Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Br:13])=[CH:6][C:5]=1[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-:22].[K+].Cl>CO>[Br:13][C:7]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]([OH:22])=[C:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1
Reactant: O=C([O-])OCc1cc([N+](=O)[O-])c(Br)cc1C1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=[N+]([O-])c1cc(O)c(C2CCCCC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a solution of (4-bromo-2-cyclohexyl-5-nitro-phenyl)methyl carbonate (1.5 g, 4.2 mmol) in methanol (15 mL) was added KOH (353 mg, 6.3 mmol) portionwise at 0° C. After addition, the reaction mixture was allowed to warm to room temperature and stirred for 3 h. The reaction mixture was acidified with 1N HCl. The solvent was evaporated and water was added. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to give 4-bromo-2-cyclohexyl-5-nitrophenol (1.2 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.39 (s, 1H), 5.10 (s, 1H), 2.90-2.83 (m, 1H), 1.91-1.89 (m, 4H), 1.83-1.80 (m, 1H), 1.51-1.24 (m, 5H)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH:9]=2)=[N:6][CH:7]=1>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-c2coc3c(C)c(C)cc(C)c23)nc1
Solvent: CO
Product: Cc1ccc(C2COc3c(C)c(C)cc(C)c32)nc1
Yield: 89 %

Procedure:
Using 5-methyl-2-(4,6,7-trimethyl-1-benzofuran-3-yl)pyridine obtained in Reference Example 192, the title compound was synthesized in the same manner as in Reference Example 144. Yield 89%. Melting point: 69-70° C. (methanol).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[CH:22][CH:21]=1.[C:31]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)(=[O:33])[CH3:32]>C1COCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:27][C:28]([C:31]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)([OH:33])[CH3:32])=[CH:29][N:30]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)c1ccncc1
Reactant: Fc1ccc(-c2nccs2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(O)(c1ccncc1)c1cnc(-c2ccc(F)cc2)s1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
To a stirred solution of diisopropylamine (0.283 mL, 2.01 mmol) in THF (15 mL) at −78° C. under nitrogen atmosphere was added 1.6M n-BuLi in hexane (1.25 mL, 2.01 mmol) slowly. The reaction mixture was stirred for 30 min at −5° C., cooled to −78° C., 2-(4-fluorophenyl)thiazole (300 mg, 1.67 mmol) in THF (5 mL) added, and then 4-acetyl pyridine (300 mg, 1.67 mmol) in THF (5 mL) added. The resulting mixture was stirred at −78° C. for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (40 mL) and extracted with ethyl acetate (4×150 mL). The organic layer was dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by flash chromatography (100-200μ; 80% ethyl acetate in hexane) to afford 1-(2-(4-fluorophenyl)thiazol-5-yl)-1-(pyridin-4-yl)ethanol as off-white solid (285 mg, 57% yield), HPLC purity 99.9%, mp 229-232° C. 1H NMR (400 MHz, DMSO-d6): δ 8.53 (d, 2H), 7.92 (t, 2H), 7.81 (s, 1H), 7.49 (d, 2H), 7.30 (t, 2H), 6.66 (s, 1H), 1.93 (s, 3H); LC-MS m/z calculated for [M+H]+301.07. found 301.6.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([OH:33])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[C:35]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]I)(=[O:38])[CH:36]=[CH2:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][N:2]([CH3:34])[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([N:13]=[N:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]=[N:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([O:33][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][O:39][C:35](=[O:38])[CH:36]=[CH2:37])=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: C=CC(=O)OCCCCCCI
Reactant: CN(C)c1ccc(N=Nc2ccc(N=Nc3ccc(O)c4ccccc34)cc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCCCOc1ccc(N=Nc2ccc(N=Nc3ccc(N(C)C)c4ccccc34)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
