Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O1C=CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1O[C:29]2([CH2:34][CH2:33][C:32](C#N)([N:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]2)[O:28]C1.[Cl-].[NH4+].Cl.N>C(OCC)C.C(Cl)(Cl)Cl.CO.C1C=CC=CC=1.O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([C:32]2([N:35]([CH3:37])[CH3:36])[CH2:33][CH2:34][C:29](=[O:28])[CH2:30][CH2:31]2)[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: Oc1cccc(Br)c1
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C)C1(c2cccc(O)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A reaction solution consisting of 5.0 gm. (0.029 mole) m-bromophenol, 5.0 gm. dihydropyran, 0.30 gm. p-toluenesulfonic acid, and 80 ml. anhydrous diethyl ether is stirred at 25° C. for 4 hours. The mixture is washed successively with 25 ml. portions of 1 N aqueous sodium hydroxide, with water, and with brine. The thus washed organic layer is taken to dryness by removing the solvent by evaporation under reduced pressure. There is thus obtained 7.42 gm. of m-(tetrahydropyranyloxy)bromobenzene which is converted to the corresponding Grignard reagent by adding 0.70 gm. magnesium and 60 ml. tetrahydrofuran. To this Grignard is added 1.50 gm. (0.0071 mole) of 4-cyano-4-dimethylaminocyclohexanone ethylene ketal (prepared in Preparation III, Part b, above) dissolved in 30 ml. tetrahydrofuran. This reaction mixture is heated at the reflux temperature for 22 hours. After cooling, the mixture is treated with 10 ml. saturated aqueous ammonium chloride and benzene. The organic solvent portion is initially washed with water and then with brine. The organic solvent is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and treated with 4 N ethereal hydrogen chloride until precipitation of the hydrochloride salt is complete. The salt is collected on a filter and then suspended in 25 ml. water containing 1 ml. 2.5 N hydrochloric acid. The acidified mixture is stirred at 25° C. for one hour, when sodium bicarbonate (solid) is added until the pH is 8. This slightly basic mixture is extracted thoroughly with diethyl ether. The ether extracts are combined and the ether removed by evaporation under reduced pressure. The residue thus obtained is transferred to a column of silica gel 1 inch in cross section by 48" long. The chromatogram is developed with a solvent medium consisting of 0.5 percent ammonia and 7.5 percent methanol in chloroform. Fractions which are shown by thin layer chromatography (TLC) to contain product are collected and combined. The solvent is removed by evaporation under reduced pressure to give 0.96 gm. (48% yield) of crude 4-(m-hydroxyphenyl)-4-dimethylaminocyclohexanone, ethylene ketal having a melting point at 169° to 175° C. An analytical sample is obtained by recrystallization from a mixture of ethyl acetate and cyclohexane. The melting point is 175° to 177° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:13].F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C=O)C>[Cl:10][C:9]1[C:4]([Cl:3])=[C:5]([O:13][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(O)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of NaH (2.5 g., 0.052 mole of a 50% mineral oil suspension) in 60 ml. of DMF was added portionwise 2,3-dichloro-4-methoxyphenol (9.0 g., 0.047 mole) prepared as described by F. Dallacker and J. Van Wersch, Chem. Ber., 105, 3301 (1972). The mixture was stirred at room temperature under nitrogen for 15 minutes and then p-fluoronitrobenzene was rapidly added. The resulting mixture was heated at 100° for 2.5 hr., cooled to room temperature, and poured into ice water. The precipitate was filtered, washed with methanol and dried to give 13 g. of product, m.p. 165°-166°.
Reaction SMILES: [C:1](#[N:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Li].[CH2:14]([NH2:17])[CH2:15]C>C(N)CN>[CH2:2]([C:1]1[NH:12][CH2:15][CH2:14][N:17]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCN
Reactant: CCCCCCCCCCC#N
Agent: [Li]
Solvent: NCCN
Product: CCCCCCCCCCC1=NCCN1
Reaction time: 0.33 h
Yield: 22 %

