Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:33])[CH:18]([N:23]4[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[N:24]4)[CH2:19][C:20](O)=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.N.C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:33])[CH:18]([N:23]4[C:27]([CH3:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[N:24]4)[CH2:19][C:20]([NH2:36])=[O:21])[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(F)(F)F)nn1C(CC(=O)O)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1C(CC(N)=O)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 4-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-3-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]-4-oxo-butanoic acid (0.029 g, 0.08 mmol) and NH3 (0.3 mL, sat. in CH2Cl2) in DMF (0.6 mL) was added HATU (0.040 g, 0.10 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo, and purified by reverse phase HPLC to afford the desired product (0.014 g, 37%). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.42 (dd, J=9.2, 4.6 Hz, 2H), 7.16 (dd, J=8.4, 8.0 Hz, 2H), 6.53 (s, 1H), 6.34 (s, 1H), 6.32 (s, 1H), 5.92 (m, 1H), 3.80 (m, 1H), 3.41 (m, 1H), 3.33 (m, 1H), 3.00 (m, 1H), 2.76 (m, 2H), 2.37 (s, 3H), 1.98 (m, 1H), 1.88 (m, 1H); MS: (ES) m/z calculated for C21H20F4N6O2 [M+H]+ 465.1, found 465.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([NH:27][C:28]([O:30]C)=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C[O-].[Na+]>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:17]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:27][C:28]2=[O:30])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12

Procedure:
To a solution of methyl 2-[(2′-cyanobiphenyl-4-yl)methylamino]-3-methoxycarbonylaminobenzoate (10.5 g) in methanol (100 ml) was added NaOMe (10 g), and the mixture was heated under reflux for 20 hours. The reaction mixture was neutralized with
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[N:9]2[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][CH:7]=1.[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:34]1([CH:30]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:31][CH2:32][NH:33][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:9]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1C(=O)NC(C)=C(C(=O)O)C1c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)NC(C)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C1c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
117 mg (0.346 mmol) of 4-(3-chlorophenyl)-3-ethoxycarbonyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 110 mg (0.519 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 99.5 mg (0.519 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (1/1) and then dried under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([CH3:16])[NH:3]1.S(Cl)([Cl:20])(=O)=O.O>C1C=CC=CC=1>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([Cl:20])([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1[nH]n(C)c(=O)c1C(=O)c1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=NN(C)C(=O)C1(Cl)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
To a solution of 2.16 g of 1,3-dimethyl-4-benzoyl-5-pyrazolone in 20 ml of dry benzene was added 1.62 g of sulfuryl chloride and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, water was added to the reaction mixture and after shaking an organic layer was separated. The organic layer was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and water, dried over anhydrous sodium sulfate and the solvent was distilled off from the solution. The so obtained residue was recrystallized from n-hexane to give 0.2 g of the desired product melting at 70.5° - 72° C. (Yield 7.6%)
Reaction SMILES: CN(C)C=O.[CH2:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[CH2:8][NH:7]1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]#[N:32]>O>[C:31]([CH2:30][N:7]1[CH2:8][C:9]2([CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6]1)#[N:32]
Reactant: c1ccc2c(c1)CC1(CNCc3ccccc31)O2
Reactant: N#CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1Cc2ccccc2C2(Cc3ccccc3O2)C1

Procedure:
To dry dimethylformamide is added spiro[benzofuran-2(3H),4'(2'H)-isoquinoline] (11.0 g), sodium bicarbonate (8.4 g) and chloroacetonitrile (6.8 g) and the mixture is heated to 70° for four hours. The dimethylformamide is evaporated to give an oil, which is stirred with water (300 ml) for 15 minutes and then extracted with ether/dichloromethane. The organic extract is washed with water (2x), saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After filtering, the solvents are evaporated to an oil which solidifies to the product (10.6 g), 83%), as an off-white solid upon trituration with petroleum ether/ether. For analysis, a sample is recrystallized twice from hexane/acetone to yield platelets.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][CH:16]([CH:19]([OH:20])[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cccs2)CC1

Procedure:
From thiophene (130 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg) by procedure D. Yield: 167 mg (40%). Yellow oil. MS (m/z): 298.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([O:19]CC)=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23.C(O)(=O)C.Cl.O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:14]([C:17]([OH:19])=[O:18])=[CH:13][N:7]3[C@@H:8]([CH3:12])[CH2:9][O:10][C:11]=1[C:6]=23
Reactant: CCOC(=O)c1cn2c3c(c(F)ccc3c1=O)OC[C@@H]2C
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: C[C@H]1COc2c(F)ccc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Yield: 81.1 %

