Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([N:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(-c2c[nH]c3ncc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cc23)cnn1Cc1cccc(F)c1
Yield: 51 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (250 mg, 0.346 mmol) was hydrolyzed by lithium hydroxide (72.8 mg, 1.734 mmol), THF/Methanol/water (2/3/1 ml) to yield 100 mg (52% yield) of the titled compound. 1H NMR (CDCl3, 400 MHz): δ 9.28 (S, 1H), 8.54 (s, 1H), 8.01 (s, 1H), 7.59-7.52 (m, 3H), 7.34-7.27 (m, 2H), 7.05-6.94 (m, 4H), 5.32 (s, 2H), 3.61-3.60 (m, 4H), 3.19 (s, 4H), 2.40 (s, 3H), 1.49 (s, 9H). MS: m/z=657.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1.[CH3:19][Mg]Br.[Cl-].[NH4+]>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:17])[CH3:19])=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)CCc1ccc(-c2ccccc2Cl)cc1
Temperature: -70 °C

Procedure:
A solution of β-(2'-chloro-4-biphenylyl)propionyl chloride (28 g.) in anhydrous ether 1 l. is cooled to -70°C. To it is added dropwise a solution of 3M methylmagnesium bromide in ether (34 ml.). The reaction is stirred vigorously throughout. When addition of the grignard is complete (approx. 1 hr), the mixture is allowed to come to room temperature and is decomposed by adding carefully a saturated ammonium chloride solution (approx. 500 ml). The ether phase is washed with brine, dried over sodium sulfate, evaporated in vacuo and the residue distilled to yield 4-(2'-chloro-4-biphenylyl)butan-2-one.
Reaction SMILES: O.[C:2]([C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[OH:22])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23](O)[CH3:24]>>[C:2]([C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][C:13]([C:14]([O:16][CH2:23][CH3:24])=[O:15])=[CH:12][C:11]=1[OH:22])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Reactant: CCO
Solvent: O
Product: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of 4-benzoyl-3-hydroxy-5-nitrobenzoic acid, monohydrate prepared as described in Example 1, step A, (100 g) in dry ethanol (2 liter) is evaporated in vacuo in order to remove the water of crystallization. The residue is redissolved in dry ethanol (2 liter), conc. sulfuric acid (45 ml) is added and the solution is refluxed for 20 hours. The excess of ethanol is removed in vacuo, and the residue is triturated with a saturated sodium hyrogen carbonate solution (about 900 ml). The resulting material is collected by filtration and washed with water. After drying and recrystallization from aqueous ethanol, ethyl 4-benzoyl-3-hydroxy-5-nitrobenzoate is obtained with a melting point of 167°-168° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1.S(Cl)(Cl)=O.[CH:32]1([CH2:35]O)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:35][CH:32]2[CH2:34][CH2:33]2)=[O:26])=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(C(=O)O)cc1
Reactant: OCC1CC1
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(C(=O)OCC2CC2)cc1
Temperature: 50 °C
Reaction time: 96 h

Procedure:
2.0 g of (+/−)-cis-8,9-dimethoxy-6-(4-carboxyphenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine are suspended in 12.0 ml of cyclopropylmethanol, admixed with 1.0 ml of thionyl chloride and stirred at 50° C. for 4 days. The solution is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and dilute sodium bicarbonate solution. The organic phase is dried with sodium sulfate and concentrated. The residue is recrystallized from ethyl acetate. This gives 1.33 g (63.7% of Th.) of the title compound of m.p.: 147-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]3[C:13](=[O:14])[N:12]=[CH:11][C:10]([C:15]([OH:17])=O)=[C:8]3[S:9][C:5]=2[CH:4]=1.O.[NH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1>CN(C)C=O>[NH:23]1[C:22]([NH:21][C:15]([C:10]2[CH:11]=[N:12][C:13](=[O:14])[N:7]3[C:6]4[CH:18]=[CH:19][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[S:9][C:8]=23)=[O:17])=[N:26][N:25]=[N:24]1
Reactant: COc1ccc2c(c1)sc1c(C(=O)O)cnc(=O)n12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)sc1c(C(=O)Nc3nnn[nH]3)cnc(=O)n12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.52 g. 7-Methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxylic acid (prepared according to Example 1) in 150 ml. dimethylformamide are mixed with 7.14 g. N,N'-carbonyldiimidazole. The reaction mixture is subsequently stirred for 90 minutes at 100° C. and for 1 hour at ambient temperature, then mixed with 2.26 g. 5-aminotetrazole monohydrate and again heated for 3 hours at 100° C. The solvent is substantially removed in vacuo and the residue stirred with water. The precipitate consists of 5.2 g. N-(5-tetrazolyl)-7-methoxy-1-oxo-1H-pyrimido[6,1-b]benzthiazole-4-carboxamide (75.7% of theory); m.p. 234°-235° C. (recrystallized from nitromethane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 12 h
Yield: 42.5 %

