Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:15])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][N:12]=1)[C:7]([Cl:15])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc([N+](=O)[O-])c1
Product: O=C(Cl)c1ccnc([N+](=O)[O-])c1

Procedure:
1.8 g. of 2-nitroisonicotinic acid and 30 ml. of thionyl chloride were refluxed for 3 hours. An excess of thionyl chloride was distilled off to leave 2-nitroisonicotinoyl chloride as an oil. The obtained acid chloride was added to 5 ml. of pyridine at -15° C., and to the resulting solution was added 1.5 g. of m-toluylamide. The mixture was stirred at room temperature for 1 hour and the solvent was evaporated at 40° C under reduced pressure. The residue was then purified by silica gel chromatography and recrystallized from ethyl acetate-n-hexane to yield 250 mg. of the desired crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:1][C:2]1[N:3]=[C:4]([NH:18][CH:19]2[CH2:24][CH2:23][N:22]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:21][CH2:20]2)[S:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([F:17])[CH:10]=1)=[O:8]
Reactant: COc1ccc(C(=O)c2sc(NC3CCNCC3)nc2N)cc1F
Reactant: CS(=O)(=O)Cl
Product: COc1ccc(C(=O)c2sc(NC3CCN(S(C)(=O)=O)CC3)nc2N)cc1F
Yield: 23 %

Procedure:
[4-Amino-2-(piperidin-4-ylamino)thiazol-5-yl]-(3-fluoro4-methoxy-phenyl)methanone (0.11 g, 0.31 mmol) (Example 7) was treated with methanesulfonyl chloride in a manner similar to Example 9 to give 30 mg (23% yield) of [4-amino-2-(1-methanesulfonylpiperidin-4-ylamino)thiazol-5-yl]-(3-fluoro-4-methoxy-phenyl)methanone. 1H NMR (DMSO−d6, 300 MHz) δ1.46 (m, 2H, CH2), 2.01 (m, 2H, CH2), 2.90 (m, 5H, CH2 & SCH3), 3.55(m, 2HCH2), 3.6-4.0 (broad, 1H, CH), 3.91 (s, 3H, OCH3), 7.24 (t,1H, Aromatic), 7.47 (t,1H, Aromatic), 7.59 (t,1H, Aromatic), 7.9-8.5 (brd, 2H, 2NH), 8.71 (brd, 1H, NH). HRMSEI: (M+H)+: observed: 428.0982; calcd for 428.0988.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11][C:12](=O)[CH2:13][CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(OCC)C>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:12]([CH3:11])([CH2:13][CH2:14][CH3:15])[O:10][C:3]=2[CH:4]=1
Reactant: CCCC(C)=O
Reactant: COc1ccc(O)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCC1(C)Oc2ccc(OC)cc2O1

Procedure:
0.35 mole (48.5 g) of 1,2-dihydroxy-4-methoxybenzene, 0.38 mole (32.7 g) of 2-pentanone and 1 g of p-toluenesulphonic acid are added to 350 ml of benzene. The mixture is heated under benzene reflux in order to remove the water formed. After 50 hours' heating, the reaction mixture is cooled and is then filtered through paper. After evaporation under reduced pressure, a brown oil is obtained and is dissolved in 500 ml of ethyl ether. After extraction with a solution of sodium carbonate in water in order to remove the unreacted 1,2-dihydroxy-4-methoxybenzene, the ethereal phase is dried with sodium sulphate. After evaporation of the ethyl ether under reduced pressure, the expected product is obtained and is employed as such in the following stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH:9]=2)=[CH:4][CH:3]=1.[ClH:36]>CO.CCOCC>[ClH:1].[ClH:36].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:35])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(Cl)cc5)cc4=O)cc31)CNCC2
Reaction time: 3 h
Yield: 40 %

