Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:39][O:40][CH2:41][CH2:42]O.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CCOC(C)=O.C1C=CC=CC=1>[CH3:39][O:40][CH2:41][CH2:42][O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=2
Reactant: CC(C)(C)OC(=O)Cc1ccc2ncc(O)cc2c1
Reactant: COCCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COCCOc1cnc2ccc(CC(=O)OC(C)(C)C)cc2c1
Temperature: 0 °C
Yield: 0.3 %

Procedure:
A flask was charged with tert-butyl 2-(3-hydroxyquinolin-6-yl)acetate (581.04 mg, 2.241 mmol) and triphenylphosphine (1.175 g, 4.482 mmol) then sealed with a septum and an placed under N2. Benzene (10 mL) was added, followed by 2-methoxyethanol (0.8838 ml, 11.20 mmol). The heterogeneous solution was cooled to 0° C., and di-tert-butyl azodicarboxylate (1.032 g, 4.482 mmol) was added as a solid in a single portion. The solution was allowed to warm to rt and maintained 20 h. The solution was then partitioned between saturated aqueous. NH4Cl, and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL), and the combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo. The resulting residue was purified by MPLC (Teledine Isco combiFlash Companion), 80 g SiO2, solvent system: 90:10 hexanes:EtOAc gradient to 50:50 hexanes:EtOAc to give tert-butyl 2-(3-(2-methoxyethoxy)quinolin-6-yl)acetate (585. 2 mg, 82% yield). LRMS (ESI) m/z calcd for C18H24NO4 (M+H) 318.2, found 318.3.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:10]([NH:12][CH2:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15])=[O:11])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH2:8][C@@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[C:10]([NH:12][CH2:13][C:14]([N:16]1[CH2:17][CH2:18][N:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:20][CH2:21]1)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccccn1)C(=O)NCC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
To a solution of (2S)-2-(tert-butoxycarbonylamino)-N-[2-[4-(4-chlorophenyl)-1-piperazinyl]-2-oxoethyl]-3-(2-pyridyl)-propanamide (42 g) in methanol (84 ml) was added 4N hydrogen chloride in ethyl acetate (209 ml) at 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours and diluted with ethyl acetate. The resulting solid was collected by filtration and washed with ethyl acetate. The solid was poured into aqueous sodium hydrogencarbonate solution and the mixture was extracted with chloroform. The aqueous layer was extracted twice with chloroform. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a crude product of the title compound (27 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].C(=O)([O-])[O-].[K+].[K+].[C:18](OCC)(=[O:26])[C:19]#[C:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[N:10]1[C:18]([OH:26])=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: NNc1cc(F)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc(O)n(-c2cc(F)ccc2F)n1
Temperature: 0 °C
Yield: 61.1 %

Procedure:
To a solution of (2,5-difluorophenyl)hydrazine hydrochloride (25.0 g) in ethanol (500 mL) were added potassium carbonate (38.3 g) and diethyl but-2-ynedioate (23.6 g). After refluxing for 18 hr, the mixture was cooled to 0° C. and acidified with 6 mol/L hydrochloric acid. Ethanol was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with a mixed solvent of ethyl acetate and diisopropyl ether, and the obtained solid was collected by filtration and dried under reduced pressure to give the title compound as a pale-yellow solid (yield 22.7 g, yield 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:18])[CH2:8][C:7]1(C(OC(C)(C)C)=O)[CH:9]=[CH2:10])=[O:5])[CH3:2].[ClH:19].O1CCOCC1>>[ClH:19].[CH2:1]([O:3][C:4]([C:6]1([NH2:18])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]
Reactant: C=CC1(C(=O)OC(C)(C)C)CC1(N)C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: C=CC1CC1(N)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester (1.50 g, 5.88 mmol) was dissolved in 4N HCl/dioxane (10 mL, 40 mmol) and was stirred overnight at room temperature. The reaction mixture was concentrated to supply racemic 1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride as a brownish oil (1.04 g, 92%). The two enantiomers were then separated by chiral HPLC. Conditions: Chiralpak AD column, 50×500 mm, 20 μM; 95% 0.01% DEA/hexane:5% ethanol as solvent; flow rate:75 mL/min; stop time:45 min; abs=207 nm; maximum load: 300 mg. After separation, 210 mg of enantiomer 50177-020A (retention time=25 min) and 235 mg of enantiomer 50177-020B (retention time=32 min) were collected. 50177-020: 1H NMR(DMSO-d6, 500 MHz) δ 8.80(s, br, 3H), 5.64 (m, 1H), 5.38 (d, J=17.1 Hz, 1H), 5.21(d, J=10.4 Hz, 1H), 4.21 (m, 2H), 2.34 (m, 1H), 1.68(m, 2H), 1.23 (t, J=7.2 Hz, 3H).; LC-MS (retention time 0.64 min), MS m/z 156(MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[CH2:19][CH2:20][O:21][CH2:22][CH:23]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3CCOCC3)cc2C1
Reaction time: 16 h
Yield: 38 %

