Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)=[C:2]=[O:3].[C:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C.C1CCN2C(=NCCC2)CC1>C1COCC1>[C:17]([O:16][C:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:6](=[O:8])[C:5]3[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=3)[NH:1][C:2]2=[O:3])=[CH:26][CH:27]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.3 %

Procedure:
To a solution of methyl 2-isocyanatobenzoate (0.97 g, 5.5 mmol) and Boc 1,4-phenylenediamine (1.04 g, 5 mmol) in THF (15 mL) was added DIEA (0.87 mL, 5 mmol) and DBU (0.75 mL, 5 mmol). The reaction mixture stirred at room temp for 5 hr, the off-white solid filtered and washed with ethyl ether to give desired compound (1.49 g, 85%). ES-MS (M+Na)+=376.1, (M-tBu+H)+=298.0.
Reaction SMILES: [CH:1]([C:5]([CH3:11])=[C:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1)=[CH:2][CH2:3][CH3:4].CCOCC.[C:17]([C:21]1[CH:33]=[CH:32][C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:29]=3)[CH2:24][C:23]=2[C:22]=1[Li])([CH3:20])([CH3:19])[CH3:18].C1C(=C)C=CC=1>CCCCC>[CH3:11][C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])([CH:6]1[CH:7]=[CH:8][CH:9]=[CH:10]1)[C:33]1[C:32]2[CH2:24][C:25]3[C:30](=[CH:29][CH:28]=[C:27]([C:34]([CH3:35])([CH3:36])[CH3:37])[CH:26]=3)[C:31]=2[CH:23]=[CH:22][C:21]=1[C:17]([CH3:19])([CH3:18])[CH3:20]
Reactant: CCC=CC(C)=C1C=CC=C1
Reactant: [Li]c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2
Agent: C=C1C=CC=C1
Solvent: CCCCC
Solvent: CCOCC
Product: C=CCCC(C)(c1c(C(C)(C)C)ccc2c1Cc1cc(C(C)(C)C)ccc1-2)C1C=CC=C1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Another one-liter flask fitted with an addition funnel is charged with 6-butenyl-6-methylfulvene (37 g, 253 mmol) and a stir bar, and cooled to 0° C. under a nitrogen atmosphere. The ether solution of 2,7-di-tert-butylfluorenyl lithium prepared as above is added in a dropwise fashion to the fulvene at 0° C. via the addition funnel over the course of approximately one hour. The resulting dark-colored reaction mixture is warmed to room temperature and stirred overnight (at least about 12 hours) under a nitrogen atmosphere. The reaction mixture is then quenched with the slow addition of a saturated NH4Cl/H2O solution (300 mL), the organic layer extracted with ether, washed twice with H2O (500 mL), dried over anhydrous Na2SO4, filtered, and the filtrate evaporated to dryness. The crude product obtained by this method is then dissolved in pentane and maintained at about 0° C. in a freezer, thereby affording the product as a white solid that is washed with cold pentane, dried under vacuum, and isolated and used without further purification. Further product could be isolated in smaller quantities through concentrating the mother liquors and combined washings and placing them back in freezer.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[H][H]>[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[CH2:10][CH:9]([CH3:11])[CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C)c(C)cc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Product: Cc1nc2c([nH]1)CC(C)C(C)C2

Procedure:
10.0 g (62.41 mmol) 2,5,6-Trimethylbenzimidazole are dissolved in 60 ml glacial acid. 2.0 g (1.89 mmol) palladium (10% on carbon) are added under argon and the reaction mixture is treated with hydrogen at a temperature of 150° C. and 80 bar pressure for 48 h. The solution is filtrated over celite and washed with glacial acid. The solvent is evaporated under vacuum, 10 ml water and sodium hydroxid solution are added the solution to a pH of 9-10. The precipitate is filtrated and washed with water. The precipitate is dissolved in ethyl acetate/dichlor-methane and extracted with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtrated and concentrated under vacuum. Diethylether is added, the crystalls are filtrated and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:19][CH3:20]>>[CH3:17][CH:18]([N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1)[CH2:19][CH3:20]
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: CCC(C)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Product: CCC(C)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
1.21 g compound 15 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.80 g of ethyl 4-(2-aminophenoxy)butyrate and 1.04 g of 3-[1-(1-methylpropyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[C:9][C:10]([OH:12])=O.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:35])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([CH3:34])[CH2:30][CH2:29]1>ClCCl.CO>[Cl:19][C:20]1[CH:21]=[C:22]([NH:35][C:10](=[O:12])[C:9]#[C:8][C:7]2[CH:6]=[CH:5][C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:3][C:2]=2[Br:1])[CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][N:28]1[CH2:29][CH2:30][CH:31]([CH3:34])[CH2:32][CH2:33]1
Reactant: O=C(O)C#Cc1ccc(-c2ccccc2)cc1Br
Reactant: CC1CCN(CCc2ccc(N)cc2Cl)CC1
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(CCc2ccc(NC(=O)C#Cc3ccc(-c4ccccc4)cc3Br)cc2Cl)CC1