Procedure:
tert-Butyl 7-(4-(4-chlorophenyl)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (59 mg, 0.12 mmol) was dissolved in MeOH (0.5 mL) and 2 N HCl in Et2O (3 mL) was added. The reaction was allowed to proceed for 3 h. The mixture was concentrated and purified by preparative HPLC. Conversion to the HCl salt (2 N HCl in Et2O) provided the title compound (22 mg, 40%) as a pale yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.80-7.78 (m, 3H), 7.66 (d, J=8.5 Hz, 1H), 7.58-7.57 (m, 3H), 7.16 (dd, J=8.3, 1.7 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 6.87 (dd, J=7.1, 1.9 Hz, 1H), 6.17 (d, J=2.7 Hz, 1H), 4.53 (s, 2H), 3.79 (s, 3H), 3.72 (t, J=5.9 Hz, 2H), 3.25 (t, J=5.9 Hz, 2H); ESI MS m/z 390 [M+H]+; HPLC (Method B) 98.2% (AUC), tR=16.3 min.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14][CH2:15][N:16]([CH3:34])[C:17]([N:19]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18])[CH:8]=2)[N:3]=1.C(O)(=[O:37])C>>[CH3:34][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:37])[CH:11]=[CH:10]2)[C:17]([N:19]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:20][CH:21]([O:24][C:25](=[O:27])[CH3:26])[CH2:22][CH3:23])=[O:18]
Reactant: CCC(CN(C(=O)N(C)CCCOc1ccc2nc(Cl)ccc2c1)C1CCCCC1)OC(C)=O
Reactant: CC(=O)O
Product: CCC(CN(C(=O)N(C)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1)OC(C)=O

Procedure:
To acetic acid (100 ml) is added 2-chloro-6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}quinoline (5.5 g), and the mixture is refluxed for 4 hours. The mixture is concentrated under reduced pressure to remove the acetic acid, and the residue is dissolved in methylene chloride and washed with a saturated aqueous sodium hydrogen carbonate solution. The mixture is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; methylene chloride:methanol=20:1), and recrystallized from methylene chloride-diethyl ether to give 6-{3-[1-methyl-3-cyclohexyl-3-(2-acetyloxybutyl)ureido]propoxy}carbostyril (2.7 g) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH:3]=[CH:4][CH3:5].C(N(CC)CC)C.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>ClCCl>[C:14]([O:6][CH:2]([CH3:1])[CH:3]=[CH:4][CH3:5])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: CC=CC(C)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C)C=CC
Temperature: 0 °C
Yield: 55 %

Procedure:
A 1-liter flask was charged with 43.9 g (0.51 mol) of 3-penten-2-ol, 51.6 g (0.51 mol) of triethylamine and 300 ml of dichloromethane, and the mixture was cooled down to 0° C. While stirring the mixture at 0° C., 52.3 g (0.50 mol) of methacryloyl chloride were added dropwise over 1 hour, and the mixture was stirred additionally for 5 hours at room temperature. Solids were separated by filtration from the resultant reaction mixture, and the filtrate was washed 3 times with water and then distilled in the presence of 5 g of p-methoxyphenol to obtain 42.4 g of 1-methyl-2-butenyl methacrylate.
Reaction SMILES: [CH3:1][CH:2]1[CH:6]=[CH:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH:10]([CH3:14])[CH2:9][CH:8]=[C:7]2[CH3:15])[O:3]1.[OH:16]C1(C#CC(O)C)C(C)(C)C(C)CCC1C.OS(O)(=O)=O>CO>[CH3:1][CH:2]1[CH2:6][CH2:5][C:4]2([C:11]([CH3:13])([CH3:12])[CH:10]([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:15])[OH:16])[O:3]1
Reactant: CC(O)C#CC1(O)C(C)CCC(C)C1(C)C
Reactant: CC1=CCC(C)C(C)(C)C12C=CC(C)O2
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC1CCC2(O1)C(C)(O)CCC(C)C2(C)C

Procedure:
2,6,9,10,10-Pentamethyl-1-oxa-spiro[4.5]deca-3,6-diene, used as starting material in step a) hereinabove could be prepared from 1-hydroxy-2,5,6,6-tetramethyl-1-(3-hydroxybut-1-yn-1-yl)-cyclohexane by treating said carbinol with a 30% aqueous solution of H2SO4 as indicated in Swiss Pat. No. 544,733. The compound possessed moreover very interesting organoleptic properties and consequently could advantageously be used as flavouring and perfuming agents. It develops a very powerful natural fruity, minty character reminiscent of certain perfuming notes typical of black-currant fruits.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:29])[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[O:29]=[C:7]([CH2:8][S:9][C:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:38]
Reactant: O=C=Nc1ccccc1
Reactant: NCCCCCC(=O)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(CCCCCNC(=O)Nc1ccccc1)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a solution of 7-amino-1-tritylsulfanyl-heptan-2-one (0.36 g, 0.86 mmol) in dichloromethane (10 mL) was added phenylisocyanate (0.10 mL, 0.92 mmol). The mixture was stirred at room temperature for 2 h. Solvent was then removed in vacuo and the crude product was purified by column chromatography (dichloromethane/MeOH=100/1 to 40/1) to provide 1-(6-Oxo-7-tritylsulfanyl-heptyl)-3-phenyl-urea (0.43 g, 93%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:50]=[CH:49][C:10]([CH2:11][N:12]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:41]CC4C=CC=CC=4)[CH:37]=3)[CH:32]=2)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:9][CH:8]=1>C1(OC)C=CC=CC=1.CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]([C:31]2[CH:40]=[CH:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([OH:41])[CH:37]=3)[CH:32]=2)[C:13](=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)[CH:15]=2)=[CH:49][CH:50]=1
Reactant: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(OCc4ccccc4)ccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: COc1ccccc1
Product: COc1ccc(CN(C(=O)c2ccc(OC)c(-c3cccc(OC)c3)c2)c2ccc3cc(O)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.2 %

