Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.[N:32]1([CH2:37][CH2:38][NH2:39])[CH:36]=[CH:35][N:34]=[N:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:32]1([CH2:37][CH2:38][NH:39][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])[CH:36]=[CH:35][N:34]=[N:33]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NCCn1ccnn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCCn2ccnn2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.43 mmol), 2-[1,2,3]triazol-1-yl ethylamine (200 mg, 1.78 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 243.3 mg, 0.64 mmol) and iPr2NEt (0.22 mL, 1.2 mmol) in CH2Cl2 (10 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (15-95% of ACN/water) rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (83.7 mg, 34.7%) as an off-white powder. HRMS ES+) m/z Calcd for C27H28Cl2F2N6O+H [(M+H)+]: 561.1743. found: 561.1741.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]=[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]3[CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]3=[N:18][CH:23]=2)=[O:14])[N:5]([CH2:24][C:25]2[N:26]([CH3:32])[C:27](=[O:31])[CH:28]=[CH:29][CH:30]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cn4ccccc4n3)c12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1nn(Cc2cccc(=O)n2C)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-carboxamide (11 mg, 0.027 mmol; prepared as in Example 17, Step A) in DMF (2 mL) was added K2CO3 (7.4 mg, 0.053 mmol) and iodomethane (19 mg, 0.13 mmol). The reaction mixture was stirred for one hour and concentrated under reduced pressure to remove DMF. Silica gel chromatography (DCM/MeOH 10:1) provided the desired product (3 mg). MS (ES+APCI) m/z=427 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4](B2OC(C)(C)C(C)(C)O2)=[CH:3]1.Br[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-:46])=[O:45].C([O-])([O-])=O.[Na+].[Na+].CCO>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:36])[C:26]2[C:6]([CH:7]=[C:8]3[C:25]=2[CH:24]=[C:23]2[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)=[CH:9]3)=[CH:5][C:4]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[N+:44]([O-:46])=[O:45])=[CH:3]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)C=C(c2ccccc2[N+](=O)[O-])C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 58.5 %

Procedure:
A mixture of 9.5 g (20.2 mmol) of 2-(10,10-dimethyl-10H-indeno[2,1-b]triphenylen-12-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, 4.3 g (21 mmol) of 1-bromo-2-nitrobenzene, 0.44 g (0.4 mmol) of tetrakis(triphenyl phosphine)palladium, 30 ml of 2M Na2CO3, 40 ml of EtOH and 80 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. overnight. After finishing the reaction, the mixture was allowed to cool to room temperature. The solution was extracted with 250 ml of ethyl acetate and 1000 ml of water. The organic layer was dried with anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica (Hx-EA) to give product 5.5 g (58%).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C1C=CC=CC=1>[CH3:18][S:19]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: On1nnc2ccccc21
Solvent: O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)On1nnc2ccccc21
Temperature: 10 °C
Reaction time: 2.2 h
Yield: 84.6 %

Procedure:
1-Hydroxy-1,2,3-benzotriazole (648 g) and triethylamine (675 ml) are dissolved in benzene (2,800 ml). To the solution is added dropwise a solution of methanesulfonyl chloride (535 g) in benzene (675 ml) with stirring at a temperature of lower than 10° C. over a period of 2.2 hours. The mixture is stirred at the same temperature for 2.3 hours and allowed to stand overnight. To the reaction mixture is added water (1,000 ml). The benzene layer is separated out. The aqueous layer is extracted twice with ethyl acetate (3,000 ml and 2,000 ml), and the extracts are combined and washed with a saturated aqueous sodium hydrogen carbonate (200 ml×2) and water and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off under a reduced pressure. The resulting crystals are washed with petroleum ether (500 ml) and dried to give faint yellow crystals of 1-methane-sulfonyloxy-1,2,3-benzotriazole (842 g), melting point: 88°-90° C.
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]([CH3:32])[CH3:31])[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN(C)C)c2ccnc3cc4c(cc23)OCO4)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCN(C)C)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 41 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-(N,N-dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide; (41% yield); reaction time 25 min; mp 283-285° C. (dec.); IR (CHCl3) 1653; 1H NMR (CDCl3) δ 2.33 (s, 6H), 3.04 (t, 2H, J=7.2), 4.07 (s, 3H), 4.14 (s, 3H), 4.64 (t, 2H, J=7.2), 6.18 (s, 2H), 7.47 (s, 1H), 7.68 (s, 1H), 7.89 (s, 2H), 9.37 (s, 1H); 13C NMR (CDCl3) δ 45.9, 49.2, 56.3, 56.3, 57.9, 101.2, 102.0, 102.3, 107.1, 108.8, 111.7, 114.8, 119.3, 127.6, 140.9, 143.5, 147.3, 147.7, 149.9, 150.3, 154.2, 164.1; HRMS calcd for C23H23N3O5H: 422.1716; found 422.1710.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[C:6]([OH:11])=[N:7][NH:8][C:9]=1[CH3:10].[C:30]([O:35][CH3:36])(=[O:34])[C@@H:31]([CH3:33])O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1.CCCCCC>[CH3:36][O:35][C:30]([C@@H:31]([O:11][C:6]1[C:5]([O:4][C:3]2[CH:12]=[C:13]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])[C:14]([F:16])=[CH:15][C:2]=2[Cl:1])=[C:9]([CH3:10])[NH:8][N:7]=1)[CH3:33])=[O:34]
Reactant: Cc1[nH]nc(O)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: COC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C)Oc1n[nH]c(C)c1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.4 %

