Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH2:6][C:7]([C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([C:7]([CH3:9])([CH3:8])[CH2:6][C:5]([C:19]([F:21])([F:22])[F:20])([OH:23])[CH2:4][OH:3])[CH:15]=1
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CO)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a chilled solution (ice-water bath) of 6 g (17.0 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanoic acid ethyl ester in 60 mL of dry THF, 2.4 g (61.5 mmol) of lithium aluminum hydride was added in portions. After the addition, the cold bath was removed and the mixture was stirred at room temperature overnight. The mixture was then warmed at reflux for 3 hours and then cautiously quenched by slow addition to 100 mL of THF containing 2 mL of water. Additional water was then cautiously added for a total of 15 mL and the resulting mixture stirred for 2 hours. The excess water was dried with magnesium sulfate and 300 mL of EtOAc was added. After 1 hour, the mixture was filtered through diatomaceous earth and concentrated in vacuo to afford 4.9 g (92%) of 4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-trifluoromethylpentane-1,2-diol as an oil.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[I:21]I>C1COCC1>[C:6]([O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[C:14]=1[I:21])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1
Reactant: II
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
tert-Butyllithium (36.3 mL, 1.7M in pentane) is added dropwise to a solution of (2-chloro-pyridin-4-yl)-carbamic acid tert-butyl ester (6.00 g, 26.2 mmol) in THF (46 mL) at −78° C. under Ar. The yellow/orange mixture is stirred for 2 h at −78° C. then warmed to −40° C. for 1 h then cooled to −78° C. before dropwise addition of I2 (15.65 g, 61.7 mmol) in THF (49 mL). The reaction mixture is stirred for 1.5 h at −78° C. then at −10° C. for 30 minutes. The reaction is quenched with saturated NH4Cl solution then diluted with CH2Cl2 and washed with saturated NH4Cl, saturated sodium thiosulfate, water then brine. The organic layer is dried over MgSO4, filtered and concentrated to dryness. The crude product is chromatographed eluting with 1-2% MeOH/CH2Cl2 to yield the title product (7.96 g, 22.5 mmol) as a bright yellow solid. 1H NMR (CDCl3, 300 MHz) δ8.14 (d, 1H), 8.02 (d, 1H), 7.32 (bs, 1H), 1.60 (s, 9H). EI MS [M]+=354, 356, Cl pattern.
Reaction SMILES: [C:1]1([C:9]([CH:11]([C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)O)=O)[CH:8]=[CH:7][C:4]([O:5][CH3:6])=[CH:3][CH:2]=1.[CH3:21][NH:22][C:23]([NH2:25])=[S:24]>>[CH3:6][O:5][C:4]1[CH:7]=[CH:8][C:1]([C:9]2[N:25]=[C:23]([SH:24])[N:22]([CH3:21])[C:11]=2[C:13]2[CH:20]=[CH:19][C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)=[CH:2][CH:3]=1
Reactant: CNC(N)=S
Reactant: COc1ccc(C(=O)C(O)c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc(S)n(C)c2-c2ccc(OC)cc2)cc1

Procedure:
13.6 g (50 mmol) of p-anisoin and 6.8 g (75 mmol) of N-methylthiourea were reacted as in example 10. The yield was 7.4 g.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[N:10][CH:9]=[N:8]1.[CH3:12][NH:13][C:14]1(C#N)[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1>O1CCCC1>[CH3:12][NH:13][C:14]1([C:11]2[N:7]([CH3:6])[N:8]=[CH:9][N:10]=2)[CH2:23][CH2:22][C:17]2([O:21][CH2:20][CH2:19][O:18]2)[CH2:16][CH2:15]1
Reactant: CNC1(C#N)CCC2(CC1)OCCO2
Reactant: Cn1cncn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC1(c2ncnn2C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Butyllithium (2.5 M in hexane, 9.2 ml, 23.0 mmole) was added to a reaction vessel under an argon atmosphere and cooled to −78° C. 1-methyl-1,2,4-triazole (1.30 ml, 23 mmole) was dissolved in absolute tetrahydrofuran (60.0 ml) and added dropwise at −78° C. while cooling with ice. The reaction mixture was then stirred for 10 minutes at this temperature. 8-methylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (2.12 g, 10.8 mmole) in absolute tetrahydrofuran (15 ml) in a cooling bath maintained at −78° C. was then quickly added dropwise to the formed solution. After the addition the reaction solution was stirred for 1 hour in the cooling bath and was then slowly heated to 0° C. The reaction mixture was stirred overnight at room temperature. The mixture was then hydrolysed at 0° C. with water (10 ml), the aqueous phase was extracted with chloroform (3×50 ml), and the organic phase was washed with water (50 ml) and saturated NaCl solution (50 ml), dried over Na2SO4 and concentrated by evaporation in vacuo. The product was purified by means of flash chromatography with chloroform/methanol (15:1).