Procedure:
A solution of AlCl3 (203 mg, 1.52 mmol) in anhydrous anisole (750 μl) was added to 38 (191 mg, 0.31 mmol) in anhydrous anisole (750 μl) and the resulting solution was stirred at room temperature for 18 hours. The reaction was diluted with MeOH (750 μl) and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 1:1 EtOAc:Hexanes) to give 39 as a light yellow amorphous solid (126 mg, 77%): 1H NMR (CDCl3, 500 MHz) δ 7.56 (m, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.47 (dd, J=8.6, 2.3 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.25 (m, 2H), 7.12-7.06 (m, 3H), 7.00 (dd, J=8.7, 2.1 Hz, 1H), 6.80 (m, 2H), 6.77 (m, 1H), 6.73 (d, J=8.7 Hz, 1H), 6.59-6.55 (m, 2H), 5.43 (s, 1H), 5.15 (s, 2H), 3.77 (s, 3H), 3.71 (s, 3H), 3.62 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.2, 159.3, 159.0, 157.6, 154.2, 139.7, 139.0, 133.1, 132.4, 130.5, 130.1, 130.1 (2C), 130.0, 129.5, 128.9, 128.9, 128.0, 127.5, 127.3, 125.9, 122.1, 118.7, 114.7, 114.0 (2C), 113.2, 110.4, 109.5, 55.7, 55.4, 55.3, 54.0; IR (film) νmax 3236, 2934, 2835, 1599, 1508, 1456, 1437, 1394, 1248, 1177, 1036 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C33H29NO5, 520.2124. found, 520.2120.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2)[CH3:2].[C:26]([O:31][CH2:32][CH3:33])(=[O:30])[C:27]#[C:28][CH3:29].O1CCCC1.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:32]([O:31][C:26](=[O:30])[CH2:27][CH:28]1[S:14][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:4][C:3]=3[CH2:1][CH3:2])=[N:13][CH2:29]1)[CH3:33]
Reactant: CCc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(CC)c3[nH]2)S1
Temperature: 40 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
To a mixed solution of 7-ethyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (2.8 g), ethyl 2-butynoate (1.8 mL), tetrahydrofuran (40 mL), and toluene (60 mL), tri-n-butylphosphine (2.2 mL) was added under an argon atmosphere at room temperature, and the mixture was stirred at 40° C. for 3 hr. The reaction solution was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=25:75 to 60:40, volume ratio) to give the title compound (3.05 g, yield 84%) as a pale-yellow amorphous solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH2:4].[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH3:6].[H-].[Na+]>C(OCC)C.O1CCCC1>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:2][CH2:3][NH:4][C:14]2=[O:15])=[CH:9][CH:8]=1)[CH3:6]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1ccc(N2CCNC2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.5 %

Procedure:
To a solution of 3.98 g of 2-chloroethylamine in 30 ml of diethyl ether, a solution of 3.68 g of 4-ethylphenyl isocyanate in 15 ml of tetrahydrofuran was added dropwise under ice cooling. After the resultant mixture was stirred at room temperature for 30 minutes, diethyl ether was added, followed by the collection of precipitated crystals by filtration. The crystals so obtained were added under ice cooling to a suspension of 10.8 g of 60%-sodium hydride in 35 ml of tetrahydrofuran, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, to which 1N hydrochloric acid was added. Resulting crystals were collected by filtration and washed with n-hexane, whereby 3.64 g of the title compound were obtained (yield: 89%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:7][CH2:8][C:9](=[O:13])[NH:10][C:11]=2[N:12]=1.C1COCC1>ClCCl.[O-2].[O-2].[Mn+4]>[O:13]=[C:9]1[CH2:8][S:7][C:6]2[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[N:12][C:11]=2[NH:10]1
Reactant: O=C1CSc2ccc(CO)nc2N1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A solution of 6-hydroxymethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine (330 mg) in dichloromethane (30 mL)/THF (30 mL) was treated with manganese dioxide (730 mg) and stirred at room temperature. Further manganese dioxide was added after 1 h (730 mg) and 16 h (300 mg). After a total of 20 h the mixture was filtered through kieselguhr and the filtrate evaporated. The product was triturated with EtOAc/hexane (1:1) and collected to give a solid (180 mg); LC/MS (APCI−) m/z 195 ([M−H]−, 95%), 165 (100%).
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[N:16]=2)=[O:14])[CH:7]=1)C.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:17]2[N:16]=[C:15]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH2:5][C:4]([OH:3])=[O:22])[CH:11]=[CH:10][CH:9]=3)=[O:14])[CH:20]=[CH:19][CH:18]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(Cl)c1
Product: O=C(O)Cc1cccc(NC(=O)c2cccc(-c3cccc(Cl)c3)n2)c1

