Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=1)=[O:4].[OH-].[Na+].CO.Cl>O>[F:24][C:23]([F:25])([F:26])[C:20]1[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:5]=2[C:3]([OH:4])=[O:2])=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 79.8 %

Procedure:
To 1.59 g of 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid methyl ester were added 10 ml of 2 M aqueous sodium hydroxide and 10 ml of methanol. After 3 h at reflux the mixture was poured unto water, treated with 2 M hydrochloric acid, and three times extracted with ethyl acetate. The combined organic layers were dried over magnesium sulphate and concentrated in vacuo. The resulting residue was purified by crystallization from pentane to yield 1.22 g of 1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carboxylic acid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:26])([CH3:25])[O:24][C@@H:20]2[C@@H:19]([CH2:27][NH:28][CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:36])[CH2:30]2)[O:18]1.I[CH:46]([CH3:48])[CH3:47]>CC#N.CCOC(C)=O>[NH2:7][C:8]1[N:16]=[CH:15][N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[C@H:17]1[C@@H:21]2[O:22][C:23]([CH3:25])([CH3:26])[O:24][C@@H:20]2[C@@H:19]([CH2:27][N:28]([CH:46]([CH3:48])[CH3:47])[CH:29]2[CH2:32][CH:31]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[CH2:30]2)[O:18]1
Reactant: CC(C)I
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CNC1CC(CCC(=O)OCc3ccccc3)C1)O[C@H]2n1cnc2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)N(C[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)C1CC(CCC(=O)OCc2ccccc2)C1
Temperature: 95 °C
Reaction time: 18 h

Procedure:
K2CO3 (528.92 mg, 3.83 mmol) was added to a solution of benzyl 3-[3-({[(3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyl-tetrahydro-2H-furo[3,4-d][1,3]dioxol-4-yl]methyl}amino)cyclobutyl]propanoate (1.00 g, 1.91 mmol) and 2-iodopropane (0.57 ml, 5.74 mmol) in MeCN and stirred at 95° C. in a sealed tube for 18 hours. The reaction mixture was diluted with EtOAc (20 ml), filtered and evaporated to dryness. Purification by silica gel chromatography, eluting with 7N NH3 in MeOH:DCM (1:99-5:95) gave the desired product as a colourless oil, 700 mg (65%); MS (ESI+) for C30H40N6O5 m/z 565.70 [M+H]+; HPLC purity 96% (ret. time, 1.48 min); 1H NMR (500 MHz, CHLOROFORM-d) δH ppm 8.35 (d, J=3.5 Hz, 1H), 7.88 (d, J=3.2 Hz, 1H), 7.44-7.29 (m, 5H), 6.03 (t, J=2.2 Hz, 1H), 5.62-5.42 (m, 3H), 5.10 (d, J=3.3 Hz, 2H), 5.06-4.92 (m, 1H), 4.26 (dt, J=9.9, 3.4 Hz, 1H), 3.46-2.84 (m, 2H), 2.88-2.61 (m, 1H), 2.51 (ddd, J=14.0, 9.1, 7.5 Hz, 1H), 2.33-2.15 (m, 2H), 2.50-2.13 (m, 2H), 2.16-1.74 (m, 4H), 1.60 (s, 3H), 1.43-1.35 (m, 4H), 0.96 (d, J=6.7 Hz, 3H), 0.79 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2](C(Cl)(Cl)Cl)=[C:3]([C:29]#[N:30])[C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([F:28])[C:12]=1[N:13]1[CH2:18][CH2:17][CH:16]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[CH2:15][CH2:14]1)=O.[OH2:35].[NH2:36][NH2:37]>CN1CCCC1=O>[NH2:1][C:2]1[C:3]([C:4]([NH:6][C:7]2[CH:8]=[N:9][CH:10]=[C:11]([F:28])[C:12]=2[N:13]2[CH2:14][CH2:15][CH:16]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[O:20])[CH2:17][CH2:18]2)=[O:35])=[C:29]([NH2:30])[NH:37][N:36]=1
Reactant: O
Reactant: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl)CC2)CC1
Reactant: NN
Solvent: CN1CCCC1=O
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)n[nH]c3N)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Amino-4,4,4-trichloro-2-cyano-N-[5-fluoro-4-[4-(4-methylpiperazine-1-carbonyl)-1-piperidyl]-3-pyridyl]but-2-enamide (4.1 g, 7.695 mmol) was dissolved in N-methylpyrrolidinone (40 mL). Hydrazine hydrate (1.002 g, 973.8 μL, 20.01 mmol) was added and the reaction mixture was stirred at room temperature for 10 mins, then heated at 80° C. for 3.5 h. The mixture was concentrated in vacuo and the residue was then partitioned between EtOAc/water. The organic layer was washed with water (2×), brine (1×), dried (MgSO4), filtered and concentrated in vacuo to provide the desired compound as a white solid. (64%). MS (ES+) 446.1, 1H NMR (500 MHz, DMSO) 11.03 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 8.52 (d, J=4.7 Hz, 1H), 7.36 (br s, 4H), 4.47-4.43 (m, 1H), 4.23-4.21 (m, 1H), 3.50-3.47 (m, 2H), 3.41-3.39 (m, 2H), 3.24-3.15 (m, 2H) 3.05-2.98 (m, 2H), 2.93-2.88 (m, 2H), 2.77-2.76 (m, 4H), 1.73-1.71 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14](Br)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+].[S:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1>O.COCCOC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([C:35]3[CH:36]=[CH:37][S:33][CH:34]=3)=[C:13]([CH3:18])[CH:12]=2)=[CH:5][C:4]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)c(C)c2)cc1N1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccsc3)c(C)c2)cc1N1CCN(C)CC1
