Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=[N:4][CH:3]=1.CN([C:14]1[CH:19]=CC=CN=1)C.[ClH:20].CN(C)CCCN=C=NCC>C(O)C>[Cl:20][C:3]1[N:4]=[N:5][C:6]([C:8]([O:10][CH2:19][CH3:14])=[O:9])=[CH:7][CH:2]=1
Reactant: Cl
Reactant: CN(C)c1ccccn1
Reactant: O=C(O)c1cc(Cl)cnn1
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Product: CCOC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
The compound resulting from Example 170B was chlorinated by the procedure described by Overend and Wiggins, J. Chem. Soc. 239 (1947) to give 4-chloro-6-methylpyridazine. 1H NMR (CDCl3, 300 MHz) δ 2.70 (s, 3H), 7.35 (d, 1H), 7.45 (d, 1H). MS (DCl/NH3) m/e 129/131 (M+H)+, 146/148 (M+H+NH3)+. The chloro-compound was oxidized by the procedure of Horner et al., J.Chem. Soc. 2195 (1948) to give 4-chloropyridazine-6-carboxylic acid. 1H NMR (CD3OD, 300 MHz) δ 7.95 (d, 1H), 8.30 (d, 1H). MS (FAB) m/e 159/161 (M+H)+. The carboxylic acid (243 mg, 1.53 mmol) was dissolved in ~15 mL of ethanol and treated with 24 mg (0.2 mmol) of dimethylaminopyridine (DMAP) followed by 324 mg (1.69 mmol) 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (EDCl). The reaction was stirred at ambient temperature for 4 hours and then worked up by the procedure described in Example 166A. The crude product was purified by flash chromatography on silica gel to give 150 mg (52%) of the title compound as a white crystalline solid. 1H NMR (CDCl3, 300 MHz) δ 1.45 (t, 3H), 4.55 (q, 2H), 7.65 (d, 1H), 8.15 (d, 1H). MS (DCl/NH3) m/e 187/189 (M+H)+, 204/206 (M+H+NH3)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#N.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1.Cl.C(=O)([O-])[OH:18].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]([CH:11]1[CH2:13][CH2:12]1)=[O:18]
Reactant: N#Cc1cc(Cl)ccc1N
Reactant: Br[Mg]C1CC1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Cl)cc1C(=O)C1CC1
Temperature: 0 °C
Yield: 83 %

Procedure:
2-Amino-5-chlorobenzonitrile (500 mg, 3.28 mmol) was dissolved in THF (10 mL), and while stirring the reaction solution at 0° C., cyclopropyl magnesium bromide (0.5 M THF solution, 26.4 mL) was added dropwise thereto. The reaction solution was stirred overnight under heating at 80° C., followed by ice-cooling, and 2 N hydrochloric acid was added thereto under ice-cooling. After the reaction solution was stirred at room temperature for 2 hours, the solution was diluted with ethyl acetate and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1), whereby (2-amino-5-chlorophenyl)(cyclopropyl)methanone (453 mg, 83%) was obtained as a yellow solid.
Reaction SMILES: [Li]CCCC.[C:6](#[N:8])[CH3:7].CO[C:11](=[O:21])[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[N:14][C:13]=1[O:19][CH3:20]>C1COCC1>[CH3:20][O:19][C:13]1[C:12]([C:11](=[O:21])[CH2:7][C:6]#[N:8])=[CH:17][CH:16]=[C:15]([CH3:18])[N:14]=1
Reactant: CC#N
Reactant: COC(=O)c1ccc(C)nc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc(C)ccc1C(=O)CC#N
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-BuLi (1.2 M, 96.0 mL, 115.6 mmol) is added to a solution of acetonitrile (6.08 mL, 115.4 mmol) in THF (300 mL) at −78° C. and allowed to stir for 30 min at −78° C. 2-Methoxy-6-methyl-nicotinic acid methyl ester (20 g, 105.1 mmol) THE (200 mL) is added and stirred at −78° C. for another 30 min. The reaction mixture is quenched at −78° C. with water (500 mL) and washed with EtOAc (2×250 mL). The aqueous layer is separated and evaporated. This is co-distilled twice with toluene to obtain 3-(2-methoxy-6-methyl-pyridin-3-yl)-3-oxo-propionitrile. Yield=21.4 g (crude). ES/MS m/z 191.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][N:17]=1)=[O:14].[CH2:22]([NH2:26])[CH2:23][CH2:24][CH3:25].C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:22]([NH:26][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)=[O:14])[CH:5]=1)[CH2:23][CH2:24][CH3:25]
Reactant: COc1ccc(C(=O)O)cc1NC(=O)Nc1cnccn1
Reactant: CCCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCCNC(=O)c1ccc(OC)c(NC(=O)Nc2cnccn2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
To a stirred solution of 4-Methoxy-3-(3-pyrazin-2-yl-ureido)-benzoic acid (32 mg; 0.11 mmol) in N-methyl pyrrolidinone (1 mL) was added O-benzotrazol-1-yl-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (HBTU; 45 mg; 0.12 mmol), butyl amine (12 μL; 0.12 mmol), and diisopropylethylamine (35 μL; 0.20 mmol). The reaction was stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (20 mL) and 10% aqueous sodium carbonate (20 mL) and stirred for 5 minutes. A precipitate formed which was filtered and dried under reduced pressure to yield an off white solid (49% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C)C=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:36])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Reactant: CNCc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CN(C)Cc3ccccc3)c2c1=O
Reaction time: 1 h
Yield: 92 %