Procedure:
To a stirred solution 0.81 mmol 5-chloro-6-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A61(a)) in 40 ml methanol was added 0.41 mmol platinum(IV) oxide and the mixture was stirred under an atmosphere of hydrogen for 16 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (38% yield). MS (m/e): 284.3 ({37Cl}[M+H-Me2C═CH2]+, 49%), 282.3 ({35Cl}[M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][CH:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)=O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([O:17][C@@H:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH3:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)OC(=O)N1CCC(C(C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1
Agent: O=C=O
Solvent: CO
Product: CC(C)OC(=O)N1CCC([C@@H](C)Oc2cnc(-c3ccc(S(C)(=O)=O)cc3)cn2)CC1

Procedure:
The racemic 1-methylethyl 4-[1-({5-[4-(methylsulfonyl)phenyl]-2-pyrazinyl}oxy)ethyl]-1-piperidinecarboxylate (prepared as in Example 162) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 85% CO2: 15% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers, which were further purified by chromatography on an ISCO silica gel column using 0 to 50% EtOAc/hexanes. The title compound was isolated as a white foam with Tr of 17.00 min (second eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=O)[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[CH3:51][NH2:52]>CO>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15]/[C:16](=[N:52]\[CH3:51])/[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: CN
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Solvent: CO
Product: C/N=C1\C=C(N[C@H]2O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]2OC)C(=O)c2cc3c(c(O)c21)C(=O)[C@]1(OC)[C@H](O)Cc2cc(C)c(C(=O)OC)c(O)c2[C@]1(O)C3=O
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (100 mg, 0.143 mmol) in methanol (2 mL) was added methylamine (40% in water, 0.1 mL) at room temperature, and the mixture was stirred under nitrogen for 1 h. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with chloroform. The combined extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by preparative TLC (silica gel, 90:10 chloroform/methanol) to afford (6R,6aS,14aR,E)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-9-(methylimino)-7,12,14-trioxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (30 mg, 29%) as a blue solid: 1H NMR (500 MHz, CDCl3) δ 11.94 (s, 1H), 7.88 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.49 (s, 1H), 5.91 (s, 1H), 5.26 (s, 1H), 5.00 (dd, J=10.0, 6.0 Hz, 1H), 4.75-4.72 (m, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75-3.68 (m, 2H), 3.61 (s, 3H), 3.57 (dd, J=19.5, 6.5 Hz, 1H), 3.40 (s, 3H), 3.39-3.36 (m, 1H), 3.34 (d, J=4.5 Hz, 3H), 3.29 (d, J=19.5 Hz, 1H), 3.15 (t, J=9.5 Hz, 1H), 2.52 (d, J=4.5 Hz, 1H), 2.36 (s, 3H), 1.38 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 711 (M+H); HPLC 93.4% (AUC), tR 10.83 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C@H:9]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10][NH:11]CC1C=CC=CC=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6](=[O:26])[N:7]([C@@H:9]([CH2:10][NH2:11])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CNCc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Product: CN(C(=O)OC(C)(C)C)[C@@H](CN)Cc1ccccc1
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A suspension of 20% palladium hydroxide on charcoal (4.63 g) and N-((1R)-1-benzyl-2-(benzylamino)ethyl)-N-methylcarbamic acid tert-butylester (4.40 g, 12.4 mmol) was kept for 8 h under a hydrogen atmosphere at (pressure: 1 atm). The reaction mixture was flushed with nitrogen and filtered through a plug of celite. The solvent was removed. The crude product was purified by flash chromatography on silica (110 g), using dichloromethane/methanol/25% aqueous ammonia as eluent, to give 830 mg of N-((1R)-1-aminomethyl-2-phenylethyl)-N-methylcarbamic acid tert-butylester.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]([N:9]([CH3:25])[C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][CH2:19]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>CO>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7](=[O:8])[N:9]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]#[C:17][CH2:18][CH2:19][N:29]([CH3:30])[CH3:28])[CH2:12][CH2:11]2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](C#CCCOS(C)(=O)=O)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)CCC#C[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 400 mg (corresponds to 0.69 mmol) of crude trans-Methanesulfonic acid 4-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexyl}-but-3-ynyl ester in 4 ml of methanol was treated with 1.23 ml (6.88 mmol) Dimethylamine (33% in EtOH, 5.6M) and stirred over night at RT. The reaction was heated at 70° C. for 2 h, cooled, evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 99:1 to 9:1) gave 84 mg (34%) of trans-[4-(4-Dimethylamino-but-1-ynyl)-cyclohexyl]-methyl-carbamic acid 4-chloro-phenyl ester, MS: 363 (MH+, 1Cl).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[N:4]1.[CH2:15]([O:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br)[CH3:16]>CN(C=O)C>[CH2:15]([O:17][C:18](=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:3]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[OH:14])=[N:4]1)[CH3:16]
Reactant: Oc1ccccc1-c1cc[nH]n1
Reactant: CCOC(=O)CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1ccc(-c2ccccc2O)n1
Temperature: 75 °C
Yield: 48.2 %

