanol. To this solution, 2.8 g of 2-aminomethylthiazole was added, followed by stirring for 2 hours, while ice cooling. The reaction product was added to 100 ml of ice water, and the resulting crystal was collected by filtration and dried. The 8.0 g crystal obtained was dissolved in 50 ml of dimethylformamide, and 2.0 g of 60% oily sodium hydride was added, followed by heating and stirring at 100° to 110° C. for 2 hours. The reaction product was added to 100 ml of ice water and extracted with dichloromethane (100 ml×3). The extract was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure, to yield 5.4 g of ethyl 1-(thiazol-2-yl)methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate. Next, 5.0 g of this ester was dissolved in a mixture of 3 ml of sulfuric acid, 20 ml of acetic acid and 18 ml of water, followed by stirring at 110° to 120° C. for 1.5 hours. The reaction product was added to 100 ml of ice water to cause crystallization. The resulting crystal was collected by filtration, washed with water and dried to yield 4.4 g of the title compound.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][NH:36][C:35](=O)[C@H:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:33][CH2:32]1>C1(C)C=CC=CC=1>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:31]1[CH2:37][NH:36][C:35](=[S:10])[C@H:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:33][CH2:32]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Temperature: 90 °C
Reaction time: 1 h
Yield: 188 %

Procedure:
Lawesson's reagent [2,4-Bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] (2.90 g, 7.18 mmol) was added to a suspension of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (4.79 g, 14.1 mmol) in toluene (250 mL) and the mixture was heated to 90° C. After 1 h, the reaction was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (100% dichloromethane→85% dichloromethane/ethyl acetate) gave a white solid. This solid was repurified by silica gel chromatography (20% ethyl acetate/hexanes→30% ethyl acetate/hexanes) to give the title compound (4.81 g). MS 357.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 8.30 (s, 1H), 7.10-7.04 (m, 2H), 6.94-6.91 (m, 1H), 6.50 (d, J=6.1 Hz, 1H), 4.62 (dd, J=10.3, 3.7 Hz, 1H), 4.13-3.88 (m, 1H), 3.36 (dd, J=14.7, 7.1 Hz, 1H), 3.07 (t, J=11.2 Hz, 1H), 2.32-2.21 (m, 2H), 2.14-2.12 (m, 1H), 1.79-1.72 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.NC1C=NC=NC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([CH3:27])[C:24]([NH2:26])=[O:25])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][CH:14]=[N:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C)c2)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cncnc2)ncc1Cl
Temperature: 120 °C

Procedure:
A mixture of 2-(2-(2-(5-chloro-2-(1-methyl-1H-pyrazol-4-ylamino)pyrimidin-4-ylethyl)phenyl)propanamide A30 (0.080 g, 0.25 mmol), 5-aminopyrimidine (0.047 g, 0.49 mmol), Xantphos (0.0057 g, 0.010 mmol) and Cs2CO3 (0.24 g, 0.74 mmol) in 1,4-dioxane (3 mL) was bubbled with nitrogen for 10 minutes. Palladium (II) acetate (0.0011 g, 0.0049 mmol) was added and the mixture was heated at 120° C. under microwave irradiation for 20 minutes. The volatiles were removed in vacuo and the residue was purified by silica gel column chromatography (Combiflash Rf, 0-10% MeOH in DCM) to give the title compound 40 as an off white solid (0.030 g, 32%). LCMS-C: rt 4.85 min; m/z 383 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])([OH:3])=[O:2].ClC(Cl)(Cl)C(=N)O[C:19]([CH3:22])([CH3:21])[CH3:20].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>ClCCl.C1CCCCC1>[C:5]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:5]=1[CH2:4][C:1]([O:3][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:2])([CH3:13])([CH3:6])[CH3:4]
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1ccc(CC(=O)O)c(C(=O)O)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Cc1ccc(CC(=O)OC(C)(C)C)c(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 166.7 %

