Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:11][N:10]=2)=[CH:5][CH:4]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:14][C:13]1[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:10][O:11][C:12]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(-c2ccc(OC)cc2)c1CBr

Procedure:
Ethyl 3-(4-methoxyphenyl)-4-methylisoxazole-5-carboxylate (12.4 g, 47.5 mmol), NBS (10.1 g, 57.0 mmol), and benzoyl peroxide (1.15 g, 4.75 mmol) were added to 250 mL of carbon tetrachloride and the mixture was refluxed for 16 h. The reaction mixture was filtered and the filtrate was removed in vacuo to give a brown solid, which was used in the next reaction without purification. MS: (+) m/z 340.35, 342.33 (M+1, 79Br/81Br).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:13][C:9]2([CH2:12][CH2:11][CH2:10]2)[O:8][N:7]=1)=[O:5])[CH3:2].CSC.B>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][C:9]2([CH2:10][CH2:11][CH2:12]2)[O:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NOC2(CCC2)C1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCOC(=O)C1CC2(CCC2)ON1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a solution of crude 5-oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester (7.5 g, <40.9 mmol) in tetrahydrofuran (270 mL) at 0° C. was slowly added a solution of borane-dimethyl sulfide complex (10 M in THF, 16.4 mL, 164 mmol). The reaction was allowed to warm to room temperature overnight then recooled to 0° C., and quenched by the careful addition of water. The mixture was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to yield a large amount of white solids. These solids were thoroughly triturated three times with dichloromethane (150 mL). The combined dichloromethane washings were concentrated and the resulting oil was purified by flash chromatography to yield 5-oxa-6-aza-spiro[3.4]octane-7-carboxylic acid ethyl ester (1.08 g, 29% over 2 steps). 1H-NMR: 400 MHz, (CDCl3) δ: 8.01-7.95 (br, 1H), 4.39-4.28 (m, 2H), 4.18-4.10 (m, 1H), 2.80-2.75 (m, 1H), 2.62-2.49 (m, 2H), 2.37-2.29 (m, 1H), 2.25-2.17 (m, 1H), 2.13-1.95 (m, 1H), 1.88-1.79 (m, 1H), 1.68-1.56 (m, 1H), 1.34 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:15])=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1nccc2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 61.9 %

Procedure:
7-Bromo-2H-isoquinolin-1-one (3.0 g, 13.4 mmol), phosphorus oxychloride (8.22 g, 53.6 mmol), and chloroform (25 mL) combined in a sealed tube and heated with stirring at 100° C. for 4 hours. Cooled to ˜60° C., poured into ice water (100 mL), neutralized carefully with saturated aqueous sodium hydrogencarbonate, extracted into methylene chloride and dried over magnesium sulfate. Flash column chromatography on silica gel gave the product as a pale cream solid (2.01 g, 8.3 mmol). 1H NMR (CDCl3) δ 8.51 (d, 1H), 8.30 (d, 1H), 7.82 (dd, 1H), 7.72 (d, 1H), 7.57 (dd, 1H). ESI MS (M+1)+: 242, 244, 246 (Br, Cl).
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:21][CH2:22][CH2:23][NH2:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[CH2:14]([O:21][CH2:22][CH2:23][NH:24][C:3](=[O:4])[C:2]([Br:1])([CH3:7])[CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCOCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)NCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-bromo-2-methylpropionylbromid (76 g), K2CO3 (55 g) and dichloromethane (700 ml) was added a solution of 2-benzyloxyethylamine (50 g) in dichloromethane (500 ml) at -10° C. After stirring at room temperature for 1.5 h the mixture was washed with water (500 ml) and dried (MgSO4). Evaporation of the solvents in vacuo afforded N-(2-benzyloxyethyl)-2-bromo-2-methylpropionamide as an oil: 104 g
Reaction SMILES: C([O:8][N:9]([C:16](=[O:56])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([O:48]CC1C=CC=CC=1)[C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([O:39]CC1C=CC=CC=1)[C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:57]>CO.[Pd]>[ClH:57].[OH:8][N:9]([C:16](=[O:56])[CH2:17][CH2:18][CH2:19][CH2:20][N:21]([OH:48])[C:22](=[O:47])[CH2:23][CH2:24][CH2:25][CH2:26][N:27]([OH:39])[C:28](=[O:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CCCCCCCCCC(=O)N(CCCCC(=O)N(CCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCCCCCCCC(=O)N(O)CCCCC(=O)N(O)CCCCC(=O)N(O)CCCCCN