Reaction SMILES: C(O)C.Cl.[CH:5]1([C:8]2[CH:9]=[C:10]([C:30]([O:32]CC)=[O:31])[C:11](=[O:29])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH:24]([CH3:28])[NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1>C1COCC1>[CH:5]1([C:8]2[CH:9]=[C:10]([C:30]([OH:32])=[O:31])[C:11](=[O:29])[N:12]3[C:17]=2[C:16]([CH3:18])=[C:15]([C:19]2[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=2)[CH:24]([CH3:28])[NH:23][CH2:22]4)[CH:14]=[CH:13]3)[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4c(c3)CNC4C)ccn2c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CNC3C)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
7.6 ml ethanol, 2.5 ml of THF and 1.3 ml of 1N hydrochloric acid were added to 312.5 mg of ethyl 1-cyclopropyl-9-methyl-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylate (XIV) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure and water was added to the resulting residue and the resulting residue was washed with ethyl acetate, and thereafter, the resulting water layer was concentrated under reduced pressure. 10 ml of water, 5 ml of ethanol and 3 ml of 1N sodium hydroxide were added to the residue, which was stirred at 50° C. for 3 hours. The reaction solution was concentrated under reduced pressure, and thereafter, dissolved in 4 ml of water and neutralized with 1N hydrochloric acid. The precipitated crystal was separated by filtering to obtain 139.1 mg of 1-cyclopropyl-9-methyl-8-(1-methylisoindoline-5-yl)-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1O)=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:9])[CH3:6]>CN(C=O)C>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[Br:2])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][CH:14]=2)=[O:9])[CH3:6]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1Br
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
PBr3 (64.5 g, 22.5 mL, 0.239 mole) was added dropwise to a stirred, ice cold suspension of 4-hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester (59 g, 0.239 mole) in DMF (750 mL); the temperature rose to 15-20° C. for 30 min and then dropped to ca. 5° C. (the starting material dissolved fairly quickly and a new solid precipitated out). After 3 hr the solid was collected, washed sequentially with cold DMF, hexane, and water, then was dried at 40° C. in vacuo overnight to give the title compound (41 g, 78%): LC/MS (ES) m/e 310/312 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[ClH:22]>CCOCC>[ClH:22].[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccccc2n1Cc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C1Cc2ccccc2N1Cc1ccccc1

Procedure:
Ethyl-1-benzylindole carboxylate is reduced as in the above example 3. The obtained oil is dissolved in ether and ethanolic hydrogen chloride is added to yield ethyl-1-benzyl-2,3-dihydroindole-carboxylate hydrochloride, m.p. 123°-124° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[Br:15][C:16]1[S:20][C:19]([C@H:21]([NH2:23])[CH3:22])=[N:18][CH:17]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Br:15][C:16]1[S:20][C:19]([C@H:21]([NH:23][C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=2)[CH3:22])=[N:18][CH:17]=1
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Reactant: C[C@@H](N)c1ncc(Br)s1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ncc(Br)s2)cc1
Reaction time: 1 h

Procedure:
To a solution of 0.050 g (0.28 mmol) 4-isopropylphenyl acetic acid in 0.50 mL DMF and 1.0 mL CH2Cl2 was added 0.072 g (0.30 mmol) (1R)-1-(5-bromo-1,3-thiazol-2-yl)ethanamine hydrochloride, 0.042 g (0.31 mmol) HOAT, 0.059 g (0.31 mmol) EDC, and 0.093 mL (0.56 mmol) DIEA. After 1 h at room temperature, the reaction mixture was purified by preparative reverse-phase HPLC (5->95% CH3CN/H2O over 15 min, 0.05% added TFA, C18) to give N-[(1R)-1-(5-bromo-1,3-thiazol-2-yl)ethyl]-2-[4-(propan-2-yl)phenyl]acetamide. 1H NMR (CDCl3, 400 MHz) δ 7.54 (s, 1H); 7.59 (ABq, J=8.4 Hz, 4H), 6.55 (br d, J=7.6 Hz, 1H), 5.32 (quintet, J=7.2 Hz, 1H), 3.59 (s, 2H), 2.91 (m, J=7.2 Hz, 3H); 1.52 (d, J=7.2 Hz, 3H), 1.25 (d, J=7.2 Hz, 6H). HRMS (ES) [M+1]+ calcd for C16H19BrN2OS: 367.0474. Found: 367.0483.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([OH:19])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl.Cl[CH2:45][CH2:46][N:47]([CH3:49])[CH3:48]>CN(C)C=O>[Cl:1][C:2]1[CH:23]=[C:22]([C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[O:25])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@H:7]([C:17]([O:19][CH2:45][CH2:46][N:47]([CH3:49])[CH3:48])=[O:18])[CH2:8][NH:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)=[O:11])=[O:5]
Reactant: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2cccs2)C(=O)O)c(Cl)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 60 °C

Procedure:
A mixture of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine (Example 303; 1 mmol), potassium carbonate (2.1 mmol), potassium iodide (0.2 mmol), and (2-chloroethyl)dimethylamine hydrochloride (1.1 mmol) in N,N-dimethyl-formamide (10 mL) is heated at 60° C. for 3 h. The reaction mixture is concentrated to remove N,N-dimethylformamide. Water (50 mL) is added and the pH is adjusted to 9. The mixture is extracted with ethyl acetate (3×50 mL). The combined ethyl acetate layers are washed with brine (100 mL), dried (MgSO4), filtered, evaporated and chromatographed to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, 2-(dimethylamino)ethyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]2)(=O)[CH3:8].[C:24]([NH:27][NH2:28])(=O)[CH3:25]>C1(C)C=CC=CC=1>[CH3:8][C:7]1[N:10]([C:11]2[CH:12]=[C:13]3[C:18](=[C:19]([CH3:21])[CH:20]=2)[N:17]=[C:16]([O:22][CH3:23])[CH:15]=[CH:14]3)[C:24]([CH3:25])=[N:27][N:28]=1
Reactant: CC(=O)NN
Reactant: COc1ccc2cc(NC(C)=O)cc(C)c2n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc2cc(-n3c(C)nnc3C)cc(C)c2n1
Reaction time: 0.25 h
Yield: 26.3 %

Procedure:
Phosphorous pentachloride (1.0 g) was added to a stirred solution of 6-acetamido-2-methoxy-8-methylquinoline (1.0 g) in toluene (50 cm3) and the mixture was stirred at 50° for 15 minutes. Acetyl hydrazine (1.35 g) was then added and the mixture was stirred for 3 hours at 60°. The toluene was removed in vacuo, the residue dissolved in ethanol, and aqueous ammonia solution (S.G. 0.88) (25 cm3) was added. Dichloromethane (100 cm3) was added and the organic phase was separated. The aqueous phase was further extracted with dichloromethane (2×25 cm3), and the combined organic phases were dried (MgS04) and evaporated to give a solid which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with dichloromethane:methanol, 19:1. Combination and evaporation of appropriate fractions afforded 6-[3,5-dimethyl-1,2,4-triazol-4-yl]-2-methoxy-8-methylquinoline (0.306 g), which was recrystallised from toluene to give microcrystals, m.p. 211°-213° (0.066 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[N:19][OH:20])[C:11]1=[O:21].[OH-:22].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:12](=[N:19][OH:20])[C:11]([OH:21])=[O:22]
Reactant: Cc1ccc(Cl)c(N2C(=O)C(=NO)c3ccccc32)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)c(Nc2ccccc2C(=NO)C(=O)O)c1Cl

Procedure:
