Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH2:4][CH2:5][CH3:6].CCOCC.C([Li])CCC.[CH3:36][C:37]1([CH3:52])[CH2:41][O:40][C:39]([C:42]2[CH:43]=[CH:44][C:45]([O:50][CH3:51])=[C:46]([CH:49]=2)[CH:47]=O)=[N:38]1>O.C1COCC1.CCCCCC>[CH:47]([C:46]1[CH:49]=[C:42]([C:39]2[O:40][CH2:41][C:37]([CH3:52])([CH3:36])[N:38]=2)[CH:43]=[CH:44][C:45]=1[O:50][CH3:51])=[CH:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C2=NC(C)(C)CO2)cc1C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCC=Cc1cc(C2=NC(C)(C)CO2)ccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
Pentyltriphenylphosphonium bromide (1.17 g, 2.83 mmol) and ether (5 ml) were mixed, and to this solution was added a hexane solution (1.6M, 1.77 ml) of n-butyllithium (2.83 mmol). The mixture was stirred at room temperature for 2 hours. A THF solution (3 ml) of 5-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-2-methoxybenzaldehyde (600.8 mg, 2.58 mmol) was added to this solution, and the mixture was stirred for 1.5 hours. Water (5 ml) was added to stop the reaction. The aqueous layer was extracted 3 times with ethyl acetate (5 ml). The organic layers were combined, and washed twice with saturated brine (20 ml1). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=2/1) to give 2-[3-(1-hexenyl)-4-methoxyphenyl]-4,4-dimethyl-4,5-dihydrooxazole (583.3 mg, 79%) as a mixture (a colorless oil) of geometrical isomers (1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH2:6]P(=O)(OCC)OCC.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[H-].[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:27]=[CH:6][C:5]2[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: CCOP(=O)(Cc1cc(OC)c(OC)c(OC)c1)OCC
Reactant: COc1ccc(C=O)cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C=Cc2cc(OC)c(OC)c(OC)c2)cc1OC

Procedure:
Reaction of diethyl 3,4,5-trimethoxybenzylphosphonate (5.4 g, 17 mmol) with 3,4-dimethoxybenzaldehyde (2 g, 12 mmol) in presence of NaH (0.97 g, 20 mmol), under the conditions noted in example 1, gave 1-(3,4-dimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl) ethylene, m.p. 150–152° C.; IR (KBr) νmax 2934, 2835, 1583, 1510, 1331, 1249, 1125, 1024, 1004, 976, 850 cm−1; 1H NMR (CDCl3, 400 MHz) δ 7.06 (1H, s), 7.05 (1H, dd, J=8.0, 1.9 Hz), 6.97 (1H, d, J=16.0 Hz), 6.89 (1H, d, J=16.0 Hz), 6.87 (1H, d, J=8.0 Hz), 6.73 (2H, s), 3.95 (3H, s), 3.92 (6H, s), 3.91 (3H, s), 3.87 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH3:21])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=2)=[CH:8][CH:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:35]=[C:31]([C:32]([NH2:34])=[O:33])[C:30]([OH:36])=[CH:29][CH:28]=1>>[C:32]([C:31]1[CH:35]=[C:27]([CH:28]=[CH:29][C:30]=1[OH:36])[O:26][CH2:25][CH2:24][NH:1][CH2:2][CH:3]([OH:22])[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:13]([CH3:21])[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[N:16]=2)=[CH:10][CH:11]=1)(=[O:33])[NH2:34]
Reactant: NC(=O)c1cc(OCCBr)ccc1O
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN)cc1
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CNCCOc2ccc(O)c(C(N)=O)c2)cc1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g of 1-amino-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol and 0.82 g of 5-(2-bromoethoxy)-salicylamide is stirred for 1 hour in an oil bath at a temperature of 100°. The melt is then extracted by boiling with 30 ml of isopropanol. The filtered solution is concentrated to 15 ml, cooled and the crystals that are precipitated are filtered off. Recrystallisation from methanol yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-(1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-phenoxy]-2-propanol having a melting point of 195°-197°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[C:3]=1[OH:10].[F:11][C:12]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:13]=1[C:14](Cl)=[O:15]>>[OH:10][C:3]1[C:4]([F:9])=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:14](=[O:15])[C:13]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:12]=1[F:11]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Reactant: Nc1ccc(F)c(F)c1O
Product: O=C(Nc1ccc(F)c(F)c1O)c1cc([N+](=O)[O-])ccc1F

