Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]2)=[CH:4][C:3]=1[F:13].[BH3-]C#[N:16].[Na+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH2:16])[CH2:9]2)=[CH:4][C:3]=1[F:13]
Reactant: [BH3-]C#N
Reactant: O=C1CCc2cc(F)c(Br)cc2C1
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(F)c(Br)cc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-Bromo-6-fluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamine XVI was prepared from commercial available 7-bromo-6-fluoro-3,4-dihydro-1H-naphthalen-2-one XV. To a stirred solution of XV (0.10 g, 0.41 mmol) in 3 mL of MeOH was added NH4OAc, followed by NaCNBH3 (0.018 g) in one portion at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. Removal of solvent under vacuum gave the crude product, which was partitioned between 2N Na2CO3 and CH2Cl2. The organic layer was separated and dried over MgSO4. The solvent was removed under vacuum and the so-obtained crude product was dissolved in 2 mL of CH2Cl2. To this solution was added TEA (0.12 mL) and (Boc)2O (90 mg, 0.41 mmol). The reaction mixture was stirred at rt overnight. Removal of the solvent under vacuum gave the crude product, which was purified by column to give the pure product XVII (119 mg, 84% over 2 steps). MS: calc'd (MH+) 344, exp (MH+) 344.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[OH:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]1[S:20][N:19]=[C:18]([CH3:21])[N:17]=1)=[O:14].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[N:34]1[C:30]2[N:31]=[CH:32][N:33]=[C:28]([O:11][C@@H:12]([CH2:22][O:23][CH:24]([CH3:26])[CH3:25])[C:13]([NH:15][C:16]3[S:20][N:19]=[C:18]([CH3:21])[N:17]=3)=[O:14])[C:29]=2[CH:36]=[N:35]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1nsc(NC(=O)[C@@H](O)COC(C)C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nsc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (0.82 mL, 0.82 mmol) was added dropwise to a stirred solution of (S)-2-hydroxy-3-isopropoxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)propanamide (Intermediate C9) (200 mg, 0.82 mmol) in anhydrous THF (5 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) in dry THF (1.5 mL) was added dropwise over 1 minute and the reaction heated to 50° C. for 20 hours. The mixture was cooled, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL). The combined aqueous extracts were acidified with 1M citric acid and extracted with EtOAc (2×20 mL), the combined organic extracts were dried (MgSO4) and evaporated. The resulting residue was purified by flash silica chromatography, eluting with an increasing gradient of 60 to 100% EtOAc in isohexane to afford (2S)-2-[1-(2-chlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-N-(3-methyl-1,2,4-thiadiazol-5-yl)-3-propan-2-yloxypropanamide (300 mg, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Nc1cc(Cl)ccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CSc2ccc(Cl)cc2N)cc1
Yield: 87.8 %

Procedure:
Following General Procedure A, the title compound (2.2 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (1.3 g, 8.14 mmol), methyl 4-(bromomethyl)benzoate (1.86 g, 8.14 mmol) and K2CO3 (5.6 g, 40.73 mmol) in DMF (20 ml).
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][N:25]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: COc1ccnc(Cl)n1
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Product: COc1ccnc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methoxypyrimidine. MS (ESI) mass calcd. for C24H24N4O2, 400.48; m/z found, 401.2 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[S:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)[CH2:22][CH2:21]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCc1nc2cccnc2s1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1N1CCN(Cc2nc3cccnc3s2)CC1

Procedure:
The product from Example 38A (200 mg, 1.1 mmol), 1-(2-methoxyphenyl)piperazine (229 mg, 1.2 mmol), and DIEA (380 μL, 2.2 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.74 (m, 4H) 3.02 (m, 4H) 3.78 (s, 3H) 4.04 (s, 2H) 6.91 (m, 3H) 7.56 (dd, J=8.31, 4.75 Hz, 2H) 8.33 (dd, J=8.14, 1.70 Hz, 1H) 8.59 (dd, J=4.75, 1.70 Hz, 1H); (ESI) m/z 341 (M+H)+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][NH:7][CH2:6]1)#[N:2].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C(C(C)=O)C>[C:1]([CH2:3][CH2:4][CH:5]1[O:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)#[N:2]
Reactant: N#CCCC1CNCCO1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCC1CN(Cc2ccccc2)CCO1
Yield: 90.2 %