Procedure:
To a solution of 0.13 g of 4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-hydroxy-5-methylpyrazole in 2.0 ml of ethyl acetate were added 0.10 g of (R)-(+)-methyl lactate, 0.26 g of triphenylphosphine and 0.5 ml of a 40% solution of diisopropyl azodicarboxylate in toluene, and the mixture was stirred for 3 hours at room temperature. 6 ml of n-hexane was poured into this reaction solution, and the precipitated insoluble substance was filtrated off. This solution was subjected to silica gel column chromatography to obtain 0.08 g of (S)-3-{1-(methoxycarbonyl)ethoxy}-4-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-5-methylpyrazole [S optical isomer of present compound 5-12, hereinafter, represented as 5-12-S].
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([CH:13]3[CH2:15][CH2:14]3)(O)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.FC(F)(F)C(O)=O.[CH3:23][S:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:31]3[C:30]4[C:34](=[C:26]([CH2:25][S:24][CH3:23])[CH:27]=[CH:28][CH:29]=4)[NH:33][CH:32]=3)([CH:13]3[CH2:15][CH2:14]3)[CH3:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(O)(c1ccc2sccc2c1)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc4sccc4c3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.75 mmol) of the compound from Example 141A and 0.25 ml (3.30 mmol) of trifluoroacetic acid were added to 487 mg (2.75 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min, and the crude product was then purified twice by preparative HPLC (mobile phase: acetonitrile/water gradient) and once by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10/1). 404 mg (39% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1([C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH3:10])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][N:19]1[CH2:23]C[CH:21](O)[CH2:20]1.CCOC(C)=O.CCO>CCCCCCC>[CH:1]1([C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:7]([O:9][CH:10]2[CH2:21][CH2:20][N:19]([CH3:23])[CH2:18]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC(O)C1
Reactant: COC(=O)C(O)(c1ccccc1)C1CCCC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN1CCC(OC(=O)C(O)(c2ccccc2)C2CCCC2)C1
Yield: 72 %

Procedure:
A solution of 2 (2.20 g, 9.4 mmol) and N-methyl-3-pyrrolidinol (3, 1.30 g, 13 mmol) in 40 ml of n-heptane was heated until 20 ml of heptane had been distilled. About 0.003 g of sodium was added, and the solution was stirred and heated for 2 h as the distillation was continued. More heptane was added at such a rate as to keep the reaction volume constant. Additional sodium was added at the end of an hour. The solution was then cooled and extracted with 3N HCl. The acid extract was made alkaline with concentrated NaOH and extracted three times with ether. Removal of the dried ether solution gave a crude oil. Flash chromatography of the crude product on silica gel with 8:1 EtOAc:EtOH gave pure product 4 (2.053 g, 72%). Analysis for C18H25NO3. Calcd: C, 71.26; H, 8.31; N, 4.62. Found: C, 71.55; H, 8.44; N, 4.68. 1H NMR (CDCl3, 500 MHz): 1.27-1.35, 1.40-1.47, 1.54-1.60, 1.75-1.90 [8H, m, (CH2)4], 2.12-2.30, 2.52-2.57, 2.64-2.81 (6H, m CH2NCH2CH2), 2.33, 2.36 (3H, 2s, NCH3), 2.93 [(1H, p, CHC(OH)], 3.83 (1H, bs, OH), 5.23 (1H, m, CO2CH), 7.23-7.36, 7.64-7.67 (5H, m, Ph) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[C:26]([CH2:28][CH3:29])[CH:25]=[CH:24][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[CH:14][C:13]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>ClCCl>[CH3:40][S:37]([N:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:10]2[CH:24]=[CH:25][C:26]([CH2:28][CH3:29])=[CH:27][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:23])[CH:14]=1)[CH2:19][CH2:20][CH2:21][NH2:22])(=[O:39])=[O:38]
Reactant: CCc1ccc(Oc2ccc(NCCCN)cc2F)c(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(Oc2ccc(N(CCCN)S(C)(=O)=O)cc2F)c(OCc2ccccc2)c1
Yield: 82.8 %