Procedure:
The compound (1.04 g, 1.8 mmol) obtained in Example 18 was dissolved in dimethylformamide (70 ml). To the solution was added diisopropylaminoethyl(1.15 g, 8.9 mmol) and N-methylbenzylamine (0.54 g, 4.5 mmol) at room temperature, and the mixture was further stirred for one hour. The reaction mixture was concentrated to dryness, and the residue was partitioned between ethyl acetate (300 ml) and water. The aqueous layer was extracted with ethyl acetate (100 ml), the extracts were combined, washed with an aqueous sodium chloride solution, dried with Na2 SO4, and the solvent was distilled off. Thus obtained residue was purified by silica gel column chromatography to give a solid form (1.09 g), and recrystallization from dichloromethane-ether-n-hexane gave pale yellow crystals (1.03 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.ClCCl>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccccc2)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(N)cc(-c2ccccc2)c1
Reaction time: 3 h

Procedure:
Pd/C (10 wt %, 161 mg, 0.151 mmol) was added to a solution of 3-methyl-5-nitrobiphenyl (322 mg, 1.51 mmol) in ethyl acetate (10 mL) and acetic acid (1 mL). The reaction mixture was stirred under an atmosphere of H2 (balloon) for 3 hours and then dichloromethane (5 mL) was added. The reaction mixture was filtered through CELITE, washed with ethyl acetate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) provided 5-methylbiphenyl-3-amine as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=7.6 Hz, 2H), 7.43 (t, J=7.6 Hz, 2H), 7.34 (t, J=7.3 Hz, 1H), 6.85 (s, 1H), 6.75 (s, 1H), 6.55 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]([NH2:13])=O)=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20].O>C(#N)C>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:10]([C:11]#[N:13])=[CH:9][C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1c([N+](=O)[O-])cc(C(N)=O)cc1[N+](=O)[O-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1c([N+](=O)[O-])cc(C#N)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
Phosphorus oxychloride (91.3 kg) is added over about 30 minutes into a mixture of 4-methyl-3,5-dinitrobenzamide (6) (66.6 kg) in acetonitrile (250.2 kg). The mixture is heated at reflux (about 80° C.) for about 2.5 hours. The solution is then cooled to ambient temperature and added to water (335 L) over about 1.5 hour, while maintaining a temperature of less than about 30° C. The mixture is cooled to about 5° C. and held at this temperature for about 18 hours. The product that precipitates is isolated via centrifugation, washed with water (469 L), and dried in a convection tray dryer at about 45° C. for about 22 hours to provide 4-methyl-3,5-dinitrobenzonitrile (4) (59 kg, 96% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][N:12]([C@H:21]([CH2:32][CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CO)[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94.4 %