Procedure:
Add sodium hydride (1.50 g, 31 mmol, 60% suspension in mineral oil) to a suspension of 2-(1H-pyrazol-3-yl)phenol (5.0 g, 31 mmol) and 7-bromoheptanoic acid ethyl ester (7.4 g, 31 mmol) in DMF (75 mL) at room temperature under nitrogen and heat the mixture at 75° C. for 16 hours. Remove the solvent under reduced pressure, dilute the residue with ethyl acetate (300 mL), wash with water (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (9:1), to provide 7-[3-(2-hydroxyphenyl)pyrazol-1-yl]heptanoic acid ethyl ester (4.73 g, 48%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.S(Cl)(Cl)=O.[Al+3].[Cl-:19].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:19][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:4]=[N:3][N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: Cn1nnc2ccc(C(=O)O)cc21
Reactant: [Cl-]
Agent: [Al+3]
Solvent: O=S(Cl)Cl
Solvent: Clc1ccccc1
Product: Cn1nnc2ccc(C(=O)c3ccc(Cl)cc3)cc21

Procedure:
The carboxylic acid (b) is converted into the corresponding acid chloride with thionyl chloride and then reacted with chlorobenzene and AlCl3, yielding the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:10]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(C)cc1
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1ccc(C)cc1Cc1ccccc1
Temperature: 167.5 °C
Reaction time: 2 h

Procedure:
A mixture of 4-methylanisole (200 g, 1.64 mol), benzyl alcohol (40.0 g, 0.37 mol) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mol) was stirred at 160 to 175° C. for two hours while eliminating water generated by the reaction. After excess 4-methylanisole was distilled off under reduced pressure (inner temperature, 132° C./25 mmHg (3.3 kPa), the residue was dissolved in toluene (50 ml) and then the organic layer was successively washed with water (20 ml), 10% aqueous caustic soda (20 ml) and water (20 ml). After the washed organic layer was concentrated, the residue was distilled under reduced pressure to collect a component fractionated at boiling point of 120-138° C. at 0.7 mmHg (0.09 kPa) as a main fraction (52.75 g, 67.2%). The component was analyzed by NMR to identify 2.7:1 mixture of 2-benzyl-4-methylanisole and 3-benzyl-4-methylanisole.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12][CH2:13][C:14](Br)=[O:15]>CN(C=O)C.O1CCOCC1>[Br:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:15]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.8 %