Yield: 68.3 %

Procedure:
N-(4Methoxy-3-(4-methyl-1-piperazinyl)phenyl)-4-bromo-3-methylbenzamide (0.35 g, 0.84 mmol), sodium carbonate (89 mg, 0.84 mmol), tetrakis (triphenylphosphine)palladium(0) (49 mg, 0.05 equiv), 3-thiophenyl boronic acid (115 mg, 0.84 mmol) in water (18 ml) and DME (18 ml) were heated at reflux under argon for 18 h. The solution was partitioned between saturated aqueous potassium carbonate solution (50 ml) and chloroform (50 ml), the organic extracts dried (sodium sulphate), filtered and evaporated to dryness under reduced pressure. The resulting oil was purified by column chromatography (silica, chloroform/methanol 5-30%) to afford the tide compound as an oil (242 mg, 63%) which was crystallised as an oxalate salt from methanol chloroform.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)=[O:24])=[CH:16]2)[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OC(C1C(OC)=CC=C2C=1C=CC(C(C1N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=1)=O)=C2)C)([C:33](C)([CH3:35])[CH3:34])(C)C.Cl.N1C=CC=CC=1>CO>[Si:1]([O:8][CH:9]([C:11]1[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15]([C:23]([C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)([OH:24])[CH:33]([CH3:35])[CH3:34])=[CH:16]2)[CH3:10])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Production of [5-[1-(tert-Butyldimethylsilyloxy)-ethyl]-6-methoxynaphthalen-2-yl]-(1H-imidazol-4-yl)ketone. [5-[1-(tert-butyldimethylsilyloxy)ethyl]-6-methoxynaphthalen-2-yl]-(1-trityl-1H-imidazol-4-yl)ketone (5.18 g) and pyridine hydrochloride (1.59 g) were dissolved in methanol (50 ml). The solution was stirred at 50° C. for 1 h. The reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was washed with saturated aqueous solution of sodium hydrogencarbonate and saturated sodium chloride solution, dried and concentrated. The obtained residue was washed with ether to give the titled compound (2.71 g) as a colorless solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(C)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[C:20]1C=CC(C)=CC=1>[Cu]>[CH3:20][C:9]1[CH:10]=[CH:11][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: Cc1ccccc1
Reactant: COC(=O)c1cccc(I)c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Product: COC(=O)c1cc(-c2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 29 %

Procedure:
To a mixture of methyl 3-iodobenzoate (26.1 g) in 4-iodotoluene (21.9 g) was added copper powder (31.8 g) gradually at 180°-190° C. The mixture was then stirred for 6 hours at 200°-210° C. The reaction mixture was cooled to room temperature, to which was added toluene. insoluble materials were filtered off, and the filtrate was concentrated to dryness. The residue gas purified by column chromatography on silica gel to afford the title compound as a colorless oil (6.61 g, 29%).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)[CH3:7].N>S(=O)(=O)(O)O>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:16][C:17]=1[N+:1]([O-:4])=[O:2])[CH3:23]
Reactant: CCN(CC)CCOc1ccc(NC(C)=O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCN(CC)CCOc1ccc(NC(C)=O)cc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 1 h

Procedure:
0.74 g (7.29 mmol) of potassium nitrate are added batchwise at −10° C. to a solution of 1.52 g (6.07 mmol) of N-[4-(2-diethylaminoethoxy)phenyl]acetamide in 25 mL of concentrated sulfuric acid and the mixture is stirred for 1 hour at −10° C. The reaction mixture is poured onto a mixture of ice and concentrated aqueous ammonia and the aqueous phase is exhaustively extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated down. Yield: 1.8 g (100% of theory); C14H21N3O4 (M=295.34); calc.: molecular ion peak (M+H)+: 296; found: molecular ion peak (M+H)+: 296; Rf value: 0.50 (Alox, dichloromethane/methanol (39:1)).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:46][CH2:45][CH:44]([CH:47]3[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]3)[CH2:43][CH2:42]2)=[C:37]([F:54])[C:36]=1[F:55])[CH2:31][CH2:32][CH3:33].O>C1COCC1.C1(C)C=CC=CC=1>[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[CH2:42][CH2:43][CH:44]([CH:47]3[CH2:52][CH2:51][C:50](=[CH:2][O:3][CH3:4])[CH2:49][CH2:48]3)[CH2:45][CH2:46]2)=[C:37]([F:54])[C:36]=1[F:55])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCOc1ccc(C2CCC(C3CCC(=O)CC3)CC2)c(F)c1F