Procedure:
Prepared analogously to Example 2.3.f. from (3-bromobiphenyl-4-yl)propynoic acid and 3-chloro-4-[2-(4-methylpiperidin-1-yl)ethyl]phenylamine. Yield: 0.24 g (50% of theory); C29H28BrClN2O (M=535.90); calc.: molecular ion peak (M+H)+: 535/37/39; found: molecular ion peak (M+H)+: 535/37/39; Rf value: 0.48 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [CH:1]([NH2:3])=O.C(O)(=O)C.[NH2:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:10]=1[C:11](O)=[O:12]>O>[F:19][C:15]1[CH:14]=[C:10]2[C:9](=[CH:17][C:16]=1[F:18])[N:8]=[CH:1][N:3]=[C:11]2[OH:12]
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Reactant: NC=O
Solvent: O
Solvent: CC(=O)O
Product: Oc1ncnc2cc(F)c(F)cc12
Temperature: 125 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a stirring mixture of formamide (10 mL) and glacial acetic acid (2.5 mL) was added 2-amino-4,5-difluorobenzoic acid (2.0 g, 11.6 mmol) and the solution stirred at 125° C. for 8 hours. After cooling to room temperature, the reaction was diluted with H2O (100 mL) and the resulting solid filtered and dried under vacuum to give 6,7-difluoro-4-hydroxyquinazoline (1.77 g, 9.7 mmol, 84%). 1H NMR (300 MHz, DMSO-d6) δ 12.49 (br s, 1H), 8.15 (s, 1H), 8.04 (dd, 1H), 7.76 (dd, 1H); LC-MS (ESI) m/z 183 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:12][C:13]([C:15]1[S:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:35])[F:34])[CH2:22][CH2:21]2)=[N:18][N:19]=1)=O)C>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:13]([C:15]2[S:16][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]([F:36])([F:35])[F:34])[CH2:24][CH2:25]3)=[N:18][N:19]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)s1

Procedure:
Following the procedure as described in Example 3, making variations only as required to use 4-fluorobenzylamine in place of isoamylamine to react with 5-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl][1,3,4]thiadiazole-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid (0.070 g, yield 50%). 1H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.64-7.52 (m, 2H), 7.42-7.39 (m, 1H), 7.34-7.26 (m, 3H), 7.03-6.97 (m, 2H), 4.56 (d, J=6 Hz, 2H), 4.09-4.02 (m, 1H), 3.91-3.83 (m, 1H), 3.75-3.59 (m, 2H), 3.57-3.48 (m, 2H), 3.37-3.29 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 174.6, 167.6, 163.9, 160.6, 158.3, 155.5, 133.9, 133.3, 133.2, 132.4, 129.7, 129.5, 129.0, 126.1, 126.8, 126.7, 125.4, 121.8, 115.7, 115.4, 49.6, 48.9, 45.9, 42.9, 40.7. MS (ES+) m/z 494 (M+1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=2)[CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:20]1([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[CH:8]=[C:9]([CH:17]=[CH:18][CH:19]=1)[CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:31]([C:27]2[N:28]=[CH:29][O:30][C:26]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:32])[CH:13]=[N:12]1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(c2cccc(Cn3cc(N)cn3)c2)OCCO1
Product: CC(=O)c1cccc(Cn2cc(NC(=O)c3ncoc3-c3ccccc3)cn2)c1

Procedure:
Following general procedure B followed by C, starting from 1-[3-(2-methyl-[1,3]dioxolan-2-yl)-benzyl]-1H-pyrazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.00 min; [M+H]+=387.06.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])=[O:4]>O>[S:3]([C:6]1[CH:7]=[C:8]([C:16]([OH:18])=[O:17])[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=1)(=[O:5])(=[O:4])[NH2:1]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCO2
Reactant: N
Solvent: O
Product: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Temperature: 25 °C
Yield: 86.4 %