Procedure:
The pyridyl bromide (77) (44 mg, 0.12 mmol) was coupled to 3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the acid. The solid was further purified by preparative HPLC to give the title compound.
Reaction SMILES: Br.[NH:2]1[CH2:6][CH2:5][C@H:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:3]1.[C:15]1([CH2:21][CH2:22][CH2:23][CH:24]=O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[C:15]1([CH2:21][CH2:22][CH2:23][CH2:24][N:2]2[CH2:6][CH2:5][C@H:4]([S:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=3)[CH2:3]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccc(S[C@H]2CCNC2)cc1
Reactant: O=CCCCc1ccccc1
Agent: Br
Solvent: ClC(Cl)Cl
Product: Oc1ccc(S[C@H]2CCN(CCCCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=328.3 (M+H+) and [α]D20=−6.26° (c=0.61, chloroform) was prepared from (S)-4-(pyrrolidin-3-yl-sulfanyl)-phenol hydrobromide and 4-phenyl-butyraldehyde.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH2:11][CH2:12]C)=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+]([O-])=O.C[CH2:18][O:19]C(C)=O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[O:7])=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][O:19][CH3:18]
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCOC(C)=O
Product: COCCOc1cc(C=O)ccc1O
Yield: 97 %

Procedure:
Followed the procedure described in Step 3 of Intermediate 65, where the reaction was refluxed for 2 days. Isolated 900 mg, yield 97% after column chromatography (PE:EtOAc=10:1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1ccnc(F)c1
Product: Cc1c2n(c3c(-c4ccnc(F)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (33 mg, 41%), MS (ISP) m/z=321.4 [(M+H)+], mp 256° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2-fluoro-pyridin-4-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[CH3:9][N:10]([CH3:16])[CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(O)CO>CC(O)C.[Cu]I>[Br:1][C:2]1[CH:3]=[C:4]([N:13]2[CH2:14][CH2:15][CH:11]([N:10]([CH3:16])[CH3:9])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(I)c1
Reactant: CN(C)C1CCNC1
Agent: [Cu]I
Solvent: CC(C)O
Solvent: OCCO
Product: CN(C)C1CCN(c2cccc(Br)c2)C1
Temperature: 80 °C

Procedure:
1-Bromo-3-iodobenzene (1 eq, 3.53 mmol, 1 g), copper(I) iodide (0.05 eq, 0.177 mmol 0.034 g) and potassium phosphate tribasic carbonate (2 eq, 7.07 mmol, 1.51 g) are dissolved in 2-propanol (15 ml) under an inert atmosphere of nitrogen. Then, N,N-dimethylpyrrolidin-3-amine (2 eq, 7.07 mmol, 0.807 g) and ethylene glycol (2 eq, 7.07 mmol, 0.394 ml) are added and the reaction mixture heated at 80° C., overnight.
Reaction SMILES: C([O:8][C:9](=[O:42])[CH2:10][C@@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)[C:12]([NH:14][C@@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:16][OH:17])=[O:13])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[CH2:18]([C@H:15]([NH:14][C:12](=[O:13])[C@H:11]([N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:34][CH:35]=2)=[CH:26]1)[CH2:10][C:9]([OH:42])=[O:8])[CH2:16][OH:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1
Reaction time: 20 h
Yield: 83.6 %

