Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[CH3:9])=[CH:13][CH:12]=1
Reactant: Cc1cc(N)cnc1Cl
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: Cc1cc(N)cnc1-c1ccc(Cl)cc1
Yield: 57.2 %

Procedure:
To a solution of 6-chloro-5-methylpyridin-3-amine (3 g, 20 mmol) in 1,2-dimethoxyethane (30 mL) was added PdCl2(dppf) (770 mg, 1.16 mmol), 4-chlorophenylboronic acid (4.94 g, 31.6 mmol), and K3PO4 (8.93 g, 42.1 mmol). The reaction mixture was purged with nitrogen and heated to reflux. Water (20 mL) was added and the reaction mixture was stirred at reflux for 48 h. The reaction mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers were concentrated under reduced pressure. Purification by silica gel chromatography provided 6-(4-chlorophenyl)-5-methylpyridin-3-amine (2.5 g) as a yellow solid. 1HNMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.30-7.36 (m, 4H), 6.83 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[C:23]([OH:24])=[CH:22][C:20]([NH2:21])=[C:19]([F:25])[CH:18]=1.ClC1C(O)=CC(N)=C(F)C=1>CC(O)CCC>[Br:16][C:17]1[C:23]([OH:24])=[CH:22][C:20]([NH:21][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:19]([F:25])[CH:18]=1
Reactant: Nc1cc(O)c(Br)cc1F
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: Nc1cc(O)c(Cl)cc1F
Solvent: CCCC(C)O
Product: COc1cc2nccc(Nc3cc(O)c(Br)cc3F)c2cc1OC
Yield: 63.6 %

Procedure:
A suspension of 4-chloro-6,7-dimethoxyquinoline (200 mg, 0.9 mmol), (prepared as described for the starting material in Example 2), and 4-bromo-2-fluoro-5-hydroxyaniline (206 mg, 1 mmol), as described in EP 61741 A2), in 2-pentanol (8 ml) was heated at reflux for 4 hours. The precipitate was collected by filtration, washed with isopropanol, followed by ether, and dried under vacuum to give 4-(4-bromo-2-fluoro-5-hydroxyanilino)-6,7-dimethoxyquinoline (225 mg, 58%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[C:18](OCC)(=[O:22])[C:19]([CH3:21])=O>>[CH3:21][C:19]1[C:18](=[O:22])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:17])[CH3:1])=[CH:8][CH:7]=2)[C:10]2[C:11]([N:16]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CCOC(=O)C(C)=O
Reactant: CN(C)c1ccc(Nc2ccccc2N)cc1
Product: Cc1nc2ccccc2n(-c2ccc(N(C)C)cc2)c1=O

Procedure:
Preparation as in Example 1 but using N-(4-dimethylaminophenyl)benzene-1,2-diamine and ethyl pyruvate gave the title compound mp 230°-231° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[C:18]([Br:19])=[C:17]([N+:20]([O-:22])=[O:21])[C:12]2[O:13][CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[C:23](Cl)=[O:24]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]([C:10]2[C:11]3[O:16][CH2:15][CH2:14][O:13][C:12]=3[C:17]([N+:20]([O-:22])=[O:21])=[C:18]([Br:19])[C:9]=2[Br:8])=[O:24])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1c(Br)c(Br)c([N+](=O)[O-])c2c1OCCO2
Product: CN1CCN(C(=O)c2c(Br)c(Br)c([N+](=O)[O-])c3c2OCCO3)CC1
Temperature: 10 °C
Yield: 69.5 %