Procedure:
Prepared by the method of Example 15a), from 2-amino-5,6-difluorophenol (334 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=2)[N:3]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CCCCO>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:12]([CH3:13])[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-:24])=[O:23])[CH:8]=3)[N:3]=[C:2]([NH:28][CH2:27][CH2:25][OH:26])[N:11]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Solvent: CCCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 120 °C

Procedure:
A mixture of 77 mg (0.22 mmol) of (2-chloro-6-nitro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine and 68 mg (1.12 mmol) of ethanolamine in n-BuOH was heated at 120° C. for 18 hours. The reaction mixture concentrated and the isolation was done by preparative HPLC to give the title compound. 1H NMR (DMSO-d6) δ 8.2-7.1 (7H), 3.83 (3H), 3.82 (s, 2H), 3.62 (d, 3H), 3.56 (s, 2H); LC-MS (ESI+; 294 ([M+H]+)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccnc(N2CCNCC2)c1
Yield: 42.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyridine (2.0 g, 11 mmol), piperazine (3 g, 30 mmol) and triethylamine (3.1 mL, 22 mmol) in DMF (10 mL) was heated at 100° C. overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9/1/0.5) to give 1.09g (43%) of pure product. MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][C:16](OC)=[O:17])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][CH2:15][CH2:16][OH:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CCc1cnoc1-c1ccc(Cl)c(Br)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1cnoc1-c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
To a solution of methyl 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propionate (1.00 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 6.5 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[5-(3-bromo-4-chlorophenyl)-4-isoxazolyl]propan-1-ol (0.85 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 75–76° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([C:25]([O:27]C)=O)=[C:11]3[C:16]=2[O:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]3[N:23]=O)=[C:5]([CH3:29])[O:4][N:3]=1.[Cl-].[NH4+]>C(OCC)(=O)C.CO.[Zn]>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:12]4[C:11]=3[C:10]([C:25](=[O:27])[NH:23]4)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2c(C)noc2C)c2c1N(N=O)C(c1ccccc1)CO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccc1
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A suspension of methyl 8-(3,5-dimethylisoxazol-4-yl)-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine-5-carboxylate (0.228 g, 0.580 mmol) in ethyl acetate (4.04 mL) and methanol (4.04 mL) at 0° C. was treated with saturated aqueous ammonium chloride solution (2.02 mL, 30.2 mmol) and then zinc (0.303 g, 4.64 mmol) was added in three portions over 6 min. The cooling bath was removed and the reaction mixture was stirred for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL), filtered through a Celite pad, and rinsed with ethyl acetate (2×10 mL). The filtrate was washed with water (20 mL), brine, (20 mL), dried over sodium sulfate, filtered, and concentrated to give a crude tan foam. Purification by flash column chromatography (100% dichloromethane to 10% methanol/dichloromethane) gave the desired product (0.14 g, 70%) as a yellow foam. 1H NMR (500 MHz, DMSO-d6) δ 10.98 (br s, 1H), 7.40-7.29 (m, 3H), 7.26 (d, J=8.3 Hz, 1H), 7.23-7.15 (m, 2H), 6.87 (d, J=8.2 Hz, 1H), 5.39 (br s, 1H), 4.74 (dd, J=11.5, 3.1 Hz, 1H), 4.61 (dd, J=11.5, 5.8 Hz, 1H), 2.31 (s, 3H), 2.15 (s, 3H). LCMS calculated for C20H18N3O3 (M+H)+: m/z=348.1. found: 348.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26](N(CC)CC)[CH3:27].C(OC(ON=C(C#N)C(OCC)=O)=O)C>C(OCC)(=O)C>[CH2:26]([O:24][C:23](=[O:25])[C@H:12]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:27]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CCOC(=O)ON=C(C#N)C(=O)OCC
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-benzyloxycarbonyl-L-tryptophan (1.69 g) and triethylamine (0.70 ml) in ethyl acetate (15 ml), ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate (1.08 g) is added, and the resulting mixture is stirred at room temperature for 1 hour and allowed to stand over night. The reaction mixture is treated as in Example A whereby crystals are obtained. The crystals are triturated with petroleum ether, and the obtained powder is collected by filtration, dried and recrystallized from an ethyl acetate-petroleum ether mixture to give N-benzyloxycarbonyl-L-tryptophan ethyl ester (1.4 g). M.P. 80 - 83°C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:18]#[CH:19])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]3([CH3:17])[CH3:16])[CH2:3][CH2:2]1.C(O)(=O)C1C=CC=CC=1.[CH2:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=1)[CH3:30].C(N(CC)CC)C.O1CCCC1>CCCCCC.[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.C(OCC)(=O)C>[CH2:29]([O:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][C:36]([C:19]#[C:18][C:6]2[CH:7]=[C:8]3[C:13](=[C:4]([CH:1]4[CH2:3][CH2:2]4)[CH:5]=2)[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]3([CH3:17])[CH3:16])=[CH:35][CH:34]=1)[CH3:30]
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following general procedure F and using 8-cyclopropyl-6-ethynyl-2,2,4,4-tetramethylchroman (Intermediate 34, 0.1 g, 0.38 mmol), ethyl-4-iodo-benzoate benzoate (Reagent A, 0.1 g, 0.34 mmol), triethyl amine (5 mL), tetrahydrofuran(10 mL), copper(I)iodide(0.025 g, 0.13 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.11 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.135 g, 89%).
Reaction SMILES: CC([O-])(C)C.[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OC([N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36](Br)[CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH2:23][C@H:22]1[CH3:40])=O)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:40][C@H:22]1[NH:21][CH2:26][CH2:25][N:24]([CH2:27][C:28]([N:30]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:37]=3)[CH2:32][CH2:31]2)=[O:29])[CH2:23]1
Reactant: Nc1ccccc1
Reactant: C[C@@H]1CN(CC(=O)N2CCc3ccc(Br)cc32)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(CC(=O)N2CCc3ccc(Nc4ccccc4)cc32)CCN1
Temperature: 100 °C
Yield: 31.1 %