Procedure:
A solution of 3.20 g (6.3 mmol) of 2-(R)-(3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl) propionic acid, benzyl ester (from Step A) in 40 mL of THF at 0° C. was treated with 10 mL of 1.0 M tetrabutylammonium fluoride solution in THF. The resulting mixture was warmed to rt and stirred for 2.5 h. The reaction mixture was partitioned between 200 mL of ether and 100 mL of 50% sat'd NaHCO3 and the layers were separated. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on 100 g of silica gel using 2:1 v/v hexanes/ether as the eluant afforded 2.34 g (94%) of the title compound: 1H NMR (500 MHz) δ1.56-2.07 (8H), 2.15 (br s, 1H), 2.27-2.37 (2H), 2.64 (t, J=11.0, 1H), 2.80 (dd, J=6.5, 11.0), 3.04-3.11 (2H), 3.23-3.30 (2H), 3.56 (dd, J=7.5, 13.0, 1H), 3.68 (dd, J=5.5, 13.0, 1H), 5.15 (ABq, J=20.0, 2H), 7.17-7.40 (10H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:6]=2[CH:22]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([C:30](=[O:32])[CH3:31])[CH2:18][CH2:17]3)[C:6]=2[CH:22]=1
Reactant: Fc1ccc2c(c1)C(N1CCNCC1)=Nc1ccccc1S2
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C2=Nc3ccccc3Sc3ccc(F)cc32)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
The compound of Formula I where Z is —C(═O)R1 and R1 is methyl was prepared as follows. To a solution of 2-fluoro-11-(piperazin-1-yl)dibenzo[b,f][1,4]thiazepine VI (see Scheme A) (0.05 g, 0.16 mmol) and triethylamine (0.05 mL, 0.32 mmol) in DCM (3 mL) was added acetyl chloride (0.02 mL, 0.32 mmol) dropwise at 0° C. under nitrogen. After stirring the mixture at 0° C. for 1 hour, the solvent was removed under reduced pressure. The reaction mixture was triturated with ether (1×20 mL), the insolubles filtered off and the filtrate concentrated under reduced pressure to give 1-(4-(2-fluorodibenzo[b,f][1,4]thiazepine-11-yl)piperazin-1-yl)ethanone (0.05 g, 80%) as a very pale yellow powder. m/z (ES+) M+1=356.0; HPLC tR=0.64 min. 1H NMR (300 MHz, DMSO-d6): δ 2.03 (s, 3H), 3.35-3.61 (br m, 8H), 6.90 (t, 1H, J=7.8 Hz), 7.01 (d, 1H, J=7.8 Hz), 7.22 (t, 1H, J=7.8 Hz), 7.31-7.40 (br m, 3H), 7.60 (dd, 1H, J=5.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:40]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(Cl)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chlorophenylboronic acid.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: COC(=O)c1ccc2[nH]cc(C=O)c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]cc(C)c2c1
Temperature: 100 °C
Yield: 59.1 %

Procedure:
To a solution of the methyl 3-formyl-1H-indole-5-carboxylate (893 mg, 4.4 mmol) in DMF (20 mL) was added the p-toluenesulfonic acid monohydrate (125 mg, 0.7 mmol) and the p-toluenesulfonyl hydrazide (982 mg, 5.3 mmol). The solution has been heated for 20 min at 100° C. The resulting mixture was diluted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The crude product is dissolved in THF (40 mL) and NaBH3 CN (1.1 g, 17.6 mmol) was added. The solution has been heated for 8 h at 75° C. The resulting mixture was diluted with ethyl acetate, washed with a solution of 0.5 N HCl, a saturated solution of NaHCO3 and brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography (Hexane/AcOEt, from 0 to 30%) to yield a white powder (500 mg, 2.6 mmol, 60%). ESI-MS (m/z): 190 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH2:11][CH2:12][OH:13]>C(O)C.O>[Cl:8][C:6]1[N:7]=[CH:2][N:3]=[C:4]([N:10]([CH3:9])[CH2:11][CH2:12][OH:13])[CH:5]=1
Reactant: CNCCO
Reactant: Clc1ccnc(Cl)n1
Solvent: O
Solvent: CCO
Product: CN(CCO)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 14.8 g (0.1 mmol) 2,4-dichloropyrimidine in 120 ml ethanol and 20 ml water, cooled to 0° C., 11.3 g (0.15 mol) 2-(N-methylamino)ethanol is added. The resulting mixture is stirred at room temperature for ½ h., then concentrated to dryness and finally partitioned between CH2Cl2 and a NaHCO3 saturated solution.
Reaction SMILES: [C:1]1([O:7][CH2:8][CH:9]2[O:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:13]([N:20]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[CH2:10][CH:9]([OH:11])[CH2:8][O:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(OCC2CO2)cc1
Reactant: Oc1ccc(CCNCc2ccccc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Oc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Yield: 88.7 %

