Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:30]=[C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])(O)[CH2:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1.C(N(S(F)(F)F)CC)C.C(OCC)(=O)C.O>ClCCl>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]2[N:30]=[C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH2:17][CH2:18][N:13]3[N:12]=2)[CH:6]=[CH:5][C:4]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: COc1nc(/C=C/c2nc3n(n2)CCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Agent: CCN(CC)S(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: COc1nc(/C=C/c2nc3n(n2)CCC=C3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.1 %

Procedure:
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol (56 mg) was dissolved in dichloromethane (2 ml). Diethylaminosulfur trifluoride (45 ul) was added under ice-cooling, and the reaction solution was stirred at room temperature for three hours. Thereafter, diethylaminosulfur trifluoride (45 ul) was added again at room temperature, and the reaction solution was further stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title compound (20 mg). The property values of the compound are as follows.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:14]2=[O:16])[C:5](=[N:17]NC2C=CC=CC=2)[CH2:4][CH2:3]1>O>[CH3:1][CH:2]1[N:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[C:14]2=[O:16])[C:5]2[NH:17][C:8]3[C:9]([C:4]=2[CH2:3]1)=[CH:10][CH:11]=[CH:12][CH:13]=3
Reactant: CC1CCC(=NNc2ccccc2)c2nc3c(c(=O)n21)CCCC3
Solvent: O
Product: CC1Cc2c([nH]c3ccccc23)-c2nc3c(c(=O)n21)CCCC3
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
1 g. of 9-methyl-6-phenylhydrazono-1,2,3,4,6,7,8,9-octahydro-pyrido[2,1-b]quinazoline-11-one is added to 15 g. of polyphosphoric acid heated to 170° C. and the mixture is stirred for 20 minutes at 180° C. After cooling the dark melt is diluted with 50 ml. of water. Greenish-yellow crystals are precipitated, which are filtered and washed with water. After drying the product is recrystallized from ethanol. 0.4 g. of 7-methyl-5-oxo-1,2,3,4,7,8-hexahydro-5H,13H-indolo[2',3';3,4]pyrido-[2,1-b]quinazoline are obtained melting at 232° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:8]=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14](Cl)=[O:15])[CH2:10][CH2:11][CH3:12].O1CCCC1>C(N(CC)CC)C>[CH2:9]([N:13]([CH2:17][CH2:18][CH3:19])[C:14]([N:6]1[CH:7]=[N:8][C:4]([S:3][CH2:1][CH3:2])=[N:5]1)=[O:15])[CH2:10][CH2:11][CH3:12]
Reactant: CCSc1nc[nH]n1
Reactant: CCCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCN(CCC)C(=O)n1cnc(SCC)n1

Procedure:
A mixture of 5.16 g. 3-ethylthio-1,2,4-triazole, 7.8 g. N-n-butyl-N-propylcarbamoyl chloride, 35 ml. dry tetrahydrofuran and 8 ml. dry triethylamine was refluxed under anhydrous conditions for 24 hours. The reaction mixture was worked up as described in Example 1 to give a residual oil. This oil was distilled under reduced pressure to give 1-(N-n-butyl-N-propylcarbamoyl)-3-ethylthio-1,2,4-triazole, b.p. 127° C./0.2 mm. (91.2% 1-isomer by GLC assay). Elemental analysis satisfactory.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][S:29]([C:32]1[S:36][C:35]([C:37](O)=[O:38])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37]([C:35]5[S:36][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:33][CH:34]=5)=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)s1

Procedure:
The title compound, white solid (120 mg, 93%), MS (ISP) m/z=519.3 [(M+H)+], mp 212° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 5-methanesulfonyl-thiophene-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]=[C:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30](=[O:31])[C:29]1[CH:28]=[CH:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][C:21]2=[O:20])=[CH:34][CH:33]=1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc(N2CCCC2=O)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid. MS: 447.5 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:43]#[CH:44])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:43]#[CH:44])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCOCC2)N1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: C#Cc1ccc(OC2CCOCC2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1

