Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1)(=O)C.[ClH:39]>CO.C(Cl)Cl>[ClH:39].[OH:6][C:7]1[CH:8]=[C:9]([CH:35]=[CH:36][C:37]=1[CH3:38])[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1nc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 37 %

Procedure:
2M Aqueous sodium hydroxide solution (900 μl) was added to a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline (290 mg, 0.6 mmol) in methanol (15 ml) and methylene chloride (12 ml) and the mixture stirred for 25 minutes at ambient temperature. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The solid residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 and 95/5). The purified white solid was suspended in methanol (20 ml) and a solution of 7.5M hydrochloric acid in methanol (2 equivalents) was added. The solid was collected by filtration, washed with methanol and then pentane and dried under vacuum at 50° C. to give 4-(3-hydroxy4-methylanilino)-6-methoxy-7-((1-methylbenzimidazol-2-yl)methoxy)quinazoline hydrochloride (106 mg, 37%).
Reaction SMILES: [CH3:1]C(C)=O.C(=O)([O-])[O-].[K+].[K+].CI.[OH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]>>[CH3:1][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH2:25][CH3:26])[O:20][C:19]([CH3:28])([CH3:27])[CH2:18][C:17]2=[O:29]
Reactant: CC(C)=O
Reactant: CCOc1cc2c(cc1O)C(=O)CC(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Temperature: 0 °C
Yield: 92 %

Procedure:
In 100 ml of acetone 4.7 g (20 millimoles) of 6-hydroxy-7-ethoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 4.1 g (30 millimoles) of potassium carbonate and 4.5 g (2 ml, 30 millimoles) of methyl iodide are added. The reaction mixture is refluxed for 4 hours, the inorganic salt is filtered off, washed twice with 20 ml of acetone and the half of the solvent is removed. The residue is cooled to 0° C., the precipitated product is filtered off and dried to constant weight. Thus 4.6 g of the desired compound are obtained, yield 92%. Mp.: 120°-122° C.
Reaction SMILES: [C:1]1([NH:7][C:8](=[S:14])[NH:9][CH2:10][C:11](N)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15](I)[CH3:16]>C(O)C>[CH2:15]([S:14][C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11](=[O:12])[CH2:10][N:9]=1)[CH3:16]
Reactant: NC(=O)CNC(=S)Nc1ccccc1
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1ccccc1
Yield: 41.5 %

Procedure:
A mixture of 2-(3-phenyl-thioureido)-acetamide (7.1 g), ethyl iodide (18.0 g), and ethanol (300 mL) was heated at reflux for 2 hours. The solvent was evaporated. The residue was dissolved in chloroform (300 mL) and water (300 mL). The organic phase was washed with water, dried over anhydrous MgSO4, then evaporated to dryness. The residue was crystallized from ethyl acetate/hexane to give the title compound (3.1 g), m.p. 79°-81° C. Anal. Calcd. for. C11H12N2O S: C, 59.97; H, 5.49; N, 12.72. Found: C, 59.67; H, 5.35; N, 12.70. Mass spectrum (EI, M.+) m/z 220. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.43-7.52 (m, 3 H), 7.28-7.31 (m, 2 H), 4.32 (s, 2 H), 3.07 (q, 2 H), and 1.27 ppm (t, 3 H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH2:22][CH2:21][CH2:20]2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:23]1[C:24]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH2:22]1)=[O:14]
Reactant: COc1ccc2c(c1)CCCN2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: COc1ccc2c(c1)CCCN2C(=O)CSc1nc2ccccc2s1

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 6-methoxy-1,2,3,4-tetrahydroquinoline to yield 39 (245 mg, 1.5 mmol). MS (APCI: m/z 371 [M+H]+. Anal. Calcd. for C19H18N2O2S2: C, 61.60; H, 4.90; N, 7.56. Found: C, 61.49; H, 4.87; N, 7.59.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][N:19]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-(3-chloro-4-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 81A (160 mg, 80% purity, 0.37 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (85 mg, 0.51 mmol) to yield 12 mg (7%).
Reaction SMILES: B.[Na].[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[C:18]([C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)=[O:24])=[C:19]([OH:22])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]>O1CCCC1.C(O)(=O)C.O>[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:38][O:39][CH3:40])[C:12]([NH:14][CH:15]2[C:36](=[O:37])[N:17]3[CH:18]([C:23]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=4)=[O:24])[CH:19]([OH:22])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=[O:4]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Agent: B
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(O)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.92 h
Yield: 76.7 %