A mixture consisting of 0.44 g of 1-[4-(4-(dimethylamino)naphthylazo)phenylazo]-4-hydroxy-naphtalene, 0.56 g of 6-iodohexyl acrylate, and 0.28 g of potassium carbonate in 10 ml of DMF was stirred under nitrogen atmosphere for 3 h at 60° C. After cooling to room temperature the reaction mixture was quenched with 100 ml 3N HCl and the resulting precipitate was filtered off, washed with water (100 ml) and ethanol (50 ml) to give 0.5 g of pure 1-[4-(4-(dimethylamino)naphthylazo)-phenylazo]-4-(6-acryloyloxyhexyloxy)naphtalene as a brownish powder; λmax. (CB 483): 504 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](O)=[C:9]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH:8]=[N:7][C:6]=12.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:39])=O>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([Cl:39])=[C:9]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)=[O:13])[CH:8]=[N:7][C:6]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(c1cnc2c(Br)cnn2c1O)N1CCC(c2ccccc2)CC1
Solvent: CCN(CC)c1ccccc1
Product: O=C(c1cnc2c(Br)cnn2c1Cl)N1CCC(c2ccccc2)CC1
Yield: 93 %

Procedure:
To 3-bromo-7-hydroxy-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (7.7 g, 19.1 mmol) obtained in step 2 were added phosphorus oxychloride (100 mL) and N,N-diethylaniline (6.1 mL, 38.3 mmol), and the mixture was heated under reflux for 5 hr. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (100 mL) and neutralized with saturated aqueous sodium hydrogen carbonate solution (300 mL) under ice-cooling, and the organic layer and the aqueous layer were separated. The organic layer was washed with 10% aqueous citric acid solution (50 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (7.5 g, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH:8]([C:19](=[O:20])[NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]#[N:10]
Reactant: O=C=Nc1ccccc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1ccccc1
Reaction time: 8 h

Procedure:
To the suspension of 12.9 of 1-methyl-β-oxo-2-pyrrolpropionitrile in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine, 10.7 g of phenylisocyanate are added while stirring. After all solids are dissolved, the dark red solution is allowed to stand 30 minutes at room temperature, 5 minutes on the steam cone and at room temperature overnight. The mixture is evaporated on the steam cone, the residue taken up in methanol and the solution poured into the mixture of 25 ml of 5 N hydrochloric acid and 600 ml of water. The light brown crystals formed are collected, washed with water, triturated with ethanol and recrystallized from about 2200 ml of methanol, to yield the 1-methyl-β-oxo-α-phenylcarbamoyl-2-pyrrol-propionitrile of the formula ##STR8## melting at 174°-175°.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1C(C(O)=O)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:34]([C:35]([Cl:37])=[O:36])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)Cl)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
2-[(Benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (320 mg) was dissolved in THF (6.0 ml), and oxalyl chloride (130 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: CS(O[C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])(=O)=O.[Br-].[C:17]1([CH3:24])[CH:22]=[CH:21][C:20]([Zn+])=[CH:19][CH:18]=1.[Cl-].[Li+].Cl>O1CCCC1.[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.O>[CH3:24][C:17]1[CH:22]=[CH:21][C:20]([C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10][CH3:11])=[O:9])=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccccc1OS(C)(=O)=O
Reactant: Cc1ccc([Zn+])cc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(C)cc1
Reaction time: 12 h
Yield: 82 %

Procedure:
A mixture of nickel chloride (0.11 g, 0.85 mmoles), triphenylphosphine (0.44 g, 1.7 mmoles), and dry tetrahydrofuran (25 ml), at room temperature and under inert atmosphere (nitrogen), is added with 1.6 M n-butyllithium (1.1 ml; 1.7 mmoles); the mixture is kept under stirring for 15′, then added with methyl 2-(methanesulfonyloxy)benzoate (10.1 g, 44 mmoles, prepared as described in Example 3) dissolved in dry tetrahydrofuran (10 ml). After further 15′ under stirring, the resulting mixture is added to a suspension of p-tolylzinc bromide prepared as described in Example 1, previously added with lithium chloride (2.3 g, 54 mmoles). The resulting mixture is kept at room temperature for 12 hours, then poured into a solution of water (100 ml) and 37% hydrochloric acid (25 ml); the phases are separated, the organic phase is extracted with a water-dichloromethane mixture (50 ml; 50:50); the phases are separated again and the organic one is dried over sodium sulfate and evaporated under vacuum to a residue, to obtain methyl 2-(4-methylphenyl)benzoate as an oil (8.2 g, yield 82%).