Procedure:
209 g of 34% ammonia and 97 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer at a temperature of 5°-10° C. The mixture was agitated at ambient temperature and then the precipitate was dissolved in 415 cm3 of water. The solution was filtered and treated with 140 cm3 of concentrated hydrochloric acid. The crystals were dried off, washed with water and dried. 78 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 272°-274° C.; yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[C:4](I)[CH:5]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]#[CH:38]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([C:38]#[C:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1
Reactant: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2I)nc1
Reactant: C#Cc1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2C#Cc2ccccc2Cl)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of protective gas, 0.1 g of 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-1-iodo-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzene, 0.03 g of 1-chloro-2-ethynylbenzene and 0.003 g of copper(I) iodide were dissolved in 1 ml of triethylamine. 0.005 g of bis(triphenylphosphine)palladium(II) chloride was added, and the mixture was stirred at 70° C. for 1 hour. The mixture was then allowed to cool and concentrated under reduced pressure, and the resulting residue was subjected to chromatographic purification. Yield: 0.085 g (84%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][CH:12]=1)(=[O:9])=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:4]=1[CH2:5][NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][O:18][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:13][CH:12]=1)(=[O:9])=[O:8]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(CO)cc2)c(OC)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNS(=O)(=O)Cc2ccc(COS(C)(=O)=O)cc2)c(OC)c1
Reaction time: 1.5 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-C-(4-hydroxymethylphenyl)methanesulfonamide (6 g) were added, at 0° C., triethylamine (4.5 ml) and, gradually, methanesulfonyl chloride in dichloromethane (2.2 ml in 50 ml). The mixture was stirred for 1.5 h and then diluted with ethyl acetate. After washing with water, 1 M hydrochloric acid and sodium chloride solution, the organic phase was dried over magnesium sulfate and concentrated. This gave the product (7 g) with a molecular weight of 429.5 g/mol (C18H23NO7S2).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([N+:17]([O-])=O)=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].C(OCC)(=O)C>[Pt]=S.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([NH2:17])=[CH:15][C:14]([Cl:20])=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCN(c2ncc(Cl)cc2[N+](=O)[O-])CC1
Agent: S=[Pt]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2ncc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.1 %

Procedure:
In a round bottom flask is placed 0.20 g (0.039 mmol) of 5% platinum sulfide on carbon. The vessel is evacuated and refilled with argon three times. To the flask is added a solution of 0.50 g (1.7 mmol) of 5′-chloro-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester in a 1:1 mixture of ethyl acetate:methanol (30 mL). The mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.45 g (quant.) of 3′-amino-5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid methyl ester as a dark oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.Cl[S:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(=[O:19])=[O:18].O>C1COCC1>[N:10]1([S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
To a solution of diisopropylethylamine (1.76 g, 13.6 mmol, 2.37 ml) and morpholine (1.98 g, 22.7 mmol, 1.98 ml) in THF (40 ml) was added, dropwise over 0.5 h, a solution of 4-(chlorosulfonyl)benzoic acid (2.50 g, 11.3 mmol) in THF (17 ml). After stirring at room temperature for 18 h the reaction was poured into H2O (150 ml) and washed with EtOAc. The aqueous layer was acidified (pH 1) with concentrated HCl, and the precipitate collected, washed with cold H2O, and dried under vacuum over P2O5 to give 2.68 g (87%) of 4-(4-morpholinylsulfonyl)-benzoic acid as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22]=O)[C:8]([F:11])=[CH:9][CH:10]=1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([NH2:34])[C@@H:26]1[OH:35]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][NH:34][C@H:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:25][C@H:26]2[OH:35])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Product: COC(=O)Cc1ccc(F)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2c3ccccc3C[C@H]2O)c1