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CCC(C3CCC(=COC)CC3)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Well-dried methoxymethyltriphenylphosphonium chloride (7.9 g) and THF (100 ml) were mixed under an atmosphere of nitrogen, and cooled to −30° C. Then, potassium t-butoxide (t-BuOK) (2.6 g) was added in four portions in the temperature range of −30° C. to −20° C. After the stirring at −20° C. for another 30 minutes, the compound (24) (6.8 g) dissolved in THF (35 ml) was added dropwise in the temperature range of −30 to −20° C. After the mixture had been stirred at −10° C. for 30 minutes, the reaction solution was poured into a mixture water (200 ml) and toluene (100 ml) and mixed with it. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed with water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the resulting residue was purified with a fractional operation by means of column chromatography using silica gel as a stationary phase powder and toluene as an eluent. The resulting eluent was concentrated under reduced pressure to leave 4-(4-butoxy-2,3-difluorophenyl)-4′-methoxymethylene-bicyclohexyl (25) (7.2 g). The yield based on the compound (24) was 95.5%.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][NH:9][CH2:8][CH2:7]2.[H][H].CS(O[CH2:21][CH:22]1[CH2:26][O:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=2[Cl:40])([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[O:23]1)(=O)=O>CS(C)=O>[Cl:40][C:34]1[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:33]=1[C:24]1([CH2:27][N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[O:23][CH:22]([CH2:21][O:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][NH:9][CH2:8][CH2:7]3)[CH2:26][O:25]1
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: [H][H]
Reactant: CS(=O)(=O)OCC1COC(Cn2ccnc2)(c2ccc(Cl)cc2Cl)O1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ccc(C2(Cn3ccnc3)OCC(COc3ccc4c(c3)CCNC4)O2)c(Cl)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
0.55 g of sodium hydride (50% suspension in oil) is added to a solution of 1.50 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline in 30 ml of dimethyl sulfoxide, and the mixture is stirred at 50° C. until evolution of hydrogen has finished. 4.07 g of (2RS,4SR)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate are added and the mixture is stirred at 80° C. for 5 hours. The solvent is removed under oil pump vacuum, the residue is taken up with a mixture of 50 ml of water and 50 ml of methylene chloride, and the organic phase is extracted twice more by shaking with water, dried and evaporated in a rotary evaporator. The residue is chromatographed on silica gel using methanol as the mobile phase. 2.45 g of colorless oil (53% of theory), which gradually crystallizes, are obtained. Melting point 143°-145° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>C(#N)C.O>[CH2:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(NCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: O=C(c1ccc(NCc2ccccc2)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-(benzylamino)benzoic acid (200 mg, 0.88 mmol) in acetonitrile (2 ml) was added piperidine (0.174 ml, 1.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (184 mg, 0.97 mmol), hydroxybenzotriazole hydrate (10 mg, catalytic) followed by triethylamine (0.31 ml, 2.2 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (2 ml) and extracted with dichloromethane (2×2 ml). The organic phases were combined, washed with brine, dried over magnesium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2) eluting with ethyl acetate/dichloromethane (1:4) to afford the title compound as an off white solid (122 mg, 47% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([NH:11][CH3:12])=[O:10])[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=1.Cl.[NH2:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([NH:8][C:9]([NH:11][CH3:12])=[O:10])[N:7]=1)[C:13]([NH:16][OH:17])=[NH:14]
Reactant: CNC(=O)Nc1cc(C#N)cc(N)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNC(=O)Nc1cc(C(=N)NO)cc(N)n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of 0.200 g 1-(6-amino-4-cyano-pyridin-2-yl)-3-methyl-urea (example 23a) in 3.2 ml ethanol and 1.6 ml water was added 0.145 g hydroxylamine hydrochloride and 0.333 g sodium carbonate and the mixture was stirred at 85° C. for 2 h. The reaction mixture was purified by solid phase extraction with ethyl acetate to yield 0.154 g of the title compound as light yellow solid. MS (ISP) M+H+=225.1