Procedure:
To a stirring solution of 4-methyl-2-aminopyridine (50 g, 460 mmol) in acetic acid (1 L) was added phthalic anhydride (68 g, 460 mmol) and the reaction was heated to reflux. After 12 h, acetic anhydride (43 mL, 460 mmol) was added and the solution continued to stir at reflux for an additional 48 h. The solvent was then removed in vacuo and the solid residue was suspended in toluene and concentrated in vacuo twice. The solid was then suspended in ethyl acetate with vigorous stirring and filtered. After repeating this ethyl acetate washing procedure the solid was dried overnight in vacuo to give 46.6 g (42%) of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[CH3:27][N:28]1[C:32](=[O:33])[NH:31][N:30]=[N:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OC)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:31]1[C:32](=[O:33])[N:28]([CH3:27])[N:29]=[N:30]1
Reactant: Cn1nn[nH]c1=O
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: Cn1nnn(Cc2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2Br)c1=O
Yield: 32.2 %

Procedure:
A solution of 3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.3 g), 1-methyl-1,4-dihydro-5H-tetrazol-5-one (0.06 g) and potassium carbonate (0.16 g) in N,N-dimethylformamide (10 mL) was stirred for 3 hours at room temperature. After the reaction mixture was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was then purified by silica gel chromatography to yield 1-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-4-methyl-1,4-dihydro-5H-tetrazol-5-one (0.1 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([Cl:13])[C:4]=1[CH2:5][NH2:6].C[Al](C)C.[CH:18]1([CH:24]2[CH2:28][CH2:27][O:26][C:25]2=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1>[CH:18]1([CH:24]([CH2:28][CH2:27][OH:26])[C:25]([NH:6][CH2:5][C:4]2[C:3]([Cl:2])=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=2[Cl:13])=[O:29])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OCCC1C1CCCCC1
Reactant: COc1cc(Cl)c(CN)c(Cl)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1cc(Cl)c(CNC(=O)C(CCO)C2CCCCC2)c(Cl)c1
Yield: 80.5 %

Procedure:
Treat a mixture of 2,6-dichloro-4-methoxy-benzylamine hydrochloride (4.0 g, 16.6 mmol) and toluene (100 mL) with trimethylaluminum (2 M in toluene, 16.6 mL, 33.2 mmol) at room temperature for 10 minutes. To the mixture, add a solution of 3-cyclohexyl-dihydro-furan-2-one (2.51 g, 14.94 mmol) in toluene (50 mL). Stir the reaction at reflux for 6 hours. Cool the reaction and quench with HCl (1 N, 50 mL). Partition the mixture with ethyl acetate and HCl (1 N). Separate the organic layer and wash with water and brine. After drying the organic layer over sodium sulfate and filtration, concentrate the filtrate to afford 4.5 g (81%) of the title compound as white solid. MS (m/z): 374 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CN(C=O)C.O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2=[O:1])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (7.50 g, 26.8 mmol) was dissolved in DMF (30 ml) and treated with potassium carbonate (7.40 g, 53.5 mmol) and 4-methoxybenzyl chloride (5.45 ml, 40.1 mmol). The mixture was stirred at ambient temperature overnight. The reaction was diluted with water (150 ml) and the solid that crashed out was collected by suction filtration. The solid was washed with water and dried to give diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (9.00 g, 84.0% yield) as a light green solid. MS(M+H)+ 401.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[NH2:11].NC1C=C(F)C=CC=1C(O)=[O:17].CCN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:12])[O:2][C:1](=[O:17])[NH:11][C:5]=2[CH:6]=1
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
2-Amino-4-fluorobenzoic acid methyl ester. 2-Amino-4-fluorobenzoic acid (5.0 g, 32 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. Hünig's base (11 ml, 64 mmol) was added followed by triphosgene (3.8 g, 13 mmol). The reaction mixture was stirred for 5 min then allowed to warm to ambient temperature over 45 min. Water was added to the mixture, which was then extracted with DCM (3×), and the combined organic layers were dried (MgSO4). Filtration and concentration provided 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione as a tan solid (3.94 g, 21.8 mmol, 68%), which was taken on directly to the next step. To a solution of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.94 g, 21.8 mmol) in DMF (20 mL) was added dry methanol (8.8 mL, 220 mmol) and DMAP (0.27 g, 2.2 mmol). The mixture was allowed to stand overnight, and was then partitioned between EtOAc and water. The organic layer was washed with water (3×) and dried (MgSO4). Filtration and purification on silica gel (MPLC, hexanes/EtOAc) provided the title methyl ester as a white solid (1.89 g, 11.1 mmol, 51%). HPLC (reversed-phase): RT=8.66 min). 1H NMR (400 MHz, CDCl3): 7.87 (m, 1H), 6.37 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.Cl.[NH2:35][CH2:36][C:37]1[NH:38][C:39]([C:45]2[CH:54]=[CH:53][CH:52]=[C:51]3[C:46]=2[N:47]=[C:48]([NH:56][CH2:57][C:58]([F:61])([F:60])[F:59])[C:49]([CH3:55])=[N:50]3)=[CH:40][C:41]=1[C:42]([OH:44])=O.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:55][C:49]1[C:48]([NH:56][CH2:57][C:58]([F:61])([F:60])[F:59])=[N:47][C:46]2[C:51](=[CH:52][CH:53]=[CH:54][C:45]=2[C:39]2[NH:38][C:37]3[CH2:36][NH:35][C:42](=[O:44])[C:41]=3[CH:40]=2)[N:50]=1
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(CN)[nH]3)c2nc1NCC(F)(F)F
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CNC4=O)c2nc1NCC(F)(F)F
Yield: 21.3 %