Procedure:
Compound (10) (1.13 g, 1.47 mmol) was hydrogenated in CH3OH (150 mL) and 0.1N HCl (16.2 mL, 1.62 mmol) with 10% Pd-C (0.6 g) by the procedure used for [A]. Purification by Sephadex LH-20 column chromatography with 20% EtOH/toluene as the eluant produced 0.508 g (64%) of [A] as a colorless solid: NMR (CD3OD) δ 0.90 (t, 3H, J=6), 1.17-1.87 (m, 28H), 2.33-2.63 (m, 6H), 2.92 (t, 2H, J=6), 3.60 (t, 6H, J=6). Anal. (C25H51ClN4O6) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13]CC)=[O:12].O[Li].O.Cl>C1COCC1.CO.O.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cl
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 82 %

Procedure:
Ethyl 3-chloro-1H-indole-2-carboxylate (19.28 mmol, 1.0 equiv.) was dissolved in THF-MeOH—H2O (2:1:1; 85 ml); LiOH.H2O (57.84 mmol, 3.0 equiv.) was added at 0° C. and the mixture was stirred for 12 h at 25° C. The solvent was reduced under reduced pressure, and the residue was taken up in water (50 ml), adjusted to pH 3 with 1 M HCl and extracted with ethyl acetate (2×100 ml). The combined organic phases were dried over Na2SO4 and concentrated under reduced pressure, and then the product was crystallized with hexane. Yield: 82%
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:34]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36][CH2:35]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:34]4[CH2:40][CH2:39][C:38](=[O:41])[NH:37][CH2:36][CH2:35]4)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1CCNCCN1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-[1,4]diazepan-5-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and [1,4]diazepan-5-one following General Procedure B.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:23]=1[NH2:24]>>[CH3:20][O:21][C:22]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:23]=1[NH:24][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)n1
Reactant: COc1ccc(C)cc1N
Product: COc1ccc(C)cc1Nc1cc(-c2ccccn2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture 4-chloro-2,6-di(2-pyridinyl)pyrimidine (25 mg, 0.093 mmol) and 2-methoxy-5-methylaniline (19 mg, 0.140 mmol) similar to Example 111 and isolated as a yellow solid (12 mg, 35%). 1H NMR (CDCl3): 8.89–8.87 (m, 1H), 8.69–8.64 (m, 3H), 7.92–7.84 (m, 3H), 7.89 (s, 1H), 7.55 (s, 1H), 7.44–7.36 (m, 2H), 6.92 (dd, J=1.8, 8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 3.86 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1B(O)O.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[N:21][C:22]=2[NH2:24])[N:17]([CH:25]([CH3:27])[CH3:26])[N:16]=1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: COc1cc(F)c(B(O)O)cc1F
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1cc(F)c(-c2nn(C(C)C)c3ncnc(N)c23)cc1F
Temperature: 80 °C
Yield: 87 %

Procedure:
A solution of 2,5-difluoro-4-methoxyphenylboronic acid (84 mg, 0.45 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (54 mg, 0.18 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by silica gel column chromatography [MeOH—CH2Cl2, 2:98] to yield BA63 (50 mg, 17% yield). ESI-MS (M+H)+ m/z calcd 320.1, found 320.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:26]#[N:27])[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:29].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[NH4+].[Cl-]>CC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]4)=[CH:15][CH:16]=3)[N:11]=[C:10]([C:26]([NH2:27])=[O:29])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1cc(-c2ccc(F)cc2)c2ccc(Cn3cc(C=O)cn3)cc2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile (3-8), 51 mg, 0.143 mmol, 1.0 equiv.) was dissolved in acetone (1.0 mL)/water (0.5 mL) and sodium percarbonate (225.0 mg, 0.716 mmol, 5.0 equiv) was added. The resulting mixture was stirred at 50° C. for two hours. The mixture was cooled and poured over aqueous NH4Cl (saturate, 1.0 mL), extracted with Ethyl Acetate (3×5.0 mL), dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 4-(4-Fluorophenyl)-7-[(4-formyl-1H-pyrazol-1-yl)methyl]quinoline-2-carbonitrile (3-9, 40.0 mg, 74.7%) as a colorless solid. 1H NMR (400 MHz, CDCl3): δ 9.879 (s, 1H); 8.262 (s, 1H); 8.056 (br s, 2H); 8.021 (br s, 2H); 7.972 (d, J=8.80 Hz, 1H); 7.462-7.512 (m, 3H); 7.216-7.259 (m, 2H); 5.705 (br s, 1H); 5.589 (s, 2H). LRMS m/z (M+H)+ 375.1 found, 375.1 required.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([NH:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[NH2:31])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Cl:33][CH2:34][C:35](=N)OCC.C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([O:8][CH2:9][C@H:10]([N:20]1[C:21]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[CH:23][C:22]=2[N:31]=[C:35]1[CH2:34][Cl:33])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](COCc1ccccc1)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 70 °C
Yield: 85.4 %