A solution of 1-(2,6-dichloro-3-methylphenyl)-1H-indole-2,3-dione-3-oxime (2.25 9) in 6 N NaOH (10 ml) and 4 ml MeOH is heated at 50° C. for two days without a reflux condenser. The resulting residue is taken up in water (50 ml) and filtered. It is neutralized with 1 N HCl with ice bath cooling. The precipitate is collected by filtration. The residue is air dried, dissolved in ether, and filtered. 2-[(2,6-Dichloro-3-methylphenylamino]-α-(hydroxylimino)-benzeneacetic acid (0.28 g, 50%) is precipitated from the ether solution by the addition of hexane, mp 152°-154° C. dec.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(Cl)Cl.[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:23][CH3:24])[CH2:19][CH2:18]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])O.[Na+]>O.C(N(CC)CC)C>[C:9]([O:13][C:14]([NH:16][C@H:17]1[CH2:18][CH2:19][C@H:20]([N:23]([CH3:24])[S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:22]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN([C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
254 μl of methanesulfonyl chloride was added to a methylene chloride solution containing 500 mg of N-tert-butoxycarbonyl-N′-methyl-trans-1,4-cyclohexanediamine (Reference Example 10-14 (1)) and 763 μl of triethylamine, and the mixture was stirred at room temperature for 14 hours. To the reaction mixture were added water, followed by an aqueous saturated sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrogencarbonate, water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was suspended in diisopropyl ether, and collected by filtration to obtain N-tert-butoxycarbonyl-N′-methyl-N′-methylsulfonyl-trans-1,4-cyclohexanediamine. Subsequently, this compound was treaded with hydrochloric acid to obtain-N-methyl-N-methyl-sulfonyl-trans-1,4-cyclohexanediamine (Reference Example 10-18 in Table 11).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[O:11]1CCO[CH:12]1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=1>>[CH:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=2)=[C:18]([CH3:23])[CH:17]=1)=[O:11]
Reactant: Cc1cc(C2OCCO2)ccc1O
Reactant: NC(=O)c1ccc(F)cn1
Product: Cc1cc(C=O)ccc1Oc1ccc(C(N)=O)nc1
Yield: 35.5 %

Procedure:
Using a method similar to Example 388 Part D, using 5-fluoropyridine-2-carboxamide (Example 388 Part C) (0.400 g, 2.85 mmol) and 4-[1,3]dioxolan-2-yl-2-methylphenol (Example 388, Part C2) (0.514 g, 2.85 mmol) gives the title compound (0.259 g): TLC [silica gel 60 F254, 30% ethyl acetate in dichloromethane] Rf=0.20; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=12.1 min, 73.1% purity.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1.O.CCOC(C)=O>C(Cl)Cl>[OH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C1NCCc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
BBr3 (4.75 mL, 47.5 mmol, in CH2Cl2) was added to a cold solution (ice-bath) of intermediate 18 (3.36 g, 18.98 mmol) in CH2Cl2 (100 mL). The mixture was then warmed to rt and stirred overnight. Water was carefully added dropwise to quench the reaction. EtOAc was added and the mixture was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated to afford 7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate 19) (2.46 g, 80%) as a white solid. mp: 201-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]([F:41])([F:40])[CH:29]([CH3:39])[O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([O:30][CH:29]([CH3:39])[C:28]([F:27])([F:40])[F:41])=[CH:32][CH:33]=1
Reactant: CC(Oc1ccc(CN)cc1)C(F)(F)F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C(F)(F)F
Yield: 89.3 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.2 mmol) with (±)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamine (515 mg, 2.3 mmol) in toluene (10 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to give (±)-7-chloro-6-[4-(2,2,2-trifluoro-1-methyl-ethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (530 mg, 90%). GC-MS m/z: 494 (M+).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:9][CH2:8][C@@H:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:6]1.N1C=CC=CC=1>C(Cl)Cl>[O:15]=[C:11]1[N:10]([C@@H:7]2[CH2:8][CH2:9][O:5][CH2:6]2)[CH2:14][CH2:13][N:12]1[C:1]([Cl:4])=[O:2]