Procedure:
Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (AK Scientific, Inc., Union City, Calif.) (415 mg, 0.80 mmol) was added to a solution of 2-(aminomethyl)-5-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (301c) (255 mg, 0.61 mmol) and DIPEA (Sigma-Aldrich) (0.43 mL, 2.45 mmol) in CH2Cl2 (15 mL) and DMF (15 mL) at RT. After 30 min the reaction mixture was concentrated. EtOAc and H2O were added and the layers were separated. The aq. layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-5% MeOH in CH2Cl2), to provide a yellow solid. The combined fractions were triturated with CH2Cl2 and the solid was collected by filtration and washed with CH2Cl2 and Et2O to provide 2-(2-methyl-3-((2,2,2-trifluoroethyl)amino)quinoxalin-5-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (301) (48 mg, 0.13 mmol, 22% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (br. s., 1H), 7.89 (d, J=7.04 Hz, 1H), 7.74 (t, J=6.55 Hz, 1H), 7.67 (d, J=8.22 Hz, 1H), 7.52 (br. s., 1H), 7.39-7.47 (m, 1H), 6.97 (s, 1H), 4.33-4.46 (m, 2H), 4.25 (br. s., 2H), 2.59 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ ppm −69.44 (s, 3F). m/z (ESI, +ve) 362.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:8][CH2:7][NH:6]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[S:32][CH:33]=[C:34]([C:36](O)=[O:37])[N:35]=2)[CH:26]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH3:2][O:3][CH2:4][CH:5]1[CH2:10][N:9]([C:11](=[O:24])[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH2:8][CH2:7][N:6]1[C:36]([C:34]1[N:35]=[C:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)[S:32][CH:33]=1)=[O:37]
Reactant: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)c1csc(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxymethyl-4-(3,4,5trimethoxybenzoyl)piperazine hydrochloride obtained in Reference Example 6 (0.52 g), 2-(3-pyridyl)thiazol-4-carboxylic acid (0.3 g), triethylamine (0.46 g) and N,N-dimethylformamide (3 ml) is added dropwise, while stirring under icecooling, diethyl cyanophosphonate (0.47 g). The reaction mixture is stirred at 0° C. for one hour, and then poured into ice-water, followed by extraction with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:AcOEt-CH2Cl2 --CH3OH=10:9:1) to give 2-methoxymethyl-1-[2-(3-pyridyl) thiazol-4-ylcarbonyl]-4-(3,4,5-trimethoxybenzoyl) piperazine. Recrystallization from ethanol gives colorless needles m.p. 149-150° C.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[S:4].[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:16][CH2:17][C:11]=2[C:10]=1[OH:26])#[N:8].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.O1CCOCC1.CCOC(C)=O>[C:7]([C:9]1[CH:25]=[CH:24][C:12]2[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:16][CH2:17][C:11]=2[C:10]=1[O:26][C:3](=[S:4])[N:2]([CH3:6])[CH3:1])#[N:8]
Reactant: N#Cc1ccc2c(c1O)CCN(C(=O)C(F)(F)F)CC2
Reactant: CN(C)C(=S)Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)C(=S)Oc1c(C#N)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 120 °C
Reaction time: 48 h
Yield: 80.3 %