Procedure:
400 ml of methylethylcetone and 11 g of methylpiperazine were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was cooled to 10° C. and then 41 g of 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carbonyl chloride were added in portions with the temperature being maintained below 20° C. After agitation of the mixture, the crystals were dried off, washed with methylethylcetone and dried and then dissolved in water and reprecipitated by addition of 50 ml of 20% ammonia. The crystals were dried off, washed with water and dried. 33 g of 5-[(4-methyl-1-piperazinyl)-carbonyl]-6,7-dibromo-8-nitro-1,4-benzodioxane were obtained (M.P.: 164° C.; yield: 69.6%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:36][O:37][CH3:38])[CH:32]=2)[CH:27]1[C:39](O)=[O:40])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:44]=[C:45]([NH2:54])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:53])([CH3:52])[CH2:49][CH2:48]2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:42][C:43]1[CH:44]=[C:45]([NH:54][C:39]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([CH2:36][O:37][CH3:38])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:40])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:52])([CH3:53])[CH2:49][CH2:48]2
Reactant: CC1(C)CCc2cc(N)cc(F)c21
Reactant: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
T3P (8.24 mL, 14.00 mmol) was added to a mixture of 2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.5 g, 4.67 mmol), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.837 g, 4.67 mmol), DIEA (4.08 mL, 23.34 mmol), DMAP (0.570 g, 4.67 mmol) and ethyl acetate (5 mL) at 60° C., and the mixture was stirred at 60° C. for 2 days. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 32→40% ethyl acetate/hexane) to give tert-butyl 1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2 (1H)-carboxylate (1.600 g, 3.32 mmol, 71.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[CH:4]2[O:14][CH:3]12.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]([CH:4]3[C:5]4[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=4)[O:11][C:2]([CH3:15])([CH3:1])[CH:3]3[OH:14])[CH:26]=[CH:25][N:24]=2)=[CH:21][CH:22]=1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: Clc1ccc(-c2ncc[nH]2)cc1
Product: CC1(C)Oc2ccc(C#N)cc2C(n2ccnc2-c2ccc(Cl)cc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and 2-(4-chloro-phenyl)-1H-imidazole as starting materials, the title compounds were prepared as white solids.
Reaction SMILES: C1C2C(OC(=O)[N:16]([CH3:27])[C@@H:17]([C@@H:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:21])[CH2:18][OH:19])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1.[Cl:35][C:36]1[N:41]=C(Cl)[CH:39]=[CH:38][N:37]=1.CCN(C(C)C)C(C)C>O.CCOC(C)=O.CCCCCCC.C(#N)C>[C:23]([O:22][C@@H:20]([CH3:21])[C@H:17]([NH:16][C:27]1[CH:39]=[CH:38][N:37]=[C:36]([Cl:35])[N:41]=1)[CH2:18][OH:19])([CH3:24])([CH3:25])[CH3:26]
Reactant: Clc1ccnc(Cl)n1
Reactant: C[C@H](OC(C)(C)C)[C@@H](CO)N(C)C(=O)OC1c2ccccc2-c2ccccc21
Solvent: O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: C[C@H](OC(C)(C)C)[C@@H](CO)Nc1ccnc(Cl)n1
Yield: 53.5 %

Procedure:
To a round bottom flask with stir bar was added (9H-fluoren-9-yl)methyl((2R,3S)-3-(tert-butoxy)-1-hydroxybutan-2-yl)carbamate (4.7 g, 12.3 mmol) and acetonitrile (100 mL) followed by the addition of piperidine (1.8 mL, 18.4 mmol). The flask was capped and stirred for 18 hr at room temperature. The volatiles were then removed. A white solid develops which contains the amino alcohol product and the fmoc deprotection by products. Solids were redissolved in acetonitrile (50 ml)(some of the fmoc polymer is insoluble) and 2,4-dichloropyrimidine (5.48 g, 36.8 mmol) and DIEA (2.141 mL, 12.26 mmol) were added. Resulting reaction mixture allowed to stir 18 hr at room temperature. The volatiles were again removed. Reaction mixture was diluted with water and extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (EtOAc/Heptane 0 to 100%) provided (2R,3S)-3-(tert-butoxy)-2-((2-chloropyrimidin-4-yl)amino)butan-1-ol (1.80 g, 6.58 mmol, 54% yield) as a colorless oil which crystallizes upon standing. LCMS m/z 274.1 (M+H)+, Rt 0.56 min.
Reaction SMILES: COCCOC.[CH3:7][O:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24]([O:31][C:32]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[CH:48][C:33]=1[C:34]([NH:36][C:37]1[CH:46]=[C:45](Br)[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>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.C(OCC)(=O)C.O>[CH2:24]([O:31][C:32]1[CH:51]=[CH:50][C:49]([CH:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[CH:48][C:33]=1[C:34]([NH:36][C:37]1[CH:46]=[C:45]([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH3:7])[CH:14]=2)[CH:44]=[CH:43][C:38]=1[C:39]([O:41][CH3:42])=[O:40])=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Reactant: COc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cccc(OC)c2)cc1NC(=O)c1cc(C2CCN(C)CC2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Ethylene glycol dimethyl ether (0.90 mL), water (0.27 mL), 3-methoxyphenylboronic acid (0.030 g), sodium carbonate (0.044 g), and bis(triphenylphosphine)palladium(II) dichloride (2.3 mg) were added to methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-bromobenzoate (0.090 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-92% chloroform/methanol] to obtain 0.093 g of methyl 2-(2-(benzyloxy)-5-(1-methylpiperidin-4-yl)benzamido)-4-(3-methoxyphenyl)benzoate as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][N:10](CC2C=CC=CC=2)[CH2:9]1>CO.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]2=[O:30])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(Cc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCNC3)c(F)c2)C(=O)O1
Reaction time: 18 h