Procedure:
Reduction of undecanenitrile in n-propylamine and ethylene-diamine. Lithium, (0.21 g, 30 mmol) in small pieces, was added to a stirred solution of undecanenitrile (0.84 g, 5 mmol) in n-propylamine and ethylenediamine (1.0 mL). The temperature began to rise after 20 min and reached 32° after 30 min and the reaction mixture turned blue. An aliquot of the reaction mixture showed no nitrile by glpc. The reaction mixture was poured over crushed ice and extracted with ethyl acetate (2×50 mL). After distillation of the ethyl acetate the residue deposited crystals. The crystals were collected and dried to give 2-(n-decyl)imidazoline (0.23 g, 22%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 18 from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone, N-tert.butoxycarbonyl-glycine, TBTU, HOBt and N-methylmorpholine in DMF.
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:9].C[OH:11]>>[ClH:9].[C:1](=[NH:8])([OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1
Reactant: CO
Agent: Cl
Product: N=C(O)c1ccccc1
Reaction time: 8 h
Yield: 96 %

Procedure:
A solution of benzonitrile (20 g, 0.194 mol) in methanol (8 ml) was bubbled with gaseous HCl to saturation. The solution was allowed to stand overnight, and then a pale yellow solid was found. The solid was triturated with ether, filtered, washed with ether, and dried to yield beige solid product (32 g, 96%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:11]=[C:12]([CH3:18])[C:13]([O:16][CH3:17])=[CH:14][CH:15]=3)[C:6]=2[CH:19]=1.[C:20](Cl)(Cl)=[O:21]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:13]1[C:12]([CH3:18])=[CH:11][C:10]([C:7]2[C:6]3[CH:19]=[C:2]([N:1]=[C:20]=[O:21])[CH:3]=[CH:4][C:5]=3[S:9][N:8]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nsc3ccc(N=C=O)cc23)cc1C
Yield: 98.2 %