Procedure:
N4-[(1S)-2-(Benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]quinoline-3,4-diamine (1.66 g, 3.80 mmol) was dissolved in 40 mL of anhydrous 1,2-dichloroethane and the solution was stirred under N2. Ethyl 2-chloroethanimidoate hydrochloride (1.80 g, 11.4 mmol) was then added and the reaction mixture was heated to 70° C. After stirring overnight, the reaction mixture was cooled and treated with 20 mL of saturated NaHCO3 solution. The layers were separated and the organic portion was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20-50% ethyl acetate/hexanes) gave 1.61 g of 1-[(1S)-2-(benzyloxy)-1-({[tert-butyl(dimethyl)silyl]oxy}methyl)ethyl]-2-(chloromethyl)-1H-imidazo[4,5-c]quinoline as a golden syrup.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]([Cl:26])([Cl:25])[C:11]([NH:13][C:14](=[O:24])[NH:15][C:16]1[S:17][CH:18]=[CH:19][C:20]=1[C:21]([NH2:23])=[O:22])=[O:12].C(OCC)C>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:18]1[S:17][C:16]([NH:15][C:14]([NH:13][C:11](=[O:12])[C:10]([Cl:9])([Cl:25])[Cl:26])=[O:24])=[C:20]([C:21]([NH2:23])=[O:22])[CH:19]=1
Reactant: NC(=O)c1ccsc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: NC(=O)c1cc(Br)sc1NC(=O)NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
N-Bromosuccinimide (1.56 g, 8.8 mmol) was added to a solution of 2-[3-(2,2,2-trichloro-ethanoyl)-ureido]-thiophene-3-carboxylic acid amide (2.9 g, 8.8 mmol) in acetic acid (30 mL) and chloroform (10 mL) at room temperature. The resulting solution was stirred under nitrogen with an aliquot was taken for LC-MS every 10 min. After 30 min., the LC-MS showed no remaining starting material. Diethyl ether (80 mL) was added to the solution and the resulting precipitate was filtered and dried under vacuum to give the above titled compound as a light brown solid (3.5 g, 8.55 mmol, 97% yield).
Reaction SMILES: [OH-].[Na+].C([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17](O)[CH:16]([C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)C1C=CC=CC=1>CO>[OH:10][C:11]1[CH:12]=[C:13]2[C:18]([CH:17]=[C:16]([C:22]([OH:24])=[O:23])[CH2:15][CH2:14]2)=[CH:19][CH:20]=1
Reactant: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1=Cc2ccc(O)cc2CC1
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
An aqueous solution (10 ml) of sodium hydroxide (3 g) is added to a solution of methyl ester of 6-benzyloxy-1-hydroxy-1,2,3,4-tetrahydro-2-naphthoic acid (1 g) dissolved in methanol (80 ml) and the mixture is left standing. After 30 minutes, the mixture is concentrated under reduced pressure. Water (50 ml) is added to the mixture, and then precipitating crystals are collected by filtration. The crystals are washed with water and acetone. The crystals (0.9 g) is added to a mixture of methanol (75 ml), water (25 ml) and 10% palladium carbon (50% water-content) (1 g). The mixture is catalytically hydrogenated at room temperature under atomospheric pressure of hydrogen gas. After hydrogen absorption has ceased, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure. To the residue are added dioxane (30 ml), concentrated hydrochloric acid (2 ml) and water (10 ml), and the mixture is left standing at room temperature for one hour. The resultant is concentrated under reduced pressure. The precipitating crystals are treated with water (10 ml) and collected by filtration to give 7-hydroxy-1,2-dihydro-3-naphthoic acid (0.4 g) as colorless prisms, m.p. 195°-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C.ClCCl>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:24][CH:21]2[CH2:20][CH2:19][N:18]([CH:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH2:23][CH2:22]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCN(C2CCOCC2)CC1
Yield: 97.6 %