Procedure:
Sodium boron hydride (160 mg.) was added to a suspension of 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 1 g.) in tetrahydrofuran (10 ml.), acetic acid (3 ml.) and water (1 ml.) at 0° C. over 10 minutes, and stirred at 0° to 3° C. for 55 minutes. After water was added to the resultant solution, the solution was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was pulverized with diethyl ether to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetamido]-3-hydroxycepham-4-carboxylate (syn isomer, 0.77 g.), mp 172° to 175° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(Cl)Cl>C(O)CCC>[Cl:18][C:15]1[N:16]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[C:12]([CH3:11])=[CH:13][N:14]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCO
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
3,4-Dichloroaniline (639 mg, 3.94 mmol) and concentrated hydrochloric acid (ca. 12M, 0.2 ml, ca. 2.4 mmol) were sequentially added to a solution of 5-methyl-2,4-dichloropyrimidine (643 mg, 3.94 mmol) in n-butanol (20 ml). The mixture was stirred at ambient temperature for 20 hours, after which time a gelatinous precipitate had fallen out of solution. DCM was added until a solution was obtained, and silica (2.5 g) was added. Volatile material was removed by evaporation and the residue was loaded on a Varian Mega Bond Elut column pre-conditioned with ethyl acetate. The column was eluted with 0-10% methanol solution in ethyl acetate containing 0.5% aqueous ammonia. The appropriate fractions were concentrated, and the residue was triturated with n-butanol (20 ml). The filtrate was evaporated onto silica (2.5 g) and loaded on a Varian Mega Bond Elut column pre-conditioned with isohexane. The column was eluted with 0-50% ethyl acetate solution in isohexane. Concentration of the appropriate fractions gave the product as a white solid (340 mg, 26%). NMR: 2.17 (s, 3H), 7.60 (d, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.11 (s, 1H), 8.97 (s, 1H); MS (MH+): 288.1, 290.1, 292.1.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:16].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:11]([F:16])=[O:13])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: Fc1nc(F)nc(F)n1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-alanine, 24b, (189.2 mg, 1.00 nmmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in CH2Cl2, and precipitated with hexane to afford 155.1 mg of a mixture of 24b and 25b as white crystals. FTIR (film) 1842 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
(S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) was dissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA(0.65 g, 5 mmol) were added to the above mixture. The mixture which resulted was stirred at room temperature for a few minutes. PyBroP(2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (150 mL) and washed with NaHCO3 (50 mL×2, sat.). The organic layer was collected and dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography to provide the desired product (0.85 g, 62%).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[C:6]([OH:19])[C:7]([Cl:18])=[CH:8][C:9]=2[Cl:17])[N:4]=1.[CH3:20][NH2:21]>C1COCC1.C(O)C>[ClH:1].[Cl:17][C:9]1[CH:8]=[C:7]([Cl:18])[C:6]([OH:19])=[C:5]2[C:10]=1[C:11](=[O:16])[N:12]([CH2:13][CH2:14][CH3:15])[C:3]([CH2:2][NH:21][CH3:20])=[N:4]2
Reactant: CCCn1c(CCl)nc2c(O)c(Cl)cc(Cl)c2c1=O
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CCCn1c(CNC)nc2c(O)c(Cl)cc(Cl)c2c1=O
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 2-chloromethyl-5,7-dichloro-8-hydroxy-3-n-propyl-3H-quinazolin-4-one (285 mg, 0.886 mmol) in anhydrous THF (1.3 mL) was added a solution of methylamine in ethanol (7.5 mL of a 8.0M solution, 60 mmol) dropwise under an argon atmosphere. The mixture was stirred at room temperature for 18 h, then concentrated, and to the resulting residue was added 2M HCl (5 mL). The mixture was evaporated and more 2M HCl (5 mL) was added. The residue was evaporated and the procedure repeated two more times. The mixture was triturated with dichloromethane and dried in vacuo to yield 5,7-dichloro-8-hydroxy-2-methylaminomethyl-3-n-propyl-3H-quinazolin-4-one hydrochloride (4-9A) as a yellow solid (157 mg, 50%)(Table 6).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH2:22]C2C=CC=CC=2)=[O:20])[CH:3]=1.CO.C[O-].[Na+]>O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([O:16][CH3:17])[C:10]=2[F:18])[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:3]=1
Reactant: COc1c(Cl)ccc(-c2nc(C(=O)OCc3ccccc3)cc(N)c2F)c1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(OC)c2F)n1
Reaction time: 24 h