Procedure:
A mixture of phenylglycidyl ether (8.0 g), N-benzyltyramine hydrochloride (13.0 g) and triethylamine (7.5 ml) in isopropanol (200 ml) was heated to reflux for 3hours. The solvent was evaporated and toluene was added to the residue. Volatile material was evaporated. The residue was purified by chromatography on K60 silica (300 g) using a gradient mixture of methanol in dichloromethane (1 to 2% methanol). Thus was obtained 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenol (16.5 g) as an oil which slowly crystallised, m.p. 103°-5° C.: NMR: 2.55-2.85[m,6H, CHCH2NHCH2CH2 ]; 3.65-4.05 [m,5H, PhOCH2CHOH +PhCH2 ]; 6.65-7.4[m,14H, aromatic H].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[S:20])[NH2:19]>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:19]=[C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[S:20][CH:2]=1
Reactant: NC(=S)c1ccccn1
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2ccccn2)n1
Yield: 23.3 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (446 mg) and pyridine-2-carbothioamide (157 mg), the title compound (67 mg) was obtained as pale-red powder crystals.
Reaction SMILES: [N:1]1([C:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH:13]3[CH2:16][N:15]([CH2:17][CH2:18][C@@H:19]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:20][N:21]([CH3:35])[C:22](=[O:34])[C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([Br:33])[CH:24]=4)[CH2:14]3)[CH2:9][CH2:8]2)=[O:6])[CH2:4][CH2:3][CH2:2]1.N1CC(N2CCC([C:53](N3CCOCC3)=[O:54])CC2)C1.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[Br:33][C:25]1[CH:24]=[C:23]([CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=1)[C:22]([N:21]([CH2:20][C@H:19]([C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)[CH2:18][CH2:17][N:15]1[CH2:14][CH:13]([N:10]2[CH2:9][CH2:8][CH:7]([C:5]([N:1]3[CH2:4][CH2:3][O:54][CH2:53][CH2:2]3)=[O:6])[CH2:12][CH2:11]2)[CH2:16]1)[CH3:35])=[O:34]
Reactant: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: O=C(C1CCN(C2CNC2)CC1)N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C[C@@H](CCN1CC(N2CCC(C(=O)N3CCOCC3)CC2)C1)c1ccc(F)cc1)C(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
3-Bromo-N-[(2S)-2-(4-fluorophenyl)-4-oxobutyl]-N-methyl-5-(trifluoromethyl)benzamide (see method 1; 0.14 g, 0.31 mmol) and 4-[(1-azetidin-3-ylpiperidin-4-yl)carbonyl]morpholine (see method 5; 0.11 g, 0.42 mmol) were dissolved in methylene chloride (10 mL) together dry methanol (0.2 mL). To the resultant solution were added DIPEA (0.12 g, 0.94 mmol) and sodium triacetoxyborohydride (0.13 g, 0.63 mmol). The mixture was stirred under nitrogen for 4 h at RT. The mixture was diluted with methylene chloride and washed twice with saturated aqueous NaHCO3 and then with brine. The organic phase was filtered through a phase separator and the solvent was removed by evaporation. The product was purified by chromatography on silica gel (methanol-methylene chloride, 10:1). There was obtained 0.11 g (53%) of the title compound as a white foam. 1H NMR (500 MHz, CDCl3): δ 1.4-3.8 (cm, 32H), 6.8-7.4 (cm, 6H), 7.7 (s, 1H); LCMS: m/z 684 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13](=[O:14])[C:12]2[CH:15]=[CH:16][S:17][C:11]=2[N:10]=[C:9]1[CH3:18].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:19][C:16]1[S:17][C:11]2[N:10]=[C:9]([CH3:18])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:13](=[O:14])[C:12]=2[CH:15]=1
Reactant: Cc1nc2sccc2c(=O)n1-c1ccccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1nc2sc(Br)cc2c(=O)n1-c1ccccc1Cl
Yield: 78.2 %