Procedure:
A mixture of 2-(2-cyanoethyl)morpholine (5.4 g), benzyl chloride (5.4 g), potassium carbonate (5.4 g), potassium iodide (0.5 g), and methyl ethyl ketone (30 ml) is heated under reflux for 1 hour. After cooling, the reaction mixture is filtered and the filtrate is concentrated. The residue is dissolved in diethyl ether, and the solution is extracted with dilute hydrochloric acid. The extracts are basified with dilute aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over sodium sulfate and evaporated to give the title compound (8 g) as an oil.
Reaction SMILES: C([O:8][C:9]1[C:10]2[N:11]([C:15]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[N:26]=3)=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:32]1([NH:31][C:27]2[N:26]=[C:25]([C:15]3[N:11]4[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[C:10]4=[N:17][C:16]=3[C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:30]=[CH:29][N:28]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Fc1ccc(-c2nc3c(OCc4ccccc4)cccn3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1cccn2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nc12
Yield: 61.1 %

Procedure:
To a solution of 4-[8-(benzyloxy)-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl]-N-cyclopentylpyrimidin-2-amine (30 mg, 0.063 mmol) in ethanol (2 mL) was added 10% palladium on carbon (4 mg). The mixture was stirred under 10 psi of hydrogen for 3 hours. Additional 10% palladium on carbon (5 mg) was added and the mixture stirred under 15 psi of hydrogen for 1 hour. The catalyst was removed by filtering the mixture through Celite. The filtrate was concentrated and the residue purified by silica chromatography, eluting with 10% acetone in dichloromethane to yield 15 mg (60%) of 3-[2-(cyclopentylamino)pyrimidin-4-yl]-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-8-ol. 1H NMR (CDCl3): δ 9.10 (m, 1H), 8.13 (d, 1H), 7.64 (dd, 2H), 7.15 (t, 2H), 6.86 (m, 2H), 6.41 (d, 1H), 5.27 (d, 1H), 4.38 (m, 1H), 2.13 (m, 2H), 1.73 (m, 6H); MS m/z 390 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11](O)=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][N:16]1CCOCC1.C(OC(Cl)=O)C(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([C:11]([NH:16][CH3:15])=[O:12])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CNC(=O)C(C)(C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
N-(tert-butoxycarbonyl)-2-methylalanine (2.87 g, 14.13 mmol) was dissolved in THF (20 ml) and cooled to −10° C. (acetone/ice). N-methylmorpholine (2.14 g, 21.2 mmol) was added followed by iso-butylchloroformate (2.12 g, 15.5 mmol, 1.1 equivalents) over a period of 3 minutes. The reaction mixture was allowed to stir for 10 minutes, split in two equal halves (approximately 12 ml each). One sample was treated with methylamine in THF (5 ml of 2.0M solution) and the resulting mixture was evaporated to dryness. The residues were re-dissolved in dichloromethane (30 ml), washed with water, saturated aqueous sodium hydrogen carbonate, water, dried over magnesium sulfate and evaporated to dryness to give N2-(tert-butoxycarbonyl)-N1,2-dimethylalaninamide (0.67 g, 42.6%), which was used without further purification, 1H NMR Spectrum: (DMSO-d6) 1.29 (s, 6H), 1.37 (s, 9H), 2.50 (s, 3H), 6.57 (br s, 1H), 6.93 (br s, 1H)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:16][CH2:15]1)[CH:6]=[C:5]2[S:26][CH2:27][C@H:28]1[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1.[CH:41]1([NH:44][C:45](=[O:63])[C:46]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[C:49]([CH3:61])=[C:48]([F:62])[CH:47]=2)[CH2:43][CH2:42]1>>[Si:19]([O:18][CH2:17][C:14]1([CH2:13][N:7]2[CH:6]=[C:5]([S:26][CH2:27][C@@H:28]3[CH2:33][CH2:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]3)[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:50]4[CH:51]=[C:46]([C:45](=[O:63])[NH:44][CH:41]5[CH2:42][CH2:43]5)[CH:47]=[C:48]([F:62])[C:49]=4[CH3:61])[CH:3]=3)[C:8]2=[O:12])[CH2:15][CH2:16]1)([C:22]([CH3:24])([CH3:23])[CH3:25])([CH3:20])[CH3:21]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CSc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CC3)c(=O)c3ccc(Br)cc23)C1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3(CO[Si](C)(C)C(C)(C)C)CC3)cc(SC[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c2c1
Yield: 102.1 %