Reactant: O=C1NCCN1[C@@H]1CCOC1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)N1CCN([C@@H]2CCOC2)C1=O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 0° C. solution of phosgene (20% in toluene, 1.132 mL, 2.151 mmol) in DCM (9 mL) was treated slowly with a solution of (R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (0.28 g, 1.793 mmol) and pyridine (0.290 mL, 3.59 mmol) in DCM (9 mL) and stirred at 0° C. for 45 min. The mixture was concentrated to dryness to afford crude (R)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carbonyl chloride (100% yield assumed) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:4]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=S)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[NH2:1][C:2]1[C:3]2[N:21]([CH2:22][CH2:23][CH2:24][OH:25])[C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[N:9][C:4]=2[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)cc(NC(=S)Nc2ccc(Cl)cc2Cl)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1cc(F)cc2nc(Nc3ccc(Cl)cc3Cl)n(CCCO)c12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A suspension of 1-{3-amino-5-fluoro-2-[(3-hydroxypropyl)amino]phenyl}-3-(2,4-dichlorophenyl)thiourea (1.95 g, 4.84 mmol), triethylamine (743 μL, 5.32 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (974 mg, 5.08 mmol) in tetrahydrofuran (25 mL) was stirred at 50° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (1.64 g, 4.43 mmol, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15]C1CCCCO1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(OCC)(=O)C.O>[OH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:2]([CH3:1])([CH3:22])[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCC(C)(C)CCCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOC(=O)CCC(C)(C)CCCCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4,4-dimethyl-9-(tetrahydro-2H-pyran-2-yloxy)nonanoate (example 285, step e) (0.86 g) in methanol (10 mL) was added p-toluenesulfonic acid monohydrate (52 mg) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate and water and the phases separated. The aqueous layer was extracted with ethyl acetate (×2) and the combined organic phase was washed with 10% citric acid, saturated aqueous sodium bicarbonate solution and brine then dried over magnesium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0-50% ethyl acetate in cyclohexane to afford the subtitled compound as colourless oil. Yield 0.44 g.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:13](C(OCC)=O)[C:12]2=[O:27])=[CH:2]1.[OH-].[K+]>C(O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[C:12](=[O:27])[CH:13]=[C:14]([NH:16][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[O:15]2)=[CH:2]1
Reactant: CCOC(=O)C1=C(NC2CCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C=C(NC2CCCC2)OC1=Cc1c[nH]c2ncccc12
Temperature: 25 °C
Yield: 1.9 %

Procedure:
To a solution of the compound (0.10 g, 0.27 mmol) of Example 103 in ethanol (4.0 mL), 50% potassium hydroxide solution (2.0 mL, 0.036 mol) was added at ambient temperature. The mixture was refluxed for 2 h. Cooled to ambient temperature, the solvent was removed under reduced pressure. Water was added to this residue, the mixture was washed with ethyl acetate then 1M hydrochloric acid was added to adjust pH to acidic, and then the solvent was removed under reduced pressure. The residue was purified by preparative HPLC to afford the titled compound as solid (0.0015 g, y. 5%).