Procedure:
To a suspension of 2-carboxymethyl-5-methyl-benzoic acid (2.544 g, 13.1 mmol) in anhydrous dichloromethane (70 ml) held at 0° C. was added tert-butyl 2,2,2-trichloroacetimidate (11.47 mg, 52.4 mmol, 2 equivalents) in cyclohexane (85 ml). BBr3 (0.52 ml) was then added, and the reaction mixture was raised to room temperature and stirred for 16 hr. Solid NaHCO3 was added to quench the reaction, the solid precipitate was filtered off and washed with ether. The combined organic washing was evaporated to dryness, and the residue obtained was purified by silica gel chromatography to obtain 2-tert-butoxycarbonylmethyl-5-methyl benzoic acid tert-butyl ester 3.345 g (83.3%) as an oil. 1H NMR (CDCl3): 7.718 (1H, s), 7.227 (1H, d, J=7.57 Hz), 3.910 (2H, s), 2.362 (3H, s), 1.584 (9H, s), 1.443 (9H, s). FABMS (+Ve), m/z 307 [MH+], 251 [MH+−C4H8], 195 [MH+−2C4H8]. Anal. calcd. for C18H26O4: C, 70.6; H, 8.6. Found: C, 70.82; H, 8.53.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:20]OS(C(F)(F)F)(=O)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][C:19]([F:33])([F:18])[C:29]([F:32])([F:31])[F:30])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCC(F)(F)C(F)(F)F)cn1

Procedure:
In a manner analogous to that described in example 24 a), the alkylation of the 5-hydroxy-pyridine-2-carboxylic acid methyl ester with potassium carbonate and trifluoro-methanesulphonic acid 2,2,3,3,3-pentafluoropropyl ester yielded the 5-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid methyl ester as a light yellow oil. MS (ISP): m/z=285 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([CH:19]=[CH2:20])[CH:16]=[C:15]([F:21])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.B1C2CCCC1CCC2.[OH-:31].[Na+].OO>C1COCC1>[F:21][C:15]1[CH:16]=[C:17]([CH2:19][CH2:20][OH:31])[CH:18]=[C:2]([F:1])[C:3]=1[O:4][C:5]1[CH:10]=[N:9][C:8]([C:11]([F:12])([F:13])[F:14])=[N:7][CH:6]=1
Reactant: C=Cc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 152.4 %

Procedure:
To the solution of 5-(2,6-difluoro-4-vinylphenoxy)-2-(trifluoromethyl)pyrimidine (1.67 g, 5.53 mmol) in dry THF (25 mL), was added 9-BBN (20 ml, 10.00 mmol) at 0° C. The mixture was stirred at room temperature overnight, and quenched with water (2 mL), followed by aq. NaOH (7 mL, 21.0 mmol), and 30% H2O2 (7 mL, 5.53 mmol). The reaction mixture was heated at 50° C. for 3 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (2.7 g, 8.43 mmol, 153% yield) as a white oil. LCMS: rt=2.97 min, [M+H+]=321
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]1[CH:11]([CH3:12])[CH2:10]1>>[OH:9][CH:11]([CH3:12])[CH2:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CC1CO1
Product: CC(O)CNc1ccc(Cl)cc1
Yield: 61 %

Procedure:
4-Chloroaniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-4-chloro-aniline with a yield of 61.0%; b.p.: 158°-164° C./0.3 mm Hg.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:10]/[CH:11]=[CH:12]/[CH3:13])[C:6]([O:8][CH3:9])=[O:7])/[CH:2]=[CH:3]/[CH3:4].[H][H]>CO.O=[Pt]=O>[CH2:1]([C:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: C/C=C/CC(C/C=C/C)(C(=O)OC)c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: CCCCC(CCCC)(C(=O)OC)c1ccccc1
Yield: 95.9 %