Procedure:
A solution of 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole (157 g, 0.581 mol) in toluene is treated with phosgene (1,074 mL of a 20% solution in toluene, 2.06 mol), heated to and stirred at reflux for 5 hours, treated with additional phosgene (100 mL of a 20% solution in toluene), refluxed overnight, and concentrated in-vacuo to give the title product as a yellow-orange solid (169 g, 98.2%) which is identified by NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([O:12]CC)=[O:11])=[C:4]([F:15])[CH:3]=1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31](=[O:32])[NH:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][C:10]([OH:12])=[O:11])=[C:4]([F:15])[CH:3]=1
Reactant: Cc1ccccc1N=C=O
Reactant: CCOC(=O)Cc1cc(F)c(N)cc1F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1NC(=O)Nc1cc(F)c(CC(=O)O)cc1F
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a stirred solution of ethyl 4-amino-2,5-difluorophenylacetate (323 mg, 1.5 mmol) in DMF (8 mL), were added triethylamine (0.209 ml, 1.5 mmol) and 2-methylphenyl isocyanate (0.372 ml, 3.0 mmol) at rt. The stirring was continued for 48 hour at 80° C. The reaction mixture was evaporated in vacuo, and the solid was suspended to n-hexane. The solid was collected through filtration. The solid was dissolved in THF-MeOH (1:1, v/v, 20 mL), and was added 4M NaOH (10 mL) at rt. The stirring was continued for 18 hours at rt. The reaction was poured into 1M HCl, and the resulting precipitate was collected through filtration. The solid was recrystallized with CHCl3-n-hexane to give 4-[(2-methylphenyl)ureido]-2,5-difluorophenylacetic acid (214 mg, 46%) as a white solid. 1H-NMR (CDCl3) δ 2.30 (s, 3 H), 3.35 (m, 2 H), 7.02 (m, 2 H), 7.18 (d, J=7.3 Hz, 2 H), 7.69 (d, J=7.8 Hz, 1 H), 8.03 (m, 1 H); MS (FAB) m/z 321 (M++1).
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:14])=[O:13])[S:11][C:7]=2[CH:6]=1.O.S(=O)(=O)(O)[OH:21]>C(OCC)(=O)C>[OH:21][CH:2]([CH2:18][OH:1])[CH2:3][O:4][C:5]1[CH:17]=[CH:16][C:8]2[N:9]=[C:10]([S:12]([NH2:15])(=[O:13])=[O:14])[S:11][C:7]=2[CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: NS(=O)(=O)c1nc2ccc(OCC3CO3)cc2s1
Solvent: CCOC(C)=O
Solvent: O
Product: NS(=O)(=O)c1nc2ccc(OCC(O)CO)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-(2,3-Epoxypropoxy)benzothiazole-2-sulfonamide (1.21 gm, 4.25 mmol) was dissolved in ethyl acetate (35 mL) and added to water (25 mL) containing concentrated sulfuric acid (2.5 mL). This two phase mixture was stirred at room temperature overnight and then was poured into water and repeatedly extracted with 5% methanol/ethyl acetate (V/V). The extracts were dried (Na2SO4) and evaporated. The residue (1.2 gm) was dissolved in methanol and allowed to sit overnight to give 1.0 gm of impure product. This material was purified by chromatography on silica gel, eluting with 1% methanol/ethyl acetate (V/V). The combined fractions containing product were evaporated and the residue was triturated with methanol to give material which was recrystallized from methanol/ethyl acetate (0.3 gm), m.p. 183°-185° C.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][CH:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[N:11]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3C=C[CH:30]=[CH:29][CH:28]=3)[C@H:10]2[S:9]1.CN(C)C1C=CC=CC=1.[S:44]1C=CC=C1CC(Cl)=O>ClCCl.CO.N1C=CC=CC=1>[CH3:7][CH:8]1[CH:13]=[C:12]([C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:20])[Cl:21])=[O:15])[N:11]2[C:22](=[O:34])[CH:23]([NH:24][C:25](=[O:33])[CH2:26][C:27]3[S:44][CH:30]=[CH:29][CH:28]=3)[C@H:10]2[S:9]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1
Reactant: O=C(Cl)Cc1cccs1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Temperature: -15 °C
Yield: 66.1 %

Procedure:
Pyridine (0.296 g) and phosphorous pentachloride (0.616 g) were added in turn under stirring and cooling at -15° C. to a solution of 2,2,2-trichloroethyl 2-methyl-7-(2-phenylacetamido)-3-cephem-4-carboxylate (1.12 g), mp 175° to 178° C., in dried dichloromethane (20 ml), and the mixture was stirred for 20 minutes at the same temperature and further for 2 hours at room temperature. To the mixture was added absolute methanol (5 ml) under cooling at -15° C., and then the mixture was stirred for 1 hour at the same temperature. To the mixture were dropwise added in turn dimethylaniline (2.2 g) and a solution of 2-thienylacetyl chloride (0.42g) in dried dichloromethane (5 ml) at the same temperature, and then the mixture was stirred for 2.5 hours at the same temperature. After the reaction, the reaction mixture was in turn washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution and water, and then dried. After the solution was concentrated, the obtained oil substance was crystallized by adding ether to give 2,2,2-trichloroethyl 2-methyl-7-[2-(2thienyl)acetamido]-3-cephem-4-carboxylate (750 mg), mp 161° to 162° C. (dec.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=c1[nH]sc2ccccc12
Product: O=C(NCc1ccccc1)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6i (88% yield) was synthesized from benzo[d]isothiazol-3-one and benzyl isocyanate as a white solid. mp 169-170° C.; IR(CHCl3) 3281, 1711, 1663, 1536 cm−1; 1H-NMR (CDCl3) δ4.64 (d, J=5.9 Hz, 2H), 7.28-7.45 (m, 5H), 7.58 (d, J=7.2 Hz, 1H), 7.70 (t, J=7.2 Hz, 1H), 8.01 (d, J=7.2 Hz, 1H), 9.26 (br s, 1H); ESIMS m/e 285 (M++1).
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH:19]=[O:20])[S:17][CH:18]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([OH:23])C.[OH-].[Na+]>O.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:19]([OH:23])=[O:20])[S:17][CH:18]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCO
Reactant: CCCCCCOc1ccc(-c2csc(C=O)c2)cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCCOc1ccc(-c2csc(C(=O)O)c2)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A mixture of silver nitrate (4.07 g, 24 mmol), compound 1026 (1.73 g, 6 mmol), ethanol (30 mL) and aqueous sodium hydroxide solution (1M, 48 mL) was stirred at 40° C. for 3 hours and then diluted with water (150 mL). The aqueous phase was washed with ethyl acetate (2×300 mL) and acidified to pH 1 with 1N aqueous hydrochloric acid solution. The aqueous solution was extracted with EtOAc (2×300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to yield compound 1027 (1.5 g) which was used directly in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 0.87 (m, 3H), 1.31-1.30 (m, 6H), 1.65 (m, 2H), 3.98 (m, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 8.05 (s, 2H), 13.19 (s, 1H). MS m/z=303 [M−H]−.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][NH:4][C:5](=[O:8])[CH2:6][OH:7].[H-].[Na+].Cl[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[N:14]1[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[N:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1>O1CCCC1>[Cl:33][C:27]1[N:26]=[C:25]2[C:30]([CH:31]=[CH:32][C:23]([N:14]3[C:15](=[O:22])[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]3[O:7][CH2:6][C:5]([NH:4][CH2:3][CH:2]([CH3:9])[CH3:1])=[O:8])=[N:24]2)=[CH:29][CH:28]=1
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)CNC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 52.3 %