Procedure:
A mixture of ethyl 10-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate (5.60 g, 19.2 mmol), acetic acid (25 ml) and concentrated hydrochloric acid (25 ml) was heated under reflux for 4 hours. After cooling the reaction solution with ice, water (100 ml) was added thereto, and the precipitated crystals were filtered out and then washed with excess water, a small amount of cold ethanol and excess diethyl ether in that order. The crude crystals obtained were then suspended in ethanol (40 ml) and stirred under room temperature. The crystals were filtered out, washed with ethanol, and then dried under a reduced pressure at 80° C. for 17 hours. 4.10 g (81%) of the title compound was thereby obtained in the form of a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8]([OH:10])=O)[CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[CH3:31][NH:32][O:33][CH3:34].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:4]([CH:18]=[N:19][CH:20]=2)[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:6]([C:8]([N:32]([O:33][CH3:34])[CH3:31])=[O:10])[CH:7]=1
Reactant: O=C(O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(Cl)c2cncn2c1-c1cccc(F)c1
Reaction time: 0.08 h
Yield: 59.9 %

Procedure:
8-Chloro-5-(3-fluorophenyl)imidazo[1,5-a]pyridine-6-carboxylic acid (0.29 g, 1.0 mmol) was stirred in N,N-dimethylformamide (2.8 mL). N,N-Diisopropylethylamine (0.87 mL, 5.0 mmol), N,O-dimethylhydroxylamine hydrochloride (0.29 g, 3.0 mmol) and a solution of 0.6 N 1-hydroxy-7-azabenzotriazole in N,N-dimethylformamide (0.33 mL, 0.2 mmol) were added. The mixture was stirred for 5 minutes and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.29 g, 1.5 mmol) was added. The mixture was stirred for 2 hours. The mixture was poured into saturated sodium bicarbonate and extracted into ethyl acetate 3×. The ethyl acetate extracts were combined and washed with water, dried over sodium sulfate, filtered, concentrated and purified by flash column chromatography with ethyl acetate in hexanes (0-80%) to give the desired compound (0.20 g, 60%). LCMS calculated for C16H14ClFN3O2 (M+H)+: m/z=334.1. found: 333.9. 1H NMR (300 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.60 (m, 2H), 7.42 (m, 3H), 7.20 (s, 1H), 3.41 (br s, 3H), 3.00 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:40]>CC(O)C>[ClH:40].[F:1][C:2]1[C:3]([CH2:24][NH:25][CH3:26])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(C)n2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (173 mg) in 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 79 mg, 53%).
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:22]([NH2:25])(=[S:24])[CH3:23]>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:25]=[C:22]([CH3:23])[S:24][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: CC(N)=S
Solvent: CC#N
Product: Cc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.437 g, 1.18 mmol) (Example 26, Step 2) in acetonitrile (10 mL) in a 25 mL round bottom flask was added thioacetamide (0.088 g, 1.18 mmol) and the solution heated to reflux (2 hours) until all solid dissolved. The reaction was cooled to room temperature. The acetonitrile was removed in vacuo and the resulting product precipitated from methanol by the addition of water yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-methylthiazole (0.226 g, 55%, ca. 85% purity by 1H NMR): mp 229°-233° C. 1HNMR (CDCl3) 300 mHz δ7.98 (d, J=8.11 Hz, 2H ), 7.66-7.61 (m, 2H), 7.52 (d, J=8.48 Hz, 2H), 7.13 (t, J=8.48 Hz, 2H), 3.31 (s, 1H), 3.10 (s, 3H). MS (EI-thermospray): m/z 348 (M+). HRMS Δ=-2.3 mmu.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si](C(C)C)(C(C)C)C(C)C)[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)[CH:10]=[O:11].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[OH:21][C:19]1[CH:18]=[C:17]([CH3:32])[C:3]([CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=2)[CH:10]=[O:11])=[C:2]([CH3:1])[CH:20]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(Cc2c(C)cc(O)cc2C)cc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
To a solution of 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (1.4 g, 3.07 mmol) in THF (15 mL) was added TBAF (1 M, 3.68 mL) at 0° C. After stirring at r.t. for 2 h, the reaction mixture was diluted with EtOAc and water. The water layer was extracted with EtOAc and the combined organic extracts were dried (NgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate-hexanes; 1:9) to afford 5-(4-hydroxy-2,6-dimethylbenzyl)-2-methoxymethoxybenzaldehyde (590 mg, 64% for two steps): 1H NMR (200 MHz, CDCl3): δ 10.45 (s, 1H), 7.54 (s, 1H), 7.27 (m, 1H), 7.09 (m, 1H), 6.56 (s, 2H), 5.25 (s, 2H), 3.92 (s, 2H), 3.50 (s, 3H), 2.16 (s, 6H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.68.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[O:8]C1CCCCO1)(=[O:4])=[O:3].Cl>CO>[CH3:1][S:2]([O:5][CH2:6][C@H:7]([OH:8])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC[C@H](OC1CCCCO1)c1ccccc1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)OC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into methanol (10 ml) were added (R)-2-phenyl-2-(3,4,5,6-tetrahydro-[2H]-pyran-2-yloxy)ethyl methanesulfonate (2.0 g) and hydrochloric acid (0.07 g), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized, concentrated, and then ethyl acetate and water were added to the resulting residue. The organic layer was collected by layer separation, washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off to obtain a colorless oily compound mentioned above (1.4 g, 97.2%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:18]([O:19]C)=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][O:23][CH2:24][CH2:25][N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[C:34]([NH2:37])[CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[C:18]([OH:19])=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:34]2[CH:35]=[CH:36][C:29]3[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][O:23][CH3:22])[CH2:32][CH2:31][C:30]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(OC)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(O)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ylamino]-pyrimidin-4-ylamino}-3-hydroxy-N-methyl-benzamide was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methoxy-N-methyl-benzamide and 3-(2-Methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (preparation in Example 34b) in an analogous manner to Example 1221d. Title product isolated as a white foam (10 mg, 15%), HPLC purity 99%. LCMS 497.09 (M+H), 1H-NMR (CDCl3, 400 MHz) δ:10.79 (s, 1H), 8.06 (s, 1H), 7.20-7.09 (m, 5H), 7.01 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 6.25 (d, J=4.8 Hz, 1H), 3.56 (d, J=5.6 Hz), 3.38 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.97-2.75 (m, 10H).
Reaction SMILES: [F:1][C:2]([CH:5]=[CH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([F:4])[F:3].C1C(C(OO)=[O:21])=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[F:1][C:2]([CH:5]=[CH:6][CH2:7][C:8]1[CH:13]2[O:21][CH:12]2[CH:11]=[CH:10][CH:9]=1)([F:3])[F:4]
Reactant: FC(F)(F)C=CCc1ccccc1
Reactant: O=C(OO)c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: FC(F)(F)C=CCC1=CC=CC2OC12
Reaction time: 168 h
Yield: 77 %