Procedure:
In chloroform was dissolved 22.85 g of 3,4-dihydro-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine, and 19.5 g of N-bromosuccinimide and trace benzoyl peroxide were added to the solution. The mixture was refluxed for 10 hours. After the resulting crystals were removed from the reaction mixture, the solvent was distilled off. The residue was crystallized from hexane-ethyl acetate to give 22.95 g of 3,4-dihydro-6-bromo-3-(2-chlorophenyl)-2-methyl-4-oxothieno[2,3-d]pyrimidine, m.p. 164.5°-166.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]([O:6][C:7]([C:10]2O[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)([CH3:9])[CH3:8])=[C:4]([F:25])[CH:3]=1.Cl.[CH2:27]([NH2:29])[CH3:28]>CO>[Cl:1][C:2]1[CH:23]=[C:22]([F:24])[C:5]([O:6][C:7]([C:10]2[N:29]([CH2:27][CH3:28])[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[CH:16]=3)=[N:12][N:11]=2)([CH3:9])[CH3:8])=[C:4]([F:25])[CH:3]=1
Reactant: CC(C)(Oc1c(F)cc(Cl)cc1F)c1nnc(-c2ccnc(N)c2)o1
Reactant: CCN
Agent: Cl
Solvent: CO
Product: CCn1c(-c2ccnc(N)c2)nnc1C(C)(C)Oc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 2.9 %

Procedure:
Methanol was added to a mixture of 4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-1,3,4-oxadiazol-2-yl}pyridin-2-amine (258 mg) and ethylamine hydrochloride (1.0 g), followed by homogenizing. The solvent was evaporated under reduced pressure, followed by melting at 150° C. for 7 hours. The reaction solution was cooled to room temperature, equivalent amounts of water and saturated brine were added thereto, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol), and the resulting solid was washed with diisopropylether, to obtain, as an ocher solid, 4-{5-[1-(4-chloro-2,6-difluorophenoxy)-1-methylethyl]-4-ethyl-4H-1,2,4-triazol-3-yl}pyridin-2-amine (8.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].S(=O)(=O)(O)O.[CH:19]([NH2:21])=[O:20]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:21]=[CH:19][O:20][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Reactant: NC=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 150 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.60 g, 2.28 mmol) was suspended in formamide (10 mL) then sulfuric acid (1 mL) was added and the tube purged with nitrogen then sealed. The mixture was heated at 150° C. by microwave irradiation for 15 minutes. The resultant solution was diluted with HCl (1 N) and water and extracted with ethyl acetate (×3). The organic phase was dried over sodium sulfate and evaporated then purified by chromatography on a silica II cartridge, eluting with 1:1 DCM:cyclohexane to afford 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as a pale yellow solid (0.197 g). LCMS m/z 210.14 [M+H]+ R. T.=3.64 min (Analytical Method 9).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=O.C=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CCCC)CCCC)CCC>C(=O)(OCC)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH:5]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(=O)OCC
Solvent: CCCCN(CCCC)CCCC
Product: COc1ccccc1C=Cc1ccccc1
Yield: 49 %

Procedure:
The procedure described in Example 1 is followed, except that 17.1 g (0.1 mol) of 2-methoxybenzoyl chloride, 13 g (0.125 mol) of styrene, 23.2 g (0.125 mol) of tri-n-butylamine and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 3 hours at a bath temperature of 140° C., in 100 ml of diethyl carbonate as the solvent, 10.3 g (0.049 mol) of 2-methoxystilbene, corresponding to a yield of 49% of theory, are obtained; melting point 69°-70° C.