Procedure:
To a solution of 2-amino-5-hydroxybenzoic acid (6.1 g, 0.04 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) was added, dropwise, bromoacetyl bromide (8.0 g, 3.5 mL, 100 mol %) while keeping the internal temperature between 0° C. and 5° C. After the addition was completed (~20 min), the ice-bath was removed and the mixture was stirred for 20 h at rt. The reaction mixture was cooled in an ice-bath, water was added (100 mL), and then the mixture was poured into ice-water. The light precipitate which formed was filtered and then dried in a vacuum oven for 20 h at 40°-45° C., giving 7.8 g (72%) of the title compound: mp 213°-215.3° C.; 1H NMR (DMSO-d6) δ13.56 (bs, 1H, OH), 11.19 (s, 1H, NH), 9.68 (s, 1H, OH), 8.19 (d, 1H, J=8.8), 7.36 (d, 1H, J=3.2), 7.01 (dd, 1H, J=3.2, J=9.2), 4.19 (s, 2H); 13C NMR (DMSO-d6) δ168.88, 164.32, 153.08, 131.69, 122.21, 120.79, 119.00, 116.60, 30.66; MS (EI, m/z) 273 (M+), 275 (M+2+). HRMS (EI) calcd for C9H8NO4Br 272.9637, found 272.9634.
Reaction SMILES: [Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([O:13]CC)=O)[C:9](=[O:10])[C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:18][C:5]2[N:6]([CH2:16][CH3:17])[CH:7]=[C:8]([C:11]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=3)=[O:13])[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(CC)c2sc(Br)cc2c1=O
Solvent: Cc1ccccc1
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(Br)sc21
Temperature: 190 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A mixture of ethyl 2-bromo-7-ethyl4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.500 g) and 4-chlorobenzylamine (1.84 mL) is stirred at 190° C. for 1 h. The reaction is then allowed to cool to rt and is diluted with toluene. The resulting precipitate is filtered off and washed with toluene followed by hexanes to yield a tan solid. This material is recrystallized from acetic acid/water then ethanol to yield 0.379 g (59%) of the title compound as a white, crystalline solid.
Reaction SMILES: C[Si](Cl)(C)C.[I-].[Na+].[Si:8]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[C:26]([NH:28][C:29]3[C:30]([O:35]C)=[N:31][CH:32]=[CH:33][CH:34]=3)[N:25]=[C:24]([NH:37][C@H:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=3)[CH3:39])[CH:23]=2)[CH2:18][CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].O>C(#N)C>[Si:8]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[C:24]([NH:37][C@H:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=3)[CH3:39])[N:25]=[C:26]([NH:28][C:29]3[C:30](=[O:35])[NH:31][CH:32]=[CH:33][CH:34]=3)[N:27]=2)[CH2:18][CH2:17]1)([C:11]([CH3:14])([CH3:12])[CH3:13])([CH3:10])[CH3:9]
Reactant: COc1ncccc1Nc1nc(N[C@@H](C)c2ccc(F)cn2)cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C[C@H](Nc1cc(N2CCC(O[Si](C)(C)C(C)(C)C)CC2)nc(Nc2ccc[nH]c2=O)n1)c1ccc(F)cn1
Temperature: 80 °C
Yield: 128.5 %

Procedure:
Trimethylsilyl chloride (0.285 mL, 2.25 mmol) and sodium iodide (337 mg, 2.25 mmol) were added to a stirred solution of 6-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-N4-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N2-(2-methoxypyridin-3-yl)pyrimidine-2,4-diamine (Preparation 10c, 415 mg, 0.75 mmol) in acetonitrile (5 mL) and the reaction mixture was heated at 80° C. for 4.5 hours. After cooling to ambient temperature, water was added and the mixture was extracted with ethyl acetate (×3). The pH was then adjusted to ca. 6 with 2M aqueous sodium hydroxide solution and the aqueous phase was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure to give the title compound (0.52 g, 100%) as a brown oil which was used in the next synthetic step without further purification.
Reaction SMILES: CO[CH:3](OC)[CH2:4][N:5]([CH3:30])[C:6]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]2=[O:19])=[CH:11][CH:10]=1)=[O:7]>C(O)=O>[CH3:30][N:5]1[CH:4]=[CH:3][N:8]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:29])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[C:6]1=[O:7]
Reactant: COC(CN(C)C(=O)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1)OC
Solvent: O=CO
Product: Cn1ccn(-c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
The 1-(2,2-dimethoxyethyl)-1-methyl-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]urea (17.5 mg, 0.0389 mmol) obtained in step A was dissolved in formic acid (0.2 ml). The obtained solution was stirred at a room temperature overnight. Thereafter, formic acid was distilled away under reduced pressure, and the obtained residue was then dissolved in methylene chloride. The obtained solution was washed with a saturated sodium bicarbonate aqueous solution, and was then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=4:1 to 1:0), so as to obtain 7-(3-methyl-2-oxo-2,3-dihydroimidazol-1-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (10.9 mg; yield: 73%) in the form of a colorless solid.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:25])([CH3:24])[CH3:23])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[OH:20])[CH2:2][CH2:3][CH3:4].[C:26](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[CH2:1]([C:5]1=[CH:6][N:7]([C:22]([CH3:24])([CH3:23])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=1[O:20][CH3:26])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C=O)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)c1cc(C=O)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
A mixture of Example 56A (350 mg, 0.97 mmol) and cesium carbonate (375 mg, 1.94 mmol) in DMF (20 mL) was treated with iodomethane (165 mg, 1.17 mmol). The mixture was stirred at rt for 2 hrs, diluted with H2O and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 246 mg (68%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 0.99 (t, J=7.36 Hz, 3 H) 1.36-1.51 (m, 2 H) 1.67 (s, 9 H) 1.68-1.78 (m, 2 H) 2.85 (dd, J=7.67 Hz, 2 H) 4.02 (s, 3 H) 7.11 (d, J=8.59 Hz, 1 H) 7.97 (dd, J=8.59, 2.15 Hz, 1 H) 7.96 (s, 1 H) 8.64 (d, J=2.15 Hz, 1 H) 9.96 (s, 1 H); MS (DCI/NH4+) m/z 375 (M+H)+.