Procedure:
To Pd2(dba)3 (4 mg, 0.005 mmol), (2-biphenyl)P(t-Bu)2 (1 mg, 0.005 mmol), and NaOtBu (31 mg, 0.32 mmol) was added a solution of the aniline (26 mg, 0.27 mmol) in toluene (0.57 mL), followed by (R)-4-[2-(6-bromo-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 0.11 mmol). The mixture was heated to 100° C. for 18 h then filtered and concentrated and the residue purified by preparative HPLC (TFA method), to give the title compound (12 mg, 24%) as a orange/brown solid. 1H NMR (Me-d3-OD): 8.05 (1H, dd), 7.30-7.17 (2H, m), 7.13 (1H, d), 7.10-7.02 (2H, m), 6.91-6.81 (2H, m), 4.58 (1H, s), 4.43-4.26 (2H, m), 4.26-4.16 (1H, m), 4.16-4.04 (2H, m), 3.71 (1H, d), 3.58-3.38 (2H, m), 3.29-3.18 (4H, m), 1.51 (9H, s), 1.43 (3H, d).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:12][CH:11]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccn3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 mg (1.41 mmol) of [4-(2-pyridyl)phenyl]acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene, and the solvent is again removed in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol and then filtered off, and the filtrate is back-extracted with 20 ml of dichloromethane. Solid and dichloromethane phase are combined, and the solvent is removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[NH:8][C:7](=O)[CH2:6][C:5]2[CH:10]=[C:11]([CH3:15])[C:12]([CH3:14])=[CH:13][C:4]=2[CH2:3]1.B.[ClH:17]>O1CCCC1>[ClH:17].[CH3:1][CH:2]1[CH2:3][C:4]2[CH:13]=[C:12]([CH3:14])[C:11]([CH3:15])=[CH:10][C:5]=2[CH2:6][CH2:7][NH:8]1
Reactant: Cc1cc2c(cc1C)CC(C)NC(=O)C2
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C)CC(C)NCC2
Reaction time: 0.08 h