Procedure:
Add dimethylthiocarbamoyl chloride (197 mg, 1.58 mmol) to a stirred solution of 7-cyano-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.53 mmol), DMAP (6 mg, 0.05 mmol) and dry triethylamine (300 μL) in dry 1,4-dioxane (5 mL) under an atmosphere of nitrogen and heat at 120° C. for 6 h. Cool and continue stirring for 2 days at ambient temperature. Dilute with EtOAc, wash with 1N aqueous HCl, water, saturated aqueous Na2CO3 and brine. Dry over MgSO4 then concentrate in vacuo. Purify by chromatography on silica gel eluting with EtOAc:heptane (0:1 to 3:10) to give the desired intermediate as a white solid (158 mg, 81%).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([C:13]1[C:19](=[O:20])C(Cl)=C(Cl)C(=O)C=1C#N)#N.O.[O-2].[O-2].[O-2].[O:29]=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(O)CO>[C:1]([O:29][CH2:13][CH2:19][OH:20])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[Si]=O
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: OCCO
Product: O=C(C=Cc1ccccc1)OCCO
Yield: 88 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), ethylene glycol (10 mL) is taken in a round bottom flask and catalytic amount of AMBERLYST® 15 (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. 2-Hydroxyethyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C2H5O) is isolated in 88% yield. 1H-NMR (CDCl3, 300 MHz) δ7.65 (1H, d, J=16.55 Hz), 7.42 (2H, m), 7.29 (3H, m), 6.38 (1H, d, J=16.55 Hz), 4.37 (2H, t), 3.66 (2H, t); 13C-NMR (CDCl3, 75.4 MHz) δ166.4, 145.6, 134.2, 130.5, 128.9, 128.2, 117.3, 64.1, 41.8.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[C:15]([Si:17]([CH3:20])([CH3:19])[CH3:18])#[CH:16].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[CH3:18][Si:17]([C:15]#[C:16][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1)([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of tert-butyl (5-bromo-1,3-thiazol-2-yl)carbamate (2.79 g, 10 mmol), ethynyltrimethylsilane (1.27 g, 13 mmol), Pd(PPh3)4 (578 mg, 0.5 mmol), CuI (143 mg, 0.75 mmol), and diisopropylethylamine (1.94 g, 15 mmol) in DMF (10 mL) was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20% EtOAc/hexanes) to give a yellow solid (2.55 g, 86%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1.C(Cl)(=[O:19])C.[Cl-].[Al+3].[Cl-].[Cl-].C(C[C:29]([CH3:32])(C)C)(C)C>>[CH3:14][C:5]1([CH3:15])[C:6]2[C:11](=[CH:10][C:9]([CH2:29][CH3:32])=[C:8]([C:12](=[O:19])[CH3:13])[CH:7]=2)[C:2]([CH3:16])([CH3:1])[CH2:3][CH2:4]1.[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([CH2:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([CH3:15])([CH3:14])[CH2:4][CH2:3]1
Reactant: CC(C)CC(C)(C)C
Reactant: CC(=O)Cl
Agent: CCc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1cc2c(cc1C(C)=O)C(C)(C)CCC2(C)C
Yield: 89 %

Procedure:
A solution of 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (528 grams) and acetyl chloride (234 grams) is added over a 31/2 hour period at 70° C. to a well-stirred slurry of aluminum chloride (534 grams), 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene (1200 grams) and isooctane (432 grams). The reaction is worked up as in Example I to afford 689 grams of 1,1,4,4-tetramethyl-6-ethyl-7-acetyl-1,2,3,4-tetrahydronaphthalene (89% based on consumed 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene) and 1106 grams of recovered 1,1,4,4-tetramethyl-6-ethyl-1,2,3,4-tetrahydronaphthalene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.C[O-].[Na+].[H][H]>CO>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Reactant: [H][H]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)OCC2CC(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (5.9 mg) and (S,S)-Et-FerroTANE (5.5 mg) was added methanol (2.5 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature for 15 min. This was added to a mixture of (6-methoxy-1-benzofuran-3-yl)acetic acid (51.5 mg) and sodium methoxide (7 mg), and the mixture was stirred at room temperature for 5 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 86.2%, and the yield was 88.4%.