Procedure:
In a manner similar to the method described in Example 2, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-Iodo-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (1.3 g, 1.97 mmol) was reacted with trimethylsilyl acetylene (0.4 g, 3.94 mmol), CuI (0.75 g, 3.94 mmol), triethylamine (0.4 mL, 3.94 mmol) and dichlorobis(triphenylphosphine) palladium(0) (0.28 g, 0.39 mmol), then treated with aqueous NaOH solution in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-ethynyl-2-(tetrahydro-pyran-4-yloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off white solid (Yield 0.62 g, 56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]/OCC)=[CH:4][CH:3]=1>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:9](=[O:15])[CH:10]=[CH:11]2
Reactant: CCO/C=C/C(=O)Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37.8 g (0.14 mol) (E)-N-(4-bromo-phenyl)-3-ethoxy-acrylamide are added batchwise to 200 mL concentrated sulphuric acid and stirred for 2 h at RT. Then the reaction mixture is poured into ice water, the precipitate is filtered off and washed with water. The solid is dried at 70° C. in the drying cupboard.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36]C)=[O:35].O.[OH-].[Li+]>CO.O>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([OH:36])=[O:35]
Reactant: COC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCn3c(=O)[nH]c4ccccc43)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.27 g, 0.49 mmol) in methanol (3 mL) was added lithium hydroxide monohydrate (0.041 g, 0.98 mmol) in water (1 mL). After stirring at room temperature for 18 h, the reaction mixture was concentrated in vacuo and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.124 g, 47%); 1H NMR (DMSO-d6): δ 1.68 (d, 2H, J=13.2 Hz), 1.85 (t, 2H, J=6.8 Hz), 2.42 (t, 2H, J=6.8 Hz), 2.59-2.65 (m, 2H), 2.71-2.75 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (s, 2H), 4.90 (s, 2H), 6.74 (t, 1H, J=7.2 Hz), 6.83 (d, 2H, J=8.8 Hz), 6.96 (d, 3H, J=3.6 Hz), 7.18-7.26 (m, 4H), 7.39 (t, 1H, J=8 Hz), 7.55 (t, 1H, J=6.8 Hz), 7.89 (dd, 1H, J=8 and 1.2 Hz), 10.83 (s, 1H), 12.60 (br, 1H); MS for C31H33N5O4 m/z 540.01 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl[CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH2:1]([C:3]1[CH:4]=[C:5]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([O:23][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[C:18]([CH2:24][CH3:25])[CH:17]=3)[N:12]=2)[CH:6]=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cnc1CC
Reactant: OC[C@H](O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CO)c(CC)c3)no2)cnc1CC
Reaction time: 48 h
Yield: 11.5 %

Procedure:
To a solution of 4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenol (100 mg, 0.296 mmol) in isopropanol (10 mL) and 3 N aq. NaOH (3 mL), (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. The mixture is stirred at 60° C. for 24 h before another portion of (S)-3-chloro-1,2-propanediol (98 mg, 0.89 mmol) is added. Stirring is continued at 60° C. for 2 days. The mixture is diluted with EA and washed with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with EA-heptane to give (S)-3-{4-[5-(5,6-diethyl-pyridin-3-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol (14 mg) as a red oil; LC-MS: tR=0.93 min, [M+1]+=412.16.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=[CH:30][C:31]([O:33][CH3:34])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:34][O:33][C:31](=[O:32])[CH:30]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[OH:1]
Reactant: O=Cc1ccc(F)cc1O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1ccc(F)cc1O
Yield: 85.6 %

Procedure:
2-Hydroxy-4-fluoro-benzaldehyde (306 mg, 1.99 mmol) was reacted with methyl (triphenylphosphoranylidene)acetate (681 g, 2.044 mmol) at 110° C. overnight as described above to yield title compound (334 mg, 85%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23]Cl)=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:7][CH2:6]1.[Cl-].[Na+].C(Cl)Cl>CC(CC(C)C)=O>[CH3:4][C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12](=[O:27])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:2]([CH3:3])[CH3:1])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:7][CH2:6]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCCl
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)CC(C)C
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCN(C)C
Temperature: 110 °C