Procedure:
To a solution of N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (90 mg, 0.23 mmol) in 5 ml of dry dichloromethane and 0.08 ml (0.57 mmol) of triethylamine, cooled to 0° C., was added mesyl chloride (26 mg, 0.23 mmol) taken in 0.5 ml of dichloromethane dropwise. The reaction was quenched after 5 minutes as the reaction was complete on TLC. The reaction mixture was diluted with water and the layers separated. The aqueous layer was extracted with dichloromethane and the combined dichloromethane fraction was washed with water, dried over anhydrous Na2SO4 and concentrated. The crude residue obtained was combined with the crude obtained from an earlier 20 mg batch and column purified over silica gel using 2% methanol in dichloromethane as eluant to get 90 mg, 68.3% of title compound.
Reaction SMILES: [Cl:1][CH:2]([C:14](=[O:16])[CH3:15])[CH2:3][S:4][CH2:5][CH2:6][NH:7][C:8]([NH:11][C:12]#[N:13])=[N:9][CH3:10].O.[Cl:18]OC(C)(C)C.C(OCC)(=O)C>CO>[C:12]([NH:11][C:8]([NH:7][CH2:6][CH2:5][S:4][CH2:3][C:2]([Cl:18])([Cl:1])[C:14](=[O:16])[CH3:15])=[N:9][CH3:10])#[N:13]
Reactant: CC(C)(C)OCl
Reactant: CN=C(NC#N)NCCSCC(Cl)C(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN=C(NC#N)NCCSCC(Cl)(Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.2 %

Procedure:
In 1 ml of methanol was dissolved 131 mg of N-[2-(2-chloro-3-oxobutylthio)]ethyl-N'-cyano-N"-methyl-guanidine, and the solution was cooled with water and 55 mg of t-butyl hypochlorite was added to the solution. The mixture was stirred at 0° C. for 1 hour and 1 ml of water and 15 ml of ethyl acetate were added to the reaction mixture. The ethyl acetate layer was recovered, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was refined by silica gel column chromatography (developing solvent: ethyl acetate/ethanol=10/1) to obtain 24 mg of a colorless oily product (the yield was 16%).
Reaction SMILES: O[CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16].C(N(CC)CC)C.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1CO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1CCl
Temperature: 25 °C

Procedure:
To a suspension of 4-hydroxymethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (22.42 g) in chloroform (50 ml) is added a catalytic amount of triethylamine. The mixture is stirred at ambient temperature, treated dropwise with thionyl chloride, and stirred at 60° C. for 6 hours. The reaction mixture is made free form insoluble materials by filtration and the filtrate is poured into water. The separated chloroform layer is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution successively, dried, and evaporated to obtain 4-chloromethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (17.23 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:40]1[C:45](=[O:46])[CH2:44][CH2:43][C:41]1=[O:42])=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl>C1COCC1.C(#N)C>[O:42]=[C:41]1[CH2:43][CH2:44][C:45](=[O:46])[N:40]1[O:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:26]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Octadecanedioic acid mono-tert-butyl ester (4.2 g, 0.011 mol) was dissolved in THF (20 mL), TSTU (4 g, 0.013 mol) in acetonitrile (20 mL) was added and pH of the solution was adjusted to 8 with dropwise addition of DIPEA. The mixture was stirred at RT for 4 h, then acidified with HCl (2M) to pH 3 and evaporated in vacuo. The residual oil was subsequently partitioned between ethyl acetate and HCl (0.1 M). The organic layer was dried (MgSO4), filtered and evaporated to dryness in vacuo. This afforded 5.2 g of octadecanedioic acid tert-butyl ester 2,5-dioxopyrrolidin-1-yl ester as an oil, which could be used in the next step without further purification. LC-MS (electrospray): m/z=468 (M+1) and 412 (M+1-tBu).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C(NC(C)C)(C)C.[Li].[Cl:20][CH2:21][C:22](Cl)=[O:23]>C1COCC1>[Cl:20][CH2:21][C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2)=[O:23]
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(Cl)CCl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CCl)Nc1ccc2cnccc2c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A 2.0-mL vial equipped with a stirrer bar was charged with 6-aminoisoquinoline (100 mg, 0.7 mmol) in THF (1.0 mL) and cooled to −78° C. Lithium diisopropylamine (40 μL, 0.35 mmol) was added to the reaction at −78° C. followed by dropwise addition of chloroacetylchloride (62 μL, 0.7 mmol). The reaction was allowed to warm to room temperature and stirred for 30 min. The reaction was concentrated in vacuo then the solid was triturated with cold methanol. The solid was collected by filtration to afford 2-chloro-N-isoquinolin-6-yl-acetamide (58 mg, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.14 (s, 2H) 8.01 (dd, J=9.08, 1.66 Hz, 1H) 8.45 (d, J=8.98 Hz, 2H) 8.66 (d, J=1.56 Hz, 1H) 11.46 (s, 1H); LCMS: 221 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH2:52])[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C.CCOC(C)=O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)c1ccc(OC[C@@H](C)N)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC[C@@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
To a stirred solution of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (459 mg, 0.96 mmol) and ethyl (R)-3-methoxy-4-(2-aminopropoxy)benzoate (242 mg, 0.96 mmol) in DMF (5 mL) was added Et3 N (200 μl, 1.43 mmol), and the resulting mixture was stirred for 2 hr. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 360 mg (69%) ethyl (R)-3-methoxy-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a colorless crystalline solid. 1H-NMR (CDCl3) δ 1.23–1.28 (m, 3 H), 1.38–1.41 (t, 3 H, J=7.3 Hz), 2.32 (s, 3 H), 3.50–4.13 (m, total 11 H), 4.36 (q, 2 H, J=7.3 Hz), 6.65–8.13 (series of m, total 12 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 3A (0.125 g) and triethylamine (0.21 mL) in acetonitrile (3 mL) at 0-5° C. was added methanesulfonyl chloride (0.0404 mL). After 30 minutes, the mixture was concentrated, and the concentrate was purified by flash chromatography on silica gel with 0-30% ethyl acetate/hexanes.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([OH:29])[CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1.[C:30](Cl)([Cl:32])=[S:31].C.Cl>C(O)(C)C.C(Cl)(Cl)Cl.C(O)C>[ClH:32].[OH:29][CH:14]([CH2:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[CH2:13][O:12][C:6]1[C:5]2[NH:4][C:30](=[S:31])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc(CCNCC(O)COc2cccc(N)c2N)cc1OC
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CCO
Product: COc1ccc(CCNCC(O)COc2cccc3[nH]c(=S)[nH]c23)cc1OC
Reaction time: 2 h