Procedure:
The procedure is as in Example 22, but starting with N-(2-methylpropyl)glycolamide (8.9 g) in tetrahydrofuran (357 cc), an oily suspension (50% by weight; 3.3 g) of sodium hydride and 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (15 g). After recrystallization in ethanol, [2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1isoindolinyloxy]-N-(2-methylpropyl)acetamide (10.1 g), m.p. 146° C., is obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH2:27])(=[O:20])=[O:19])[CH2:9][CH2:8]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[NH:27][C:28](=[O:30])[CH3:29])(=[O:20])=[O:19])[CH2:11][CH2:12]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1
Product: CC(=O)Nc1ccccc1S(=O)(=O)NCCCCN1CCN(c2ncccn2)CC1

Procedure:
0.02 mol of N-(4-(4-(2-pyrimidinyl)-1-piperazinyl)butyl)-2-aminobenzenesulphonamide and 0.05 mol of acetic anhydride are stirred at room temperature for 2 hours. The mixture is evaporated to dryness, concentrated aqueous ammonia solution is poured onto the residue and the base is extracted by shaking with methylene chloride, Purification is carried out by chromatography on silica gel; the eluting agent is CH2Cl2 /CH3OH (9:1). The substance is recrystallised from isopropanol.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:22]=[CH:23][C:24]([OH:31])=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27])=[CH2:20]>>[OH:31][C:24]1[CH:23]=[CH:22][C:21]([CH:19]=[CH:20][C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]3[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: C=Cc1ccc(O)c(C(=O)OC)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Product: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Yield: 52 %