Procedure:
40 ml of a 50% aqueous dimethylamine solution was added to a solution of 2 g of N-(cis-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 106) in 40 ml of methylisobutylketone. The solution was reacted for 18 hours by heating heated to 110° C., in a closed system. After reaction, the reaction solution was added with 200 ml of an aqueous sodium chloride solution and 100 ml of methylene chloride, and subjected to extraction. The aqueous layer was extracted twice with 100 ml of methylene chloride. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 1.6 g of N-(cis-4-methylcyclohexyl)-4-(2-dimethylaminoethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20].[NH2:22][CH2:23][C:24]([CH3:27])([OH:26])[CH3:25].O>CN(C=O)C>[CH3:25][C:24]([OH:26])([CH3:27])[CH2:23][NH:22][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(O)CN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O)CNc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Triethylamine (50.0 mL, 360 mmol) was added to a suspension of 4-chloro-3-nitroquinoline (50.0 g, 240 mmol) in DMF (200 mL), followed by dropwise addition of a solution of 1-amino-2-methyl-propan-2-ol (23.5 g, 264 mmol) in DMF (50 mL). The reaction mixture was stirred overnight at room temperature, then water (500 mL) was added and stirring was continued for 30 minutes. A solid was isolated by filtration, washed with water, and dried to yield 60.9 g of 2-methyl-1-[(3-nitroquinolin-4-yl)amino]propan-2-ol, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([BH3-])#N.[Na+].Cl.C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C:6](=[O:17])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:8][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
16.9 g (71.5 mmol) of tyrosine-tert-butyl ester and 8.33 g (78.6 mmol) of benzaldehyde are stirred in 50 ml of methanol for 3 hours at 24° C. and then mixed with 3.37 g (53.6 mmol) of sodium cyanoborohydride. After 24 hours of stirring at room temperature, the batch is adjusted to pH 2 by careful addition of semiconcentrated hydrochloric acid, then neutralized with concentrated aqueous sodium bicarbonate solution and after substantial evaporation of methanol with ethyl acetate, it is shaken out. The organic phase is dried on anhydrous magnesium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with diethyl ether/hexane/triethylamine; the product-containing fractions are combined and concentrated by evaporation.
Reaction SMILES: C(C1OC2C=CC(C)=CC=2C=1)(=O)C1C=CC=CC=1.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26](/[C:28](/[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1>>[CH3:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26](/[C:28](/[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:24]=2[CH:41]=1
Reactant: CCOC(=O)/C=C(/c1ccccc1)c1cc2cc(C)ccc2o1
Agent: Cc1ccc2oc(C(=O)c3ccccc3)cc2c1
Product: CCOC(=O)/C=C(\c1ccccc1)c1cc2cc(C)ccc2o1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 2-benzoyl-5-methylbenzofuran, a mixture of (Z)-ethyl 3-(5-methyl-2-benzofuranyl)-3-phenylacrylate and (E)-ethyl 3-(5-methyl-2-benzofuranyl)-3-phenylacrylate was obtained as yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][OH:18])[O:10]2)=[CH:5][CH:4]=1.O[C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][O:18][C:25]3[CH:26]=[N:27][C:28]4[C:23]([CH:24]=3)=[CH:22][CH:21]=[CH:20][CH:29]=4)[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC(CNCCCO)CC2
Reactant: Oc1ccc2cccnc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2c(c1)OC(CNCCCOc1cnc3ccccc3c1)CC2
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a solution of 3-(7-methoxy-chroman-2-ylmethyl-amino)-propanol (3.07 g, 13 mmol), 7-hydroxy quinoline (1.88 g, 13 mmol), triphenylphosphine (3.67 g, 14 mmol) in anhydrous tetrahydrofuran (50 mL) was slowly added a solution of diethylazodicarboxylate (2.44 g, 14 mmol) in tetrahydrofuran (10 ml). The reaction was allowed to stir for 3 hours and was then quenched with water, extracted with methylene chloride (150 mL) dried over anhydrous magnesium sulfate, filtered and the solvent removed under vacuum. Chromatography (2.5% MeOH -methylene chloride) afforded 2.72 g of the title compound (55% yield) which was converted to the monohydrate, dimaleate salt in tetrahydrofuran, mp 132°-134° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([O:32]C)=[O:31])=[C:4]([CH3:34])[N:3]=1.ClC1N=C(Cl)C(C(OC)=O)=C(C)[N:37]=1.O.[N-]=[N+]=[N-].[Na+]>CN(C)C=O>[NH2:37][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([O:15][CH2:16][C:17]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:18]=3[F:26])[C:12]([O:27][CH3:28])=[CH:11][C:10]=2[Cl:29])[C:5]([C:30]([OH:32])=[O:31])=[C:4]([CH3:34])[N:3]=1
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Reactant: COC(=O)c1c(C)nc(Cl)nc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c(Nc2nc(N)nc(C)c2C(=O)O)cc1OCc1c(OC)ccc(F)c1F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of methyl 2-chloro-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.42 g), which was prepared in a similar manner to that described in Example 380 using methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate instead of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate, in N,N-dimethylformamide (12 mL) were added water (2 mL) and sodium azide (0.26 g), and the mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (12 mL), methanol (12 mL) and 10% platinum-carbon powder (0.1 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. To the mixture were added tetrahydrofuran (12 mL) and 2 mol/L aqueous sodium hydroxide solution (12 mL), and the resulting mixture was stirred at 60° C. for 2 hours. The insoluble material was removed by filtration, and the filtrate was acidified by adding 1 mol/L hydrochloric acid. The precipitated crystals were collected by filtration. The crystals were washed with water, and dried under reduced pressure to give 2-amino-4-[2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.35 g). To this material were added 1,4-dioxane (30 mL), tetrahydrofuran (10 mL), triethylamine (3 mL) and diphenylphosphoryl azide (0.38 mL), and the reaction vessel was equipped with a reflux condenser, and the mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (0.2 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([Mg]Cl)=[CH:12][CH:11]=1)=[CH2:9].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O1CCCC1>[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:11]=1)=[CH2:9]
Reactant: Brc1ccccc1
Reactant: C=Cc1ccc([Mg]Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2ccccc2)cc1

Procedure:
A 100-ml four-necked flask was equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 0.0674 g (0.3 mmol) of palladium (II) acetate and 6 ml of tetrahydrofuran were weighed in the flask, followed by stirring. Further, 0.347 g (0.6 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 19° C. for 30 minutes. 4.710 g (30 mmol) of bromobenzene was added, followed by stirring at 19° C. for 30 minutes. 40 ml (50 mmol) of 1.25M tetrahydrofuran solution of 4-vinylphenylmagnesium chloride was added dropwise at 19° C. over a period of 2 hours, followed by stirring at 30° C. for 2 hours. After the completion of the reaction, 10 ml of saturated aqueous ammonium chloride solution was added, followed by separation. The organic phase was purified by column chromatography to afford 4.434 g of 4-vinylbiphenyl (yield: 82 mol % based on bromobenzene). The identification of the product was made by mass spectroscopy.