Procedure:
17.4 g. 2,3-Diamino-1-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)-propoxy]-benzene trihydrochloride are dissolved in 450 ml. chloroform and 50 ml. ethanol and mixed dropwise at ambient temperature with 3.2 ml. thiophosgene in 30 ml. chloroform. After 2 hours, the reaction mixture is treated with active charcoal and then evaporated to dryness. The residue is purified over a column of silica gel, using chloroform/methanol (8:2 v/v) as elution agent, to give 10 g. (62% of theory) of uniform product. After taking up in isopropanol and mixing with ethereal hydrochloric acid, followed by precipitation by the addition of ethyl acetate, there is obtained 4-[2-hydroxy-3-(3,4-dimethoxyphenethylamino)propoxy]-benzimidazoline-2-thione hydrochloride; m.p. 108°-110° C.
Reaction SMILES: C(Cl)Cl.O1CCCC1.[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([F:21])[C:19]=1[F:20])[N:16]([NH:22][CH3:23])[CH:15]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]2=[O:29].[C:30]([O:34][C:35]([C:37](=[CH2:45])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:36])([CH3:33])([CH3:32])[CH3:31]>[Ti](Cl)(Cl)(Cl)Cl.O.C(OCC)(=O)C>[F:9][C:10]1[CH:11]=[C:12]2[C:17](=[C:18]([F:21])[C:19]=1[F:20])[N:16]([N:22]([CH3:23])[CH2:45][CH:37]([C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:36])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:15]=[C:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]2=[O:29]
Reactant: C=C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn(NC)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(N(C)CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 15 h
Yield: 220.4 %

Procedure:
Methylene chloride solution (0.667 ml) of 1M titanium tetrachloride was gradually added to a solution of methylene chloride (2 ml) and tetrahydrofuran (54.3 μ) containing ethyl 6,7,8-trifluoro-1-methylamino-1,4-dihydro-4-oxoquinoline-3-carboxylate (200 mg), with stirring under ice-cooling, and then tert-butyl 2-tert-butoxycarbonylacrylate (0.228 g) was added thereto and stirred for 10 minutes with ice-cooling and then for 15 hours at room temperature. The mixture was poured into a mixture of ethyl acetate (20 ml) and water (20 ml). The organic layer separated was washed with brine and dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was then triturated with n-hexane. The precipitates were taken out by filtration and dried with air to obtain ethyl 6,7,8-trifluoro-1-[N-methyl-N-{2,2-bis(tert-butoxycarbonyl)ethyl}amino]-1,4-dihydro-4-oxoquinoline-3-carboxylate (775.8 mg) as a pale yellow powder.