Procedure:
A mixture of (5S)-N-[[3-[3-fluoro-4-[1-(phenylmethyl)-3-pyrrolidinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, 1.09 g) and 20% palladium hydroxide on carbon (545 mg) in methanol (30 mL) is shaken on the Parr apparatus under a hydrogen atmosphere at 40 psi for 1.5 hours and at 10 psi for 18 hours. The catalyst is then removed by filtration through Celite, and the filtrate is concentrated under reduced pressure to give the title compound, NMR (CDCl3, 400 MHz) 7.39, 7.24, 7.11, 6.35, 4.78, 4.04, 3.77, 3.67, 3.44, 3.37, 3.18, 3.11, 2.88, 2.21 2.02, 1.86 δ.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14](=[O:27])[NH:15][C:16]1[C:25]2[CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.O>C(Cl)Cl>[CH2:6]([O:13][C:14](=[O:27])[NH:15][C:16]1[C:25]2[CH2:24][CH:23]([NH:26][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][CH2:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
Methanesulfonyl chloride (176 mg, 1.54 mmol) was added dropwise to a solution of the product from Example 20C (381 mg, 1.29 mmol) and diisopropylethylamine (332 mg, 2.57 mmol) in 15 mL CH2Cl2 at ambient temperature. The mixture was stirred 30 minutes, diluted with methylene chloride and poured into water. The separated organic phase was washed with 1N aq HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. Flash chromatography (4% CH3OH/CH2Cl2) yielded 281 mg (58%) of the title compound as a white amorphous solid. 1H NMR (DMSO-d6) δ 8.92 (s, 1H), 7.45-7.30 (m, 5H), 7.22 (d, J=7.1 Hz, 1H), 7.15 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.93 (m, 1H), 5.13 (s, 2H), 3.51 (m, 1H), 3.02 (m, 1H), 2.96 (s, 3H), 2.85 (m, 2H), 2.50 (m, 1H+DMSO), 2.01 (m, 1H), 1.61 (m, 1H); MS (ESI+) m/z 375 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:31][CH:32]([F:34])[F:33])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[F:34][CH:32]([F:33])[O:31][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:35])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-pyrazol-1-ylbenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.19 g) in tetrahydrofuran (5.0 mL) was treated with 1.0 M aqueous lithium hydroxide solution (0.78 mL), and the resulting solution was stirred at room temperature for 1 hour. The tetrahydrofuran was removed under reduced pressure and the residue acidified by the addition of 0.1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound (0.18 g).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([CH3:13])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>C1(C)C=CC=CC=1>[CH3:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:27]([CH2:28][CH:29]([OH:31])[CH3:30])[C:5]=32)=[CH:10][CH:9]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C2
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(c1)-c1c(ccn1CC(C)O)C2
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A solution of 1.88 g of (RS)-2-(2-oxoethyl)-6-methyl-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 7:3). 0.99 g (44%) of (RS)-1-(7-methyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([C:13]([CH2:31][CH3:32])([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:18]([CH3:30])[CH:17]=3)[CH2:14][CH3:15])=[CH:10][C:9]=2[CH:33]=1)=[O:4].[OH-].[Na+]>CO.C1COCC1>[CH2:14]([C:13]([C:11]1[O:12][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:33][C:9]=2[CH:10]=1)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]([OH:29])[C:25]([CH3:27])([CH3:28])[CH3:26])=[C:18]([CH3:30])[CH:17]=1)[CH2:31][CH3:32])[CH3:15]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)OC)ccc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)O)ccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A solution of 2-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-benzofuran-5-carboxylic acid methyl ester (555 mg, 1.226 mmol) in methanol (3.0 mL) and THF (3.0 mL) and is treated with NaOH (2.0 M, 6.0 mL). The resulting mixture is stirred at RT for 18 h. The mixture is concentrated and neutralized with HCl (1 N) till pH˜2, and extracted with EtOAc (3×10 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (530 mg, 99%).
Reaction SMILES: [N:1]([CH:4]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH:21]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=1)=[C:2]=[O:3].[NH3:33]>C(Cl)Cl>[NH2:33][C:2]([NH:1][CH:4]([O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([CH3:26])[CH:21]1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:5]1[CH:6]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1)=[O:3]
Reactant: CC1CCCC(OC(N=C=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: N
Solvent: ClCCl
Product: CC1CCCC(OC(NC(N)=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 56 mg (0.12 mmole) of α-isocyanato-3-(SR)-(3,5-Bis(trifluoromethyl)-benzyloxy)-2-(SR)-phenyl-1-(SR)-methylcyclohexane in 1 mL of methylene chloride was treated with 3 mL of ammonia-saturated methylene chloride at room temperature. After 1 hr, the solution was concentrated in vacuo and the residue purified by flash chromatography on 16 g of silica eluting with 400 mL of 100:2 methylene chloride: methanol to provide 54 mg (93%) of a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[C:10](OC(=O)C)=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-:27].[K+].[K+]>CO>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:27])=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cccc(C=C(OC(C)=O)C(=O)NC2CCC(C)(C)CC2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C=CC(=O)NC2CCC(C)(C)CC2)ccc1O
Yield: 93 %