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:11][O:12][C:13]2[C:18]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:17][CH:16]=[C:15]([O:29][CH3:30])[C:14]=2[O:31][CH3:32])[CH2:10][O:9][CH2:8]1)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O>[N:33]([CH2:6][C:7]1([CH2:11][O:12][C:13]2[C:14]([O:31][CH3:32])=[C:15]([O:29][CH3:30])[CH:16]=[CH:17][C:18]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:10][O:9][CH2:8]1)=[N+:34]=[N-:35]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COS(C)(=O)=O)COC2)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN=[N+]=[N-])COC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of (3-((2,3-dimethoxy-6-(1-oxo-2,3-dihydro-1H-inden-4-yl)phenoxy)methyl)oxetan-3-yl)methyl methanesulfonate (5 g, 10.82 mmol) in dimethylformamide (40 mL), was added sodium azide (3.5 g, 54.11 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 4-(2-((3-(azidomethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15]O)[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[C@H:14]([CH2:15][N:21]2[C:17](=[O:27])[C:18]3[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:20]2=[O:22])[CH2:13][CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)CC[C@H]2C[C@H]21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CN2C(=O)c3ccccc3C2=O)CC[C@H]2C[C@H]21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension of D7 (10 g, 44 mmol), phtalimide (10.29 g, 70 mmol) and triphenylphosphine (18.34 g, 70 mmol) in THF (150 mL) was cooled at 0° C., then a 40% solution of DEAD in toluene (31.94 mL, 70 mmol) was added. The mixture was stirred at room temperature for 3 hours, then water was added and the mixture was concentrated under vacuum; the residue was dissolved in DCM, washed with water and organics were evaporated. Cyclohexane (300 mL) and DCM (10 mL) were added, the precipitate was discarded and the filtrate was concentrated. The crude mixture was purified by silica gel column chromatography (cyclohexane/ethyl acetate=95:5 to 70/30) to give the title compound as a white solid. Yield (11 g, 71%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31]C=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.CC1ON=C(N)C=1>ClC(Cl)C.CO>[CH3:31][C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:13]2[CH:14]=[CH:15][C:10]3[N:9]=[C:8]4[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]4[C:11]=3[CH:12]=2)=[O:18])[CH:29]=1
Reactant: O=C(O)c1ccc2nc3n(c2c1)CCCNC3=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cc1cc(N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(Cl)Cl
Solvent: CO
Product: Cc1cc(NC(=O)c2ccc3nc4n(c3c2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A mixture of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]benzimidazole-8-carboxylic acid (Intermediate B, 51 mg, 0.21 mmol) and HATU (89 mg, 0.23 mmol) in dichloroethane (3 mL) is stirred at room temperature for 1 h. 2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (64 mg, 0.64 mmol) is added and the mixture is stirred at room temperature for 10 min. 5-Methyl-3-aminoisoxazole (62 mg, 0.64 mmol) is added and the reaction is stirred at 60° C. for 16 h and is cooled to room temperature. The mixture is diluted with methanol, filtered and evaporated. The residue is purified via flash column chromatography using a gradient elution of 0-10% CH2Cl2/methanol and is triturated with CH2Cl2 (3 mL), filtered and dried to afford the title compound (25 mg, 36%).
Reaction SMILES: [Na].C([O-])(=O)C=C.[NH4+].[Na+].[C:9]([NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([O-:21])=[O:20])(=[O:13])[C:10]([CH3:12])=[CH2:11].[Na+].C(NC(C)(C)CS([O-])(=O)=O)(=O)C=C.C(N)(=O)C=C>>[C:9]([NH:14][C:15]1[CH:16]=[C:17]([OH:24])[C:18](=[CH:22][CH:23]=1)[C:19]([OH:21])=[O:20])(=[O:13])[C:10]([CH3:12])=[CH2:11]
Reactant: C=C(C)C(=O)Nc1ccc(C(=O)[O-])c(O)c1
Agent: C=CC(=O)NC(C)(C)CS(=O)(=O)[O-]
Agent: C=CC(=O)[O-]
Agent: C=CC(N)=O
Product: C=C(C)C(=O)Nc1ccc(C(=O)O)c(O)c1

Procedure:
Representative high molecular weight inverse emulsion polymers prepared according to the method of Examples 13 and 14 are listed in Table 3. In Table 3, Na or (NH4) AA=sodium or ammonium acrylate, 4-MASA=4-methacrylamidosalicylic acid sodium salt, NaAMPS=2acrylamido-2-methylpropanesulfonate sodium salt, and AcAm=acrylamide.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:18][C@@H:19]([N:23]3[CH2:27][CH2:26][C@H:25]([NH:28][S:29]([C:32]4[S:36][C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:34][CH:33]=4)(=[O:31])=[O:30])[C:24]3=[O:42])[C:20]([OH:22])=[O:21])=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[CH:11]=2)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:49](=[O:60])([O:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)[O:50][CH2:51]Cl.[I-].[K+]>CN(C=O)C.O>[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([CH2:18][C@@H:19]([N:23]3[CH2:27][CH2:26][C@H:25]([NH:28][S:29]([C:32]4[S:36][C:35]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)=[N:34][CH:33]=4)(=[O:31])=[O:30])[C:24]3=[O:42])[C:20]([O:22][CH2:51][O:50][C:49]([O:53][CH:54]3[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]3)=[O:60])=[O:21])=[C:10]([O:13][C:14]([F:15])([F:17])[F:16])[CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=C(OCCl)OC1CCCCC1