Procedure:
A slurry of 3.7 g of the lactam (0.0182 moles) prepared in Example 12 in 20 ml of tetrahydrofuran was cooled to 0° and 40 ml of a 1M solution of borane in tetrahydrofuran gradually added. After five minutes at 0°-5°, almost all of the lactam had dissolved, whereupon the mixture was heated to boiling. The clear refluxing solution deposited some gelatinous material at the liquid-vapor interface after about fifteen minutes. Refluxing was continued for another three hours, then the mixture was cooled in an ice bath and the excess borane cautiously decomposed by the dropwise addition of 50 ml of 10 percent hydrochloric acid. The mixture was warmed on the steam bath to boil off the tetrahydrofuran and the cooled residual solution extracted with several portions of benzene to remove any non-basic material. After alkalizing to pH 11, the base was extracted with three 50-ml portions of benzene and one 50-ml portion of ether. The combined extracts were washed with water, dried (K2CO3), and the solvent distilled in the rotary evaporator. The base was then dissolved in 25 ml of ether and an excess of ethereal hydrogen chloride added. The solvent and excess acid were distilled in vacuo and the syrupy residue crystallized when rubbed under ethyl acetate. This crystalline hydrochloride, of the above named product melted at 219.5°-221°. It was recrystallized from a mixture of ethyl acetate and isopropanol and formed white crystals, m.p. 218°-219°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([OH:19])=O)=[O:12].[NH2:24][C:25]1[CH:26]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1C(=O)CCC1>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[S:4][C:3]=1[C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:17](=[O:19])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)[CH:20]=[CH:21][C:22]=1[CH3:23])=[O:12]
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1sc2nccnc2c1N
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1sc2nccnc2c1N
Yield: 9.7 %

Procedure:
A solution of 109 (0.305 mmol, 100 mg), 3-aminobenzotrifluoride (0.305 mmol, 0.038 mL), TBTU (0.457 mmol, 147 mg) and DIPEA (0.914 mmol, 0.150 mL) in NMP (5 ml) stirred overnight at 80° C. The light brown solution was poured into citric acid solution and extracted with ethyl acetate. The combined organic layers were washed with brine and evaporated. The crude compound was purified by HPLC and chromatography (0-5% methanol in CH2Cl2) gave 7-amino-N-(2-methyl-5-(3-(trifluoromethyl)phenylcarbamoyl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide 110 (14 mg, 10%). NMR (400 MHz, DMSO-d6) 2.33 (s, 3H), 7.10 (s, 2H), 7.47 (m, 2H), 7.61 (m, 1H), 7.85 (dd, J=7.8 Hz and 1.6 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 8.09 (d, J=8.2 Hz, 1H), 8.25 (s, 1H), 8.79 (d, J=2.3 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 9.62 (s, 1H), 10.52 (s, 1H). (m/z)=472 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([NH:27]C(OC(C)(C)C)=O)[CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:35])[CH2:10][C@@H:11]([NH2:27])[CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](CC(=O)OCc1ccccc1)CN1CCC(Oc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (R)-3-tert-butoxycarbonylamino-4-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-butyric acid benzyl ester (0.488 g, 1.0 mmol) in DCM (8 ml) is treated with trifluoroacetic acid (2 ml). The reaction mixture is stirred at ambient temperature for 1 hour. The solvent is evaporated and the residue taken up in DCM and washed with saturated aqueous NaHCO3. The organic phase is dried over MgSO4 and evaporated to yield (R)-3-amino-4-[4-(4-fluorophenoxy)-piperidin-1-yl]-butyric acid benzyl ester. [MH]+ 387.1
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][C:49]([CH2:52][CH2:53][O:54][CH3:55])=[CH:48][CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:55][O:54][CH2:53][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:47][CH:48]=1
Reactant: COCCc1ccc(OB([O-])[O-])cc1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: COCCc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (420 mg) was added toluene/ethanol/water (10/1/1, 16.2 ml) and then were added 4-(2-methoxyethyl)phenyl borate (216 mg) and potassium carbonate (245 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (47 mg), and the mixture was stirred at 100° C. for 10 hours and cooled to room temperature. The mixture was added to water, and the mixture was extracted with ethyl acetate/THF, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give 7-[4-(2-methoxyethyl)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 81) (99 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH2:35][CH:36]1[CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:36]1([CH2:35][O:1][C:2]2[CH:3]=[C:4]([C:10]3[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]4[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]5[C:27](=[O:32])[CH2:28][CH2:29][C:30]5=[O:31])[CH2:20][CH2:19]4)[N:11]=3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH2:38][CH2:37]1
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1OCC1CC1

Procedure:
A mixture of 1 g 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4), 0.7 g of bromomethylcyclopropane and 1 g of potassium carbonate in 100 ml of acetonitril is refluxed for 8 h after which the solvent is evaporated. The residue is partitioned between water and ethyl acetate, the organic layer is dried over magnesium sulfate and the EA evaporated. The residue is crystallized from ethyl acetate.