Procedure:
Using 8.99 g of N-(4,4-dimethylcyclohexyl)-acetoxy-3-methoxycinnamamide (Example 63), 100 ml of methanol, and 10 g of potassium carbonate, a reaction similar to that conducted in Example 54 was carried out. As a result, 7.34 g of N-(4,4-dimethylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[C:24](/[CH2:27][CH2:28]O)\[CH2:25][OH:26])/[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([F:23])[CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[F:23][C:18]1[CH:17]=[C:16](/[C:15](=[C:24]2/[CH2:25][O:26][CH2:28][CH2:27]/2)/[C:12]2[CH:13]=[CH:14][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:10][CH:11]=2)[CH:21]=[CH:20][C:19]=1[CH3:22]
Reactant: Cc1ccc(/C(=C(/CO)CCO)c2ccc(S(=O)(=O)NC(C)(C)C)cc2)cc1F
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(/C(=C2\CCOC2)c2ccc(S(N)(=O)=O)cc2)cc1F
Yield: 77 %

Procedure:
A solution of 6.3 g of (E) -2-[1-(4-t-butylaminosulfonylphenyl)-1-(3-fluoro-4-methylphenyl)methylidene]butane-1,4-diol prepared in Example 138 in 75 ml of trifluoroacetic acid is heated for 10 hours under reflux. The solvent is concentrated under vacuum and the residue is taken up in a dilute solution of sodium hydroxide, washed with dichloromethane and then acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phases are combined and dried over magnesium sulfate and then evaporated under vacuum. The residue is crystallized in tert-butyl methyl ether to give 4 g of (E)-4-[(3-fluoro-4-methylphenyl)-(tetrahydro-furan-3-ylidene)methyl]benzenesulfonamide in the form of crystals melting at 174°-176° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[CH3:23][C:24]([OH:41])([CH3:40])[CH2:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+].C(=O)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.CCO>[C:18]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][C:24]([OH:41])([CH3:40])[CH3:23])[CH:30]=3)=[CH:13][CH:12]=2)[C@H:7]([NH:6][C:5](=[O:22])[O:4][CH:2]([CH3:3])[CH3:1])[CH2:8][C@@H:9]1[CH3:21])(=[O:20])[CH3:19]
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: C1COCCO1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3cnn(CC(C)(C)O)c3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 32 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Example 4) (0.185 g, 0.500 mmol), 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-2-propanol (for a preparation see Intermediate 119) (160 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80° C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave an oil which was dissolved in 1,4-dioxane, freezed using an acetone bath cooled with solid CO2 and left on a freeze drier for 16 h to give 1-methylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (73.4 mg, 0.171 mmol, 32%) as a white solid. LCMS (method A): Retention time 0.81 min, [M+H]+=429.10