Procedure:
7.4 g of m-trifluoromethylallylbenzene was added to chloroform solution containing perbenzoic acid prepared from 29.3 g of benzoyl peroxide and the mixture was allowed to stand at about 5° C for 7 days. After the completion of reaction, the resulting mixture was washed with sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated and the concentrated was distilled under reduced pressure, there was obtained 6.2 g (yield 77%) of m-trifluoromethylallylbenzene oxide having a boiling point of 110° - 111° C/23 mmHg as colourless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].[Br:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][O:65][C@H:66]3[CH2:70][NH2+:69][C@H:68]([C:71]([O:73][CH3:74])=[O:72])[CH2:67]3)[CH:59]=2)[CH:55]=[CH:56][CH:57]=1.Cl>CN(C=O)C.CCOC(C)=O.O>[Br:51][C:52]1[CH:53]=[C:54]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([CH2:64][O:65][C@H:66]3[CH2:70][N:69]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[C@H:68]([C:71]([O:73][CH3:74])=[O:72])[CH2:67]3)[CH:59]=2)[CH:55]=[CH:56][CH:57]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C1CCCCC1
Reactant: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)C[NH2+]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](OCc2cccc(-c3cccc(Br)c3)c2)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2S)-[(tert-butoxycarbonyl)amino](cyclohexyl)acetic acid (1.05 eq.), DIPEA (3.2 eq.) and TBTU (1.1 eq.) were added to a 0.12M solution of methyl (4R)-4-[(3′-bromobiphenyl-3-yl)methoxy]-L-prolinate hydrochloride 97 in DMF. The reaction mixture was stirred at RT for 2 h then it was diluted with EtOAc:H2O and acidified with aqueous (1N) HCl. The phases were separated and the organic layer was washed sequentially with aqueous (1N) HCl, aqueous (2N) NaOH and brine, dried (Na2SO4) and evaporated under reduced pressure to afford the title compound 106 (95% crude yield) as a pale yellow foam which was used without further purification. 1H NMR (400 MHz, DMSO-d6, 300 K) δ 7.86 (s, 1H), 7.70 (d, J 7.8, 1H), 7.66-7.57 (m, 3H), 7.54-7.33 (m, 3H), 6.94 (d, J 8.6, 1H), 4.65 (d, J 11.6, 1H), 4.58 (d, J 11.6, 1H), 4.36 (t, J 8.5, 1H), 4.32 (bs, 1H), 4.19 (d, J 11.1, 1H), 4.11 (t, J 11.1, 1H), 3.74-3.66 (m, 1H), 3.65 (s, 3H), 2.48-2.35 (m, 1H), 2.08-1.97 (m, 1H), 1.83-1.55 (m, 6H), 1.44-1.37 (m, 1H), 1.34 (s, 9H), 1.22-1.09 (m, 2H), 1.08-0.93 (m, 2H). MS (ES+) m/z 629, 631 (M+H)+
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:11]([CH3:14])([CH3:13])[CH2:10][CH2:9][C:8]([CH3:16])([CH3:15])[C:7]=2[C:6]([O:17]C)=[CH:5][CH:4]=1.[N+]([O-])(O)=O>O1CCOCC1.[Ag]=O>[CH3:13][C:11]1([CH3:14])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:16])[C:7]2[C:6](=[O:17])[CH:5]=[CH:4][C:3](=[O:2])[C:12]1=2
Reactant: COc1ccc(OC)c2c1C(C)(C)CCC2(C)C
Agent: O=[Ag]
Solvent: C1COCCO1
Solvent: O=[N+]([O-])O
Product: CC1(C)CCC(C)(C)C2=C1C(=O)C=CC2=O