Procedure:
Prepared according to the procedure described in Example 25, Step 4, using the following starting materials: (6-fluoro-2′-formyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (1S,2R)-(−)-cis-1-amino-2-indanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[C:8]([CH3:13])([CH3:12])[CH:7]2[OH:14].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].[BH4-].[Na+]>ClCCl.O.C(O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([OH:11])[C:8]([CH3:12])([CH3:13])[CH:7]2[O:14][C:21](=[O:23])[CH3:22]
Reactant: CC1(C)C(=O)c2c(Cl)cccc2C1O
Reactant: CC(=O)OC(C)=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC1c2cccc(Cl)c2C(O)C1(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-3-hydroxy-2,2-dimethyl-indan-1-one, which can be prepared as described in Example 58, (287 mg, 1.36 mmol) in dichloromethane (15 mL) is added pyridine (1.1 mL, 13.6 mmol), and acetic anhydride (0.26 mL, 2.72 mmol). The reaction is permitted to stir for 1 hour and is then diluted with water and extracted twice with dichloromethane. The combined organic extracts are washed successively with 4N aqueous HCl and saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated. The resulting residue is then diluted with ethanol (10.0 mL) and cooled to −10° C. The solution is then charged with a solution of NaBH4 (100 mg, 2.63 mmol) in ethanol (6 mL). The reaction is permitted to warm to room temperature over 1 hour, at which time additional NaBH4 (50 mg, 1.31 mmol) is added. The reaction is permitted to stir for another 1.5 hours and then diluted with saturated aqueous NH4Cl. The reaction mixture is concentrated to remove the organic volatiles and then extracted three times with ethyl acetate. The organic extracts are combined, dried over Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:2) to furnish acetic acid 4-chloro-3-hydroxy-2,2-dimethyl-indan-1-yl ester; MS: (ESI) m/z 237.17 (M−OH)+
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH:9]1([C:12](=[O:25])[CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([S:23][CH3:24])[CH:17]=2)=[O:15])[CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH:9]1([C:12](=[O:25])[C:13](=[CH:3][N:4]([CH3:5])[CH3:6])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([S:23][CH3:24])[CH:17]=2)=[O:15])[CH2:11][CH2:10]1
Reactant: COC(OC)N(C)C
Reactant: CSc1cc(C(=O)CC(=O)C2CC2)ccc1C
Solvent: Cc1ccccc1
Product: CSc1cc(C(=O)C(=CN(C)C)C(=O)C2CC2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl formamide dimethyl acetal (6.0 ml) was added to a solution of 3-cyclopropyl-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (8.71 g) in toluene. The mixture was stirred at room temperature overnight. Further dimethyl formamide dimethyl acetal (2.0 ml) was added and the mixture was stirred and heated at 50° C. for 24 hours. It was cooled and evaporated to dryness to give 3-cyclopropyl-2-(N,N-dimethylaminomethylene)-1-(4-methyl-3-methylsulphenylphenyl)propan-1,3-dione (10.6 g) as a brown oil.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[C:22]([CH3:29])[N:21]=1
Reactant: Cc1cc2[nH]ncc2c(Cl)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(cnn2C2CCCCO2)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
p-Toluenesulfonic acid monohydrate (29 mg, 0.15 mmol) and 3,4-dihydro-2H-pyran (99%, 205 μL, 2.39 mmol) were sequentially added to a suspension of C1 (250 mg, 1.49 mmol) and 4 Å molecular sieves in dichloromethane (10 mL). The reaction mixture was allowed to stir at room temperature for 4 hours, at which time it was filtered, concentrated in vacuo, and washed three times with heptane. Purification via silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane) afforded the product as a colorless oil. Yield: 65 mg, 0.26 mmol, 17%. LCMS m/z 252.1 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.08 (d, J=0.9 Hz, 1H), 7.26-7.27 (m, 1H), 5.67 (dd, J=9.1, 2.8 Hz, 1H), 3.99-4.05 (m, 1H), 3.71-3.79 (m, 1H), 2.65 (d, J=0.8 Hz, 3H), 2.06-2.2 (m, 2H).
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]2)=[CH:10][CH:9]=1)#[N:7]>CN(C)C=O.O>[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]2[CH2:4][CH3:5])=[CH:10][CH:9]=1)#[N:7]
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(C#N)cc2n1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1 l flask, 23.5 g of ethyl 6-cyanoindole-2-carboxylate was dissolved in 300 ml of dimethylformamide, and 6.6 g of 60% NaH was slowly added thereto at 0° C. 17.6 ml of iodoethane was then added thereto at −10˜0° C. and the mixture was stirred for 2 hours at room temperature. The reaction solution was cooled and, after adding ice, diluted with water and then extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(1:3)]. The fractions containing the desired product were combined and then evaporated to obtain 26.2 g of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:13]([C:4]1[CH:3]=[C:2]([B:26]([OH:27])[OH:25])[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Cc1cc(Br)c2c(c1)C(C)(C)CO2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc(B(O)O)c2c(c1)C(C)(C)CO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
To a mixture of 7-bromo-5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran (9.9 g, 34.96 mmol) in THF (50 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (25.17 mL, 2.5 M, 62.93 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (24.2 mL, 104.87 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 1.0 N HCl (100 mL) was slowly added to the reaction mixture. After 1 hour the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (0 to 20% ethyl acetate in hexane) to give 4.3 g of 5-isobutyl-3,3-dimethyl-2,3-dihydro-benzofuran-7-boronic acid (46%). 1H NMR (300 MHz; CDCL3): 0.90 (d, J=6.6 Hz, 6H), 1.33 (s, 6H), 1.81 (m, 1H), 2.43 (d, J=7.5 Hz, 2H), 4.28 (s, 2H), 5.86 (br s, 2H), 6.98 (d, J=2.1 Hz, 1H), 7.33 (d, J=2.1 Hz, 1H).