Procedure:
Benzyl 4-amino-5-fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinate (3.00 g, 7.41 mmol) was added to CH3OH (35 mL). Sodium methoxide (25 wt % in CH3OH; 2.0 mL, 8.9 mmol) was added to the reaction mixture and allowed to stir for 24 h. Water (50 mL) was added to the reaction mixture and the mixture was concentrated under reduced pressure to remove most of the CH3OH. The mixture was extracted with EtOAc (2×40 mL), and the combined organic layers were washed with water (40 mL) and satd sodium chloride (40 mL) and concentrated under reduced pressure to provide methyl 4-amino-6-(4-chloro-2-fluoro-3-methoxyphenyl)-5-fluoropicolinate as a pale yellow solid (1.86 g; 67% purity by LC area).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]#[N:13])[O:8][CH2:7][CH2:6]/[C:5]/2=[CH:14]\[O:15]C.BrB(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]#[N:13])[O:8][CH2:7][CH2:6][CH:5]2[CH:14]=[O:15]
Reactant: CO/C=C1\CCOc2cc(C#N)c(F)cc21
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cc2c(cc1F)C(C=O)CCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
(4E)-6-fluoro-4-(methyoxymethylidene)-3,4-dihydro-2H-chromene-7-carbonitrile (38 mg, 0.17 mmol) was dissolved in dichloromethane (6 mL). The solution was cooled to −78° C. To above solution was added tribromoborane (260 μL, 1 M, 0.26 mmol) dropwise. The reaction was stirred for 30 min at −78° C. To the reaction mixture was added saturated sodium bicarbonate, extracted with dichloromethane (2×20 mL). The organic phase was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and used without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=C[C:22]([C:25](F)([F:27])F)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].ClC1C2C=C(F)C=CC=2SC=1C(Cl)=O>>[Cl:1][C:2]1[C:3]2[CH:24]=[C:25]([F:27])[CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Agent: O=C(Cl)c1sc2ccc(F)cc2c1Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2ccc(F)cc2c1Cl

Procedure:
Following the 5a synthetic method, using 3-chloro-5-fluorobenzo[b]thiophene-2-carbonyl chloride (62.27 mg, 0.25 mmol) instead of 5 gave 12a as a white powder; (82.6 mg, 91.7%). [α]D25: −16.8 (c=0.16, CHCl3); 1H-NMR (300 MHz, acetone-d6): δ 8.10-8.06 (m, 1H), 7.81 (d, J=6.9, 1H), 7.61-7.57 (m, 1H), 7.46-7.28 (m, 6H), 5.03-4.97 (m, 1H), 3.45-3.26 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.51, 163.02, 159.79, 138.08, 136.67, 135.36, 133.43, 129.49, 128.39, 126.88, 125.28, 118.22, 116.80, 116.46, 108.25, 107.92, 54.15, 36.79; HRMS (ESI): calcd for: C18H13ClFNO3S [M−H]−=376.0216, obsd [M−H]−=376.0200.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([CH3:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[CH3:21])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:22][CH:23]([C:28](=O)[CH2:29][CH3:30])[C:24](OC)=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:3]([O:12][C:13]2[C:19]([CH3:20])=[C:18]3[C:16](=[CH:15][C:14]=2[CH3:21])[N:17]=[C:28]([CH2:29][CH3:30])[C:23]([CH3:22])=[C:24]3[OH:25])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: Cc1cc(N)cc(C)c1Oc1ncc(C(F)(F)F)cc1Cl
Reactant: CCC(=O)C(C)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CCc1nc2cc(C)c(Oc3ncc(C(F)(F)F)cc3Cl)c(C)c2c(O)c1C

Procedure:
A solution of 1.52 9 of 4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-3,5-dimethylaniline, 1.75 g of methyl 2-methyl-3-oxopentanoate, and 0.92 g of p-toluenesulfonic acid dissolved in 49 mL of xylene was heated under reflux for 8 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with n-hexane and distilled water and were dried to give 2.56 g of 6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-4-hydroxy-3,5,7-trimethyl-quinoline. Dimethylacetamide (30 mL) was then added to 1.97 g of the crystals thus obtained, and 0.38 g of 60% sodium hydride and 0.9 g of methyl chloroformate were added thereto at room temperature. The mixture was stirred at room temperature for 2 hr, and ethyl acetate and distilled water were then added. The organic layer was washed with brine and was then concentrated under the reduced pressure. The crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane /ethyl acetate) to give 1.25 g of 4-methoxycarbonyloxy-6-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-2-ethyl-3,5,7-trimethylquinoline (yield 55.6%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28](O)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:34]
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Reactant: Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Reaction time: 9 h
Yield: 77.4 %