Procedure:
A suspension of 10% Pd/C (wet DeGussa type, 15 mg ) and N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester (68 mg, 0.12 mmol) in EtOAc (5 mL) was stirred under H2 for 20 hours. The catalyst was filtered onto Celite and rinsed with MeOH. The filtrate was concentrated under reduced pressure to give a yellow oil, which was purified via flash column chromatography with a 1% HOAc/2-5% MeOH/CH2Cl2 stepwise gradient elution to provide 47 mg (82%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid as a white solid. 1H NMR (CDCl3): δ 7.66-7.48 (m, 3H), 7.42 (t, 2H, J=7.2 Hz), 7.34-7.28 (m, 1H), 7.21-7.12 (m, 2H), 7.04-6.96 (m, 1H), 6.94 (bs, 1H), 6.68 (dd, 1H, J=2.5, 2.5 Hz), 6.55 (dd, 1H, J=1.6, 1.6 Hz), 5.78 (bd, 1H, J=7.5 Hz), 4.90 (t, 1H, J=7.2 Hz), 4.36-4.02 (m, 1H), 3.68 (dd, 1H, J=3.4, 11.2 Hz), 3.50 (dd, 1H, J=5.3, 9.0 Hz), 3.31 (dd, J=5.9, 7.4 Hz), 3.12 (dd, 1H, J=7.2, 17.1 Hz), 2.74 (ddd, 1H, J=6.2, 14.3, 14.3 Hz), 2.68 (ddd, J=8.7, 14.0, 14.3 Hz). IR (film): 3387, 3028, 2931, 1715, 1660, 1532, 1494, 1204, 702, 698 cm−1. HRFABMS: Calculated for C29H28N2O4Cs (M+Cs+): 643.1209. Found: 643.1185. Anal. calculated for C29H28N2O4.0.1 CHCl3.0.35 H2O: C, 71.80; H, 5.96; N, 5.75. Found: C, 71.92; H, 5.87; N, 5.77.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].IC.[C:16](OCC)(=O)C>CN(C)C=O>[F:1][CH2:2][CH2:3][N:4]([CH3:16])[C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)NCCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(CCF)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Under nitrogen atmosphere, tert-butyl (2-fluoroethyl)carbamate (I-286) (2 g, 20.1 mmol) was dissolved in N,N-dimethylformamide (50 ml), then sodium hydride (55%, w/w) (803 mg, 18.4 mmol) was added to the solution at 0° C., followed by stirring at 0° C. for 30 minutes. After 30 minutes, iodomethane (1.2 ml, 19.7 mmol) was added, followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction liquid, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=3:1, v/V) to obtain the entitled compound (970 mg, 45%) as a white crystal.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7](/[CH:11]=[N:12]/[OH:13])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.ClN1C(=O)CCC1=O.[CH2:22]([Sn:26]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:29][CH2:30][CH2:31][CH3:32])[C:27]#[CH:28])[CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:33]([Sn:26]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:22][CH2:23][CH2:24][CH3:25])[C:27]1[O:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)[CH:28]=1)[CH2:34][CH2:35][CH3:36]
Reactant: O/N=C/c1ccc2cnccc2c1
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2ccc3cnccc3c2)no1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 31.1 %

Procedure:
To a solution of (E)-isoquinoline-6-carbaldehyde oxime (2.14 g, 12.4 mmol) in 60 mL of DMF at 0° C. was added 1-chloropyrrolidine-2,5-dione (1.66 g, 12.4 mmol) (commercially available from Aldrich). The mixture was stirred for 10 minutes and then heated to 5° C. After 2½ hours, the DMF was removed by rotary evaporation. The residue was dissolved in 100 mL of THF and chilled to 0° C. To this mixture was added tributyl(ethynyl)stannane (4.50 g, 14.3 mmol) (commercially available from Aldrich). TEA (3.81 mL, 27.3 mmol) was then added dropwise. The mixture was gradually warmed to room temperature over 12 hours. The reaction was quenched with 50 mL of aqueous NH4Cl and diluted with 50 mL of water. The mixture was partitioned in a separatory funnel. The aqueous portion was extracted twice with 100 mL of EtOAc, and the combined organic layers were washed with 100 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 30% EtOAc/hexanes), afforded 6-(5-(tributylstannyl)isoxazol-3-yl)isoquinoline (1.87 g, 31.0% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 9.29 (s, 1H), 8.58 (d, J=5.8 Hz, 1H), 8.26 (s, 1H), 8.14 (dd, J=1.3 Hz, 8.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 7.72 (d, J=5.7 Hz, 1H), 6.83 (s, 1H), 1.65-1.57 (m, 6H), 1.38 (q, 7.3 Hz, 6H), 1.23 (t, J=8.2 Hz, 6H), 0.92 (t, 7.2 Hz, 9H).