Procedure:
This compound was prepared analogously to Example 3 from 4-iodo-N-(3-methyl-2-pyridinyl)-benzenesulfonamide, prepared according to Example 2a, and methyl 5-ethenyl-2-hydroxybenzoate prepared according to Example 3a. Yield 52%.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([CH3:44])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([NH:37][C:38](=[O:43])[CH2:39][CH2:40][CH2:41]Cl)[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+]>CN(C=O)C.O>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([N:13]([CH3:45])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([C@H:31]3[CH2:36][CH2:35][C@H:34]([N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:43])[CH2:33][CH2:32]3)=[O:30])[CH2:18]2)[CH3:44])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](NC(=O)CCCCl)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)[C@H]2CC[C@H](N3CCCC3=O)CC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the compound (0.2 g) obtained in step 1 in DMF (5.6 mL) was added sodium hydride (0.017 g) at 0° C., and the mixture was stirred at room temperature for 6 hr. To the mixture was added sodium hydride (0.017 g), and the mixture was stirred at room temperature for 12 hr, and sodium hydride (0.017 g) was further added. The mixture was stirred at room temperature for 6 hr, diluted with water and extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, water and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 0→10% methanol/ethyl acetate) to give the title compound (0.14 g, 76%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]2=[O:13].[F:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37](O)=[O:38])[CH:29]=[CH:30][C:31]=1[C:32]([F:35])([F:34])[F:33].C(N(CC)C(C)C)(C)C.CN(C)C=O>>[F:25][C:26]1[CH:27]=[C:28]([CH2:36][C:37]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]([CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:7]3=[O:13])=[O:38])[CH:29]=[CH:30][C:31]=1[C:32]([F:34])([F:35])[F:33]
Reactant: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
A reaction vial was charged with tert-butyl 2-(5-amino-6-methyl-1-oxoisoquinolin-2(1H)-yl)ethyl(methyl)carbamate (150 mg, 0.00041 mol), 2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (200 mg, 0.0009 mol), N,N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (700 mg, 0.002 mol), N,N-diisopropylethylamine (0.3 mL, 0.002 mol), N,N-dimethylformamide (4 mL, 0.05 mol) and the reaction was stirred at 45° C. overnight. The reaction was then quenched with water, extracted with warm ethyl acetate, and the solvent removed under reduced pressure. The residue was purified by flash chromatography and then by reversed phase preparative HPLC to afford the product as an off white solid.
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([C:11]1([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]>FC(F)(F)C(O)=O>[C:9]([C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)#[N:10]
Reactant: CC(C)(C)OC(=O)CC1(C#N)CCCCC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(CC(=O)O)CCCCC1

Procedure:
To a solution of 2.4 mL (2.4 g, 22 mmol) of anisole in 50 mL of trifluoroacetic acid is added 5.00 g (22.4 mmol) of (1-cyanocyclohexyl)acetic acid, t-butyl ester. The reaction is monitored (TLC) for the loss of starting material and when the reaction is complete it is concentrated under reduced pressure. Water (˜10 mL) is added to the residue and the mixture is adjusted to pH=10-12 with base (NaOH). The basic aqueous layer is extracted with a suitable organic solvent (EtOAc) to remove impurities. The aqueous layer is acidified with acid (HCl) to pH=0-4 and extracted with a suitable solvent (EtOAc). The combined organic extracts of the acidified aqueous layer are dried and concentrated under reduced pressure to afford the product.
Reaction SMILES: Cl[CH2:2][C:3](=[O:19])[C:4](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([F:17])[C:11]=1[F:18])[C:5]([O:7][CH3:8])=[O:6].[S-2:20].[Na+].[Na+]>CO>[F:18][C:11]1[C:12]([F:17])=[C:13]([CH3:16])[CH:14]=[CH:15][C:10]=1[CH:9]1[CH:4]([C:5]([O:7][CH3:8])=[O:6])[C:3](=[O:19])[CH2:2][S:20]1
Reactant: COC(=O)C(=Cc1ccc(C)c(F)c1F)C(=O)CCl
Reactant: [S-2]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(=O)CSC1c1ccc(C)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.6 %

Procedure:
Compound 371 (18.7 g, 65 mmol) suspended in anhydrous methanol (50 ml) was added slowly to a solution of dry sodium sulfide (10.0 g, 129 mmol) in methanol (50 ml) while keeping the internal temperature below 40° C. The solution was stirred for 1 h at room temperature then quenched by pouring into a rapidly stirred mixture of ice (350 ml) and 2M HCl (200 ml). The mixture was extracted with dichloromethane (3×250 ml) and the combined extracts dried with brine (100 ml) then sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 372 (12.2 g, 66%) as a crystalline solid.