Procedure:
tert-Butyl (3S)-3-{[(6-bromo-2-{[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopropyl]methyl}-1-oxo-1,2-dihydroisoquinolin-4-yl)sulfanyl]methyl}piperidine-1-carboxylate (Example 63d, 109 mg) was reacted with N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (45 mg) by the method of Example 58d to afford the subtitle compound (110 mg) as a colourless oil.
Reaction SMILES: OC1C=CC(C(CC2C=NC=CC=2)C[NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=CC=1.C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH2:10])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=S(=O)(NCC(Cc1cccnc1)c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A portion of 53 mg of N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide and 78 mg of triethylamine were dissolved in 8 ml of tetrahydrofuran, followed by addition of 25 mg of ethyl chlorocarbonate dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 10 minutes. The crystalline deposited was filtered, and the filtrate was then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 53 mg of N-[2-(4-ethoxycarbonyloxyphenyl)-3-(3-pyridyl)}propyl]-4-chlorobenzenesulfonamide. The spectrometric data supports the structure of [32] as follows.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:1])=[CH:5][CH:6]=1
Reactant: [Li]c1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Solvent: CCOCC
Product: C=C(c1ccccc1)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 84.6 %

Procedure:
A solution of 4-bromoacetophenone (10.0 g, 50.2 mmol) in 130 mL of dry diethyl ether was added over 1.5 hours to a solution of phenyllithium (30.7 mL of 1.8 M a solution in dibutyl ether, 55.2 mmol) in 70 mL of dry diethyl ether at room temperature under an inert atmosphere. The reaction mixture was stirred while heating to reflux for 3 hours and then was examined by [C-MS which showed complete consumption of starting material. The reaction was quenched with water (500 mL), until gas evolution ceased, and 1 N HCL (31 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was used without any further purification. A solution of the crude (1-(4-bromo-phenyl)-1-phenyl-ethanol) and a catalytic amount of p-toluenesulfonic acid in toluene (100 mL) was heated at 120° C. for 16 h in a flask equipped with a Dean-Stark apparatus. The reaction mixture was examined by LC-MS which showed complete consumption of starting material. Solvent was evaporated under reduced pressure and the crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate (100:0 to 98:2) giving 11 g of the title compound as a colorless oil (Yield: 84%)
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].CO>O1CCCC1>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C@H:53]3[O:57][N:56]4[CH2:58][CH2:59][CH2:60][C@@H:55]4[CH2:54]3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2ccc([C@@H]3C[C@H]4CCCN4O3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 86.9 %