Reactant: Nc1nccc2cc(C[C@H](C(=O)O)N3CC[C@H](NS(=O)(=O)c4cnc(N5CCCC5)s4)C3=O)c(OC(F)(F)F)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nccc2cc(C[C@H](C(=O)OCOC(=O)OC3CCCCC3)N3CC[C@H](NS(=O)(=O)c4cnc(N5CCCC5)s4)C3=O)c(OC(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2R)-3-[1-amino-7-(trifluoromethoxy)isoquinolin-6-yl]-2-[(3S)-2-oxo-3-({[2-(pyrrolidin-1-yl)-1,3-thiazol-5-yl]sulfonyl}amino)pyrrolidin-1-yl]propanoic acid hydrochloride (compound of example 4) (0.5 g, 0.73 mmol) in anhydrous DMF (3 ml) were added potassium carbonate (0.3 g, 2.2 mmol) and chloromethyl cyclohexyl carbonate (0.21 g, 1.1 mmol), followed by potassium iodide (12 mg, 0.07 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 hours, and then was poured onto cold water, the resulting precipitate was filtered of, washed with water and dried under P2O5.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH:24]2[CH2:26][CH2:25]2)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][C:15]([N:18]([CH2:23][CH:24]2[CH2:25][CH2:26]2)[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:10]=1[C:11]([O:13][CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)O
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
A mixture of 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)-methylsulfonamido)benzoic acid (0.300 g, 0.778 mmol), benzyl 2-hydroxyacetate (0.129 g, 0.778 mmol), EDC (0.448 g, 2.335 mmol) and DMAP (0.048 g, 0.389 mmol) in DCM (30 ml) was stirred at RT overnight. The reaction mixture was washed twice with HCl 1N and then with NaHCO3 5%. The organic phase was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by filtration on silica gel cartridge (petroleum ether:EtOAc=80:20 to 70:30) to give 2-(benzyloxy)-2-oxoethyl 2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropylmethyl)methylsulfonamido)benzoate (0.288 g, 0.540 mmol, 69.3% yield, MS/ESI+ 555.96 [MNa]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=O)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:32][C:33]#[N:34])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH:9]=[CH:32][C:33]#[N:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](C=O)NC(=O)OC(C)(C)C
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: C[C@H](C=CC#N)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
In a 20 mL scintillation vial, ((R)-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (2.5 g, 14.4 mmol) and (triphenylphosphoranylidene)acetonitrile (6.52 g, 21.7 mmol) were mixed in dichloromethane (20 mL) and stirred at room temperature for 16 h. The solvent was evaporated to give the crude material, which was purified by column chromatography (silica gel, gradient n-hexanes ethyl acetate) to provide 1.8 g (63%) of ((R)-3-cyano-1-methyl-allyl)-carbamic acid tert-butyl ester in a 3:1 diastereoselectivity (E:Z) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 6.38-6.79 (m, 1H), 5.47 (dd, J=16.24, 1.89 Hz, 1H), 4.48 (bs, 1H), 4.47 (bs, 1H), 1.45 (s, 1H), 1.28 (d, J=7.18 Hz, 9H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>>[Cl:33][C:30]1[CH:29]=[N:28][C:27]([N:23]2[CH2:24][CH2:25][CH:20]([C@@H:18]3[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:32][CH:31]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(Cl)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2,5-dichloro-pyrimidine following a procedure analogous to that described for Example 79. LC (method 7): tR=1.63 min; Mass spectrum (ESI+): m/z=476/478 (Cl) [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]([O-:18])=O)[CH:9]=[C:10]([CH:15]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C([N:23](CC)CC)C>CN(C=O)C>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:15]=1)[C:16]([NH2:23])=[O:18])=[O:12]
Reactant: COC(=O)c1cc(C(=O)[O-])cc(N2CCCC2)c1
Reactant: CCN(CC)CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(N)=O)cc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N′-carbonylimidazole (114 mg, 0.70 mmol) was added to a DMF (3 mL) solution of methyl 5-(1-pyrrolidinyl)isophthalate (146 mg, 0.59 mmol), and stirred at room temperature for 1 hour. Ammonium chloride (94 mg, 1.76 mmol) and triethylamine (0.246 mL, 1.76 mmol) were added to it, and further stirred at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the formed insoluble matter was taken out through filtration, washed and dried to obtain the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Br:6][C:7]1[CH:8]=[C:9]([NH2:14])[CH:10]=[CH:11][C:12]=1[CH3:13].O>N1C=CC=CC=1>[CH3:5][O:4][C:2](=[O:3])[NH:14][C:9]1[CH:10]=[CH:11][C:12]([CH3:13])=[C:7]([Br:6])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(N)cc1Br
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(C)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Methyl chloroformate (0.202 ml, 2.62 mmol) was added to a solution of 3-bromo-4-methyl-phenylamine (243 mg, 1.31 mmol) in pyridine (2 ml), and the mixture was stirred at room temperature overnight. H2O was added to the reaction mixture, followed by extraction with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane/AcOEt) to give (3-bromo-4-methyl-phenyl)-carbamic acid methyl ester (288 mg, 90%).