Procedure:
In 30 ml of dichloromethane was dissolved 0.50 g of (−)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N′-(3-methoxyphenyl)ureido)indolin-2-one, and 0.22 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 0.20 g of p-toluidine were successively added thereto. After stirring the mixture for 9 hours, the reaction mixture was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.46 g of the title compound as a white powder. Because the compound is an enantiomer of the compound of Example 188, the NMR data are the same as those of the latter compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([O:16]CC1C=CC=CC=1)=[CH:5][C:6]([C:13](=[O:15])[CH3:14])=[N:7]2.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([C:13](=[O:15])[CH3:14])[NH:7]2
Reactant: CC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-4-benzyloxy-2-acetylquinoline (0.75 g, 2.2 mmol) and trifluoroacetic acid (55 mL) and heat to 80° C. After 4 hours evaporate the reaction mixture in vacuo to give a residue. Recrystallize the residue from acetonitrile to give the title compound; mp, 277°-278° C. (dec). Rf =0.29 TLC/silica gel/5% acetone in dichloromethane. Elem. Anal. Calcd. for C11H7Cl2 NO2 : C, 51.59; H, 2.76; N, 5.47. Found: C, 50.65; H, 2.83; N, 5.26.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=1)(=[O:4])=[O:3].O.[OH-].[Li+]>CO.O>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C:13]([OH:15])=[O:14])=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)Cc1ccc(NS(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1

Procedure:
The solution of ethyl 2-(4-(methylsulfonamido)phenyl)acetate (200 mg, 0.77 mmol) and lithium hydroxide hydrate (130.4 mg, 3.11 mmol) in MeOH/H2O (10 mL, 1:1) was stirred at room temperature for 12 h. The reaction mixture was evaporated under reduced pressure. The residue was used for the next step without purification. LC-MS: m/z (M+H)=230.4
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]1[O:4][CH2:3]1.[OH2:14]>C(O)(=O)CCCCCCCCCCC.[OH-].[Na+]>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH:2]([CH2:3][OH:14])[OH:4]
Reactant: CCCCCCCCOCC1CO1
Reactant: O
Agent: CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCC(O)CO
Temperature: 157 °C
Yield: 86 %

Procedure:
The crude octyl glycidyl ether (175 g), water (110 g; 6.111 mol), lauric acid (7.10 g; 0.033 mol) and sodium hydroxide (0.71 g; 0.018 mol) were placed in a 2-l autoclave, and the mixture was heated up to 157° C. while stirring it. The mixture was stirred for 5 hours as it was, and was then allowed to cool down to room temperature. The mixture was extracted with ethyl acetate (500 ml), and the extract was washed twice with water (300 ml). The solvent was then distilled off to obtain 165 g of crude monooctyl glyceryl ether. This crude product was purified by vacuum distillation (0.4-0.5 mmHg, 120-123° C.) to obtain 124 g of monooctyl glyceryl ether as a colorless transparent oil (total yield: 75%). Quenching of a proton signal (methylene in an epoxy ring) at δ=2.65, 2.80 was observed by 1H-NMR (200 MHz), thereby identifying the compound. The purity of the compound was found to be 99% by GLC.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1.C=O.[C:21](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]([CH3:21])[CH2:10][C:11]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(CNCc1cccc(Br)n1)NC1CCCC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(CC(=O)NC1CCCC1)Cc1cccc(Br)n1
Reaction time: 0.75 h

Procedure:
N2-[(6-Bromopyridin-2-yl)methyl]-N-cyclopentylglycinamide (Example 187, Step 1) (0.33 g, 1.06 mmol) was dissolved in dichloromethane (5.30 mL) and formaldehyde (0.087 mL, 1.17 mmol) and acetic acid (0.12 mL, 2.12 mmol) were added. The reaction was stirred for 45 minutes and sodium triacetoxyborohydride (0.36 g, 1.70 mmol) was added. Once complete, the reaction was then quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude mixture was purified by silica gel chromatography to yield the title compound.