Procedure:
To a solution of 0.886 g of CIS-(+/-)-2-Butyl-6-(hexahydropyrrolo[1,2-b]isoxazol-2-yl)-3-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]methyl]-4(3H)-quinazolinone dissolved in 2.0 ml of tetrahydrofuran is added 10.0 ml of methanol. The reaction mixture is heated at reflux for 18 hours, cooled and concentrated in vacuo to a residue which is purified by chromatography on silica gel using 9:1 chloroform-methanol to give 0.534 g of the desired product as a white foam. FAB mass spec 548 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]1=2.C([Li])CCC.[B:21](OC(C)C)([O:26]C(C)C)[O:22]C(C)C.Cl>C1COCC1>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([B:21]([OH:26])[OH:22])[CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(B(O)O)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.38 g (80.0 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-bromonaphthalene and 50 ml of THF are introduced into a three-necked flask under a stream of nitrogen. 38.4 ml (96.0 mmol) of n-butyllithium (2.5 M in hexane) are added dropwise, at −78° C., and the mixture is stirred for one hour. 27.7 ml (120.0 mmol) of triisopropyl borate are added dropwise at this same temperature and the mixture is stirred for 2 hours. 350 ml of hydrochloric acid (1 N) are added at −50° C. and the mixture is allowed to warm to room temperature. The reaction medium is extracted with dichloromethane and the organic phase is separated out after settling has taken place, dried over magnesium sulphate and evaporated. 18.60 g (100%) of the expected boronic acid are collected in the form of an oil which crystallizes slowly. Melting point 190–192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][CH2:27][C:28]#[N:29]>>[C:26]([CH2:27][CH2:28][NH:29][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=2)[CH:5]=1)#[N:25]
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: N#CCCN
Product: COc1ccc(C(=O)NCCC#N)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 3-aminopropionitrile in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]=1[C:14]([O:16]CC)=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]=1[C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:2]
Reactant: CCOC(=O)c1c(OCC)ncc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ncc2ccccc2c1C(=O)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
The title compound of Step B (492 mg, 2 mmol) dissolved in MeOH (15 mL) was added NaOH(aq) 2M (2.5 mL). The reaction mixture was stirred at 60° C. for 16 h and then NaOH(aq) 4M (2 mL) was added and the mixture was stirred at 70° C. for 4 h. MeOH was evaporated and the aqueous phase was cooled to 0° C. and acidified with the addition of HCl(aq) 6N. The solid was filtered, washed with cold water and dried to afford the title compound (285 mg, 65%). MS (ESI) mass calcd. for C12H11NO3, 217.1. m/z found 218.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.15 (s, 1H), 8.13-8.06 (m, 1H), 7.82-7.70 (m, 2H), 7.54-7.47 (m, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.35 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:7]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1nc(Cl)nc(Nc2ccc(O)cc2)n1
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 2,4-dichloro-6-methoxy-1,3,5-triazine (9.00 g, 50.0 mmol) in 100 mL of acetone was cooled to 0° C. and, under stirring, solid 4-amino phenol (5.46 g, 50.0 mmol) was added in small portion, over ca 2 min. The white suspension was then let to warm to room temperature and stirred for further 1 h, while being neutralized with a 2 M aqueous solution of Na2CO3 during the reaction. The mixture was then poured into 500 mL of ice/water and the resulting white precipitate was filtered and dried, to give 9.6 g (38.0 mmol, yield 76%) of 4-[(4-chloro-6-methoxy-1,3,5-triazin-2-yl)amino]phenol that can be used without further purifications. An analytical sample can be obtained by flash chromatography (CC, SiO2, petroleum ether/Et2O 1:1, Rf=: 0.14). The NMR analysis (DMSO d6) reveals the presence, in solution, of 2 rotational isomers (molar ratio 7:3). M.p was 172° C. IR ν(NH) 3476 cm−1. ν(OH) 3269 cm−1. Major isomer: 1H NMR (DMSO d6) δ=3.94 (s, 3H, OCH3); 6.79 (d, J=8.8 Hz, 2H, CH Ar), 7.48 (d, J=8.8 Hz, 2H, CH Ar), 9.40 (s, 1H, OH), 10.46 (s, 1H, NH). 13C NMR (DMSO d6) δ 55.52 (1C, OCH3); 115.46 (2C, CH Ar), 123.91 (2C, CH Ar), 129.49 (1C, C Ar), 154.44 (1C, C Ar), 164.81 (1C, C Ar), 169.57 (1C, C Ar), 171.23 (1C, C Ar). Minor isomer: 1H NMR (DMSO d6) δ 3.96 (s, 3H, OCH3); 6.79 (d, J=8.9 Hz, 2H, CH Ar), 7.39 (d, J=8.9 Hz, 2H, CH Ar), 9.42 (bs, 1H, OH), 10.10.32 (s, 1H, NH). 13C NMR (DMSO d6) δ=55.10 (1C, OCH3); 115.46 (2C, CH Ar), 123.03 (2C, CH Ar), 129.26 (1C, C Ar), 154.76 (1C, C Ar), 165.20 (1C, C Ar), 170.48 (1C, C Ar), 170.64 (1C, C Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][CH2:18][C:19]([OH:21])=O)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:23]([OH:25])[CH3:24]>[Zn]>[C:23]([N:8]1[C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:19](=[O:21])[CH2:18][CH2:17][CH:6]([C:5]=23)[CH:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)CCc1c(-c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: CCO
Agent: Cl
Agent: [Zn]
Product: CC(=O)N1c2cc(Cl)cc3c2C(CCC3=O)C1c1ccccc1
Yield: 20 %

Procedure:
6-chloro-2-phenylindole-3-propionic acid (19.5 g) synthesized as in Example 1, step 1 was suspended in ethanol (200 ml), and to the suspension were added zinc powder (42.5 g), then conc. hydrochloric acid (50 ml). The mixture was heated to reflux for 3 hours. In the meantime, two portions (50 ml and 20 ml) of conc. hydrochloric acid were further added 1 hour and 2 hours later respectively. After allowing the mixture to cool, the zinc was filtered off and the filtrate was diluted with water, adjusted to about pH 4 with potassium carbonate and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9:1) to yield 4.2 g (20%) of the titled compound as a pale yellow syrup.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[Li+].[OH-]>C1COCC1.O>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(CN)cc([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl 3-aminomethyl-5-nitrobenzoate (5890 mg, 28 mmol) in THF (100 mL) was added a solution of LiOH (2350 mg, 56 mmol) in water (100 mL) and the mixture was stirred at r.t. for 2.5 hours. THF was evaporated and the aqueous solution was washed with Et2O (100 mL). The solution was neutralized with concentrated HCl (6 mL) and evaporated in vacuo. To a solution of evaporated residue in water (150 mL) and concentrated HCl (3 mL) was added 1N LiOH (50 mL). Brown fine needles were precipitated out and collected on a glass filter (5300 mg, 96%): 1H NMR (300 MHz, D2O) δ 8.645 (s, 1H), 8.412 (s, 1H), 8.232 (s, 1H), 4.332 (s, 2H).