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([C@H:38]([OH:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([C@H:38]([OH:45])[C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][N+:40]=5[O-:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3S(C)(=O)=O)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.3 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.45 g) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C. and the mixture was stirred for 20 hours at room temperature. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4) and further recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 94) (292.1 mg) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=4)[CH2:22]3)[C@@H:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:14][OH:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].O.[CH3:44]N(C=O)C>IC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:16][C@H:17]2[CH2:25][CH2:24][C@H:23]3[C@@H:19]([CH2:20][N:21]([C:26]4[CH2:30][CH2:29][C:28](=[O:31])[CH:27]=4)[CH2:22]3)[C@@H:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[CH2:14][O:15][CH3:44])[CH:4]=[C:3]([C:2]([F:39])([F:1])[F:40])[CH:8]=1
Reactant: CN(C)C=O
Reactant: Cc1ccccc1[C@H]1[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2CC[C@@H]1O[C@H](CO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COC[C@@H](O[C@H]1CC[C@@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccccc1C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
The compound from EXAMPLE 3 (0.02 g, 0.035 mmol) was dissolved in DMF (15 mL) and cooled to 0° C. NaH solid (12.8 mg, 0.07 mmol) was added, and the reaction mixture was stirred at 0° C. for 5 min. A few drops of iodomethane (excess) were added to the mixture. After stirring for another 10 min at 0° C., water (1 mL) was added and the water/DMF were removed in vacuo. The residue was taken into ethyl acetate. The mixture was washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by preparative TLC (10% methanol in ethyl acetate) to afford the title compound. M++1: 582.47.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(#N)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15])(=[O:29])=[O:28]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a mixture of EXAMPLE 3A (0.125 g) and triethylamine (0.21 mL) in acetonitrile (3 mL) at 0-5° C. was added methanesulfonyl chloride (0.0404 mL). After 30 minutes, the mixture was concentrated, and the concentrate was purified by flash chromatography on silica gel with 0-30% ethyl acetate/hexanes.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][CH3:11])[CH:7]=1.B([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1)(O)O>>[CH2:10]([O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)[CH:3]=[N:4][CH:5]=1)[CH3:11]
Reactant: CCOCc1cncc(Br)c1
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Product: CCOCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Yield: 90 %

Procedure:
Prepared in a similar manner as example 21a starting from 3-Bromo-5-(ethoxymethyl)pyridine (example 26b) and 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b). Yield: 90%. MS (M+H, 300).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH3:10])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][CH:24]=O)[CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19]>>[F:11][C:12]1[CH:13]=[C:14]([CH2:22][CH2:23][CH:24]2[NH:9][CH2:8][CH2:7][N:5]3[C:4]([CH3:10])=[N:3][C:2]([I:1])=[C:6]23)[CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21]
Reactant: O=CCCc1ccc(C(F)(F)F)c(F)c1
Reactant: Cc1nc(I)cn1CCN
Product: Cc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
According to the general procedure (GP10), microwave-assisted Pictet-Spengler reaction (60 W; 140° C.; 6.5 bars; 10 min.) between 2-(4-iodo-2-methyl-imidazol-1-yl)-ethylamine (51.840 mmol) and 3-(3-fluoro-4-trifluoromethyl-phenyl)-propionaldehyde (13.125 g; 59.616 mmol) afforded 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine. LC-MS: tR=0.76 min.; [M+H]+=453.93 g/mol. Subsequent protection of the secondary amine, and purification by FC (DCM/MeOH=20/1) allowed the isolation of the pure product 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-1-iodo-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a pale yellow solid (15.450 g; 54%). LC-MS: tR=0.97 min.; [M+H]+=554.84 g/mol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH:13]([CH3:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1.[CH2:29](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:13]([O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][C:19]([O:18][CH3:17])=[O:28])=[CH:22][CH:23]=3)=[CH:8][C:7]=2[CH3:29])[CH2:10][CH2:11]1)([CH3:14])[CH3:15]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(C2(OC(C)C)CC2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-isopropoxycyclopropyl)-3-methyl-benzene (Intermediate 81, 100.0 mg, 0.47 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 129.0 mg, 0.45 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (30.0 mg, 0.16 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (110 mg, 0.16 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 120.0 mg (71%) of the title compound.