Procedure:
To a mixture of 4-bromo-2-fluoro-1-nitrobenzene (1.05 g, 0.0048 mol) and 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine (0.883 g, 0.0048 mol) D9 in dimethylformamide (10 mL) was added diisopropylethylamine (1.175 mL, 0.0068 mol). The resulting mixture was sealed in a 20 mL Biotage Process Vial and irradiated at 200° C. for 1 min in the Smith Synthesizer. After irradiation, dichloromethane (15 mL) was added to the reaction solution. The resulted solution was washed with H2O (2×10 mL). The combined aqueous layers were extracted with dichloromethane (2×10 mL). The organic layers were combined, dried with Na2SO4, and concentrated in vacuo to yield the title compound (1.8 g) which was used in next step directly without purification. MS (ESI): 384 [M+]; 1H NMR (400 MHz, CDCl3): δ 1.68 (6H, m), 2.09 (2H, d), 2.49 (3H, m), 2.89 (2H, d), 3.39 (2H, t), 3.51 (1H, m), 4.04 (2H, dd), 6.72 (1H, dd), 7.01 (1H, d), 8.03 (1H, d), 8.14 (1H, d).
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][CH2:5][NH:6][C:7](=[O:38])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.Br[C:41]1[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[C:43]([F:51])[CH:42]=1>>[F:20][C:18]([F:19])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:39])=[O:38])=[CH:13][CH:12]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:50])[F:48])=[C:43]([F:51])[CH:42]=2)=[CH:25][CH:24]=1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)c(F)c3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 359 starting from 3-(4-{5,5,5-trifluoro-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-pentyl}-benzoylamino)-propionic acid methyl ester and 4-bromo-2-fluoro-1-trifluoromethyl-benzene. MS: 570.2 [M−H]−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[C:16]([C:18]1[C@@H:23]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[N:22]2[N:32]=[C:33]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:34]=[C:21]2[N:20]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:54])[F:53])[CH:47]=2)[C:19]=1[CH3:56])#[N:17]>CN(C=O)C>[CH2:38]([O:37][C:36]([N:35]([C:33]1[N:34]=[C:21]2[N:20]([C:46]3[CH:51]=[CH:50][CH:49]=[C:48]([C:52]([F:55])([F:53])[F:54])[CH:47]=3)[C:19]([CH3:56])=[C:18]([C:16]#[N:17])[C@@H:23]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=3)[N:22]2[N:32]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (8.0 mg, 58 μmol, 1.6 eq.) and tert-butyl bromoacetate (11.2 mg, 58 μmol, 1.6 eq.) were added to a solution of benzyl {(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (20 mg, 36 μmol) in dry DMF (5 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure, and the residue purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 76% of theory).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:33][NH2:34]>>[CH3:33][NH:34][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:29]([F:32])([F:31])[F:30])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:15]=2[O:14]1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cccc(F)c4)c3O2)cc1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cccc(F)c3)c2O1

Procedure:
The title compound was prepared (0.026 g, 60%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(3-fluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.055 g, 0.18 mmol) and methylamine (0.12 g, 3.9 mmol). mp 238-240° C.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(O)C.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>O>[O:11]1[C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[N:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:5][C:4]=2[O:9][CH2:10]1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: C(=Nc1ccccc1)c1ccc2c(c1)OCO2
Yield: 45 %

Procedure:
Piperonal (0.63 g, 4.22 mmol), ethanol (4 ml), and aniline (0.38 g, 4.22 mmol) were put in a 25 ml flask, and acetic acid (10 ml) was slowly added dropwise thereto while the mixture was stirred under nitrogen charging conditions, followed by stirring at 80° C. for 12 hours. Then, the temperature of the mixture was lowered to 0° C., followed by the addition of a little water to obtain a solid. The filtering was performed while the solid was washed with cool ethanol, thereby giving clean E)-N-(benz[d][1,3]dioxol-5-ylmethylene)aniline (LJ-2477) with a yield of 45%.