Procedure:
To a solution of 17.42 g (0.07 mole) of 1,4-dimethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro naphthalene, obtained in Example VIa, in 340 cm3 of dioxane, cooled to +5° C., there are added, with stirring, 34.7 g (0.28 mole) of silver oxide, AgO(II), then rapidly drop-by-drop, 70 cm3 (0.42 mole) of 6N HNO3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17](O)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1.[NH2:24][C:25]1[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:22]#[N:23])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:20])[C:17]([NH:24][C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=3)=[O:18])[C:10](=[O:21])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.53 g (purity 73%, 3.35 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 1.52 g (purity 93%, 83% of theory)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([CH:14]=O)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].N1CCCCC1>C(O)C>[CH2:1]([O:8][C:9]1[C:13](/[CH:14]=[C:26]2/[C:25](=[O:27])[NH:24][C:23](=[O:28])[S:22]/2)=[CH:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccccc2)nc1OCc1ccccc1
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)/C(=C/c2cn(-c3ccccc3)nc2OCc2ccccc2)S1
Yield: 87.8 %

Procedure:
A mixture of 3-benzyloxy-1-phenyl-1H-pyrazole-4-carbaldehyde (2.50 g), 1,3-thiazolidine-2,4-dione (1.05 g), piperidine (0.15 g) and ethanol (80 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-[(3-benzyloxy-1-phenyl-1H-pyrazol-4-yl)methylene]-1,3-thiazolidine-2,4-dione as yellow crystals (2.97 g, yield 87%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: >300° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(=O)OC)ccc1OC
Temperature: 60 °C
Reaction time: 5 h

Procedure:
22 g of methyl 3-hydroxy-4-methoxybenzoate are dissolved in 200 ml of anhydrous DMF and 41 g of ground potassium carbonate and 14.7 ml of 3-chloro-2-methylpropene are then added. The mixture is stirred at 60° C. for 5 h. After cooling, the precipitate is filtered off with suction, water is added to the filtrate and it is then extracted 3 times with ethyl acetate. The residue which remains after concentrating the extracts is crystallized using petroleum ether. 21 g of the title compound of m.p. 62-63° C. are obtained.