Procedure:
A solution of the product of Example 4A (7.78 g, 30.16 mmol) in methanol (70 mL) was treated with Adams' catalyst (PtO2, 790 mg) and hydrogenated under 60 psi hydrogen pressure for 16 hours at 25° C. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (7.59 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.27 (m, 5 H), 3.64 (s, 3 H), 1.99 (m, 4 H), 1.29 (m, 4 H), 1.03 (m, 4 H), 0.86 (t, J=7.17 Hz, 6 H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:17])[NH:11][C:12]1[CH:16]=[CH:15][O:14][N:13]=1)(C)(C)C.[ClH:19]>O1CCOCC1>[ClH:19].[NH2:7][CH2:8][CH2:9][C:10]([NH:11][C:12]1[CH:16]=[CH:15][O:14][N:13]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)NCCC(=O)Nc1ccon1
Agent: Cl
Solvent: C1COCCO1
Product: NCCC(=O)Nc1ccon1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
[2-(Isoxazol-3-ylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (0.702 g, 2.76 mmol) in dioxane (5 ml) is treated with 4M HCl in dioxane (3.44 ml) and stirred at room temperature for 3 days. The solvent is removed in vacuo and co-evaporated with toluene to afford the title compound as a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][C:13]([C:19]([O:21]C)=[O:20])=[CH:12][C:11]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:16](=[O:17])(=[O:18])[CH2:15][CH2:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[CH:23]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccccc3OC)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Into a solution of methyl 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (230 mg) in THF-methanol (5-2.5 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (164 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was mixed with 1 N hydrochloric acid (10 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (172 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40]C)=[O:39])=[CH:34][C:33]=2[Cl:42])[C:26]([F:31])=[CH:27][C:28]=1[O:29][CH3:30])[C:8]([O:10][CH3:11])=[O:9].O.[OH-].[Li+].O.Cl>[Cl-].[Na+].O.O1CCOCC1>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:24]=[C:25]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([OH:40])=[O:39])=[CH:34][C:33]=2[Cl:42])[C:26]([F:31])=[CH:27][C:28]=1[O:29][CH3:30])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C(=O)OC)c(OC)cc2F)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(-c2ccc(C(=O)O)cc2Cl)c(F)cc1OC

Procedure:
Methyl 2″-{[[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino]methyl}-2-chloro-6′-fluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′, 1″-terphenyl-4-carboxylate (34.7 mg, 0.0486 mmol), lithium hydroxide monohydrate (10 mg, 0.238 mmol), water (0.4 mL) and 1,4-dioxane (1 mL) were stirred at room temperature for 5.5 hours to complete the reaction. Crude mixture was acidified by HCl (aq, 1N, 6 mL). The resulting mixture was worked up with brine and extracted with ethyl acetate. The combined extracts were back-washed with water. The resulting organic layer was dried over Na2SO4, filtered and evaporated in vacuo to afford a clear oil. The resulting oil was purified on SiO2 to afford as a clear glass 2″-{[[3,5-bis(trifluoromethyl)benzyl](methoxycarbonyl)amino]methyl}-2-chloro-6′-fluoro-4′-methoxy-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylic acid. LCMS calc.=699.17; found=700.29 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.01 (s, 1H), 7.95 (d, J=7.5 Hz, 1H), 7.72 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.55-7.46 (m, 1.5H), 7.43-7.34 (m, 2.5H), 7.32-7.25 (m, 1H), 7.07-7.5 (m, 1H), 4.62-4.22 (m, 4H), 3.77 (s, 3H), 3.73 (d, J=17 Hz, 3H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18]([O-:20])=O)[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Na+].F[C:25]1C=CC(COC2C=C3C(C=C(C(OCC)=O)C=N3)=CC=2)=CC=1.[OH-].[Na+]>CO.C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:18](=[O:20])[CH3:25])[CH:14]=[N:15]3)=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Reactant: O=C([O-])c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1cnc2cc(OCc3ccc(F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium 7-((4-fluorobenzyl)oxy)quinoline-3-carboxylate. To a solution of ethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2, 430 mg, 1.32 mmol) in MeOH (2 mL) and THF (2 mL) was added NaOH (95 mg, 2.38 mmol) in H2O (2.0 mL). The reaction was stirred for 15 minutes at ambient temperature. The crude reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.63 (dd, J=5.5, 8.6 Hz, 2H), 7.50 (d, J=2.7 Hz, 1H), 7.35-7.25 (m, 3H), 5.31 (s, 2H). [M+H]=298.2
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>O1CCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(O)cc(CO)c1
Yield: 82.9 %

Procedure:
To a solution of dimethyl 5-hydroxyisophthalate (28 g, 133 mmol, 1 eq.) in 1400 mL of dry tetrahydrofuran (THF) at ice-bath temperature, lithium aluminum hydride (LiAlH4 or LAH, 4 eq.) was slowly added with stirring. The resultant mixture was allowed warm to 40° C., stirred at this temperature for 16 hours, and then was added an ammonium chloride (NH4Cl) aqueous solution to quench the reaction. After stirring for 1.5 hours, the mixture was filtered with celite, washed with THF. Organic volatiles were evaporated and the residue was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc three times. The combined EtOAc layers were dried over MgSO4 to give product (5-hydroxy-1,3-phenylene)dimethanol (17 g, 82%).