Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2].Cl[C:36]([O:38][CH3:39])=[O:37]>>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:36]([O:38][CH3:39])=[O:37])[CH:7]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CNCc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(Cc2ccccc2)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-(benzylamino-methyl)-4-trifluoromethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[CH2:17]([NH:20][CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19].[CH2:24]=O>>[CH2:17]([N:20]([CH2:24][CH:13]([C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]#[N:15])[CH2:21][CH2:22][CH3:23])[CH2:18][CH3:19]
Reactant: C=O
Reactant: COc1cc(CC#N)cc(OC)c1OC
Reactant: CCCNCCC
Agent: Cl
Product: CCCN(CCC)CC(C#N)c1cc(OC)c(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 11 react 3,4,5-trimethoxybenzeneacetonitrile with dipropylamine hydrochloride and paraformaldehyde to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[NH:23])[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:5]=1.[O-]Cl.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:23]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:24]
Reactant: COC(=O)c1ccc(OC)c(NC(=N)c2ccc([N+](=O)[O-])cc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc12
Temperature: 25 °C
Yield: 46.1 %

Procedure:
3-[(4-nitro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (1.63 g, 4.95 mmol) was dissolved in 50% methanol, and 5% NaOCl was added dropwise thereto at room temperature. After checking the reaction by TLC, Na2CO3 (1.05 g, 9.38 mmol) seas added dropwise thereto and refluxed for 40 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate and the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (0.75 g, 2.28 mmol) in a yield of 46%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][P:31]([O:41]CC1C=CC=CC=1)([O:33]CC1C=CC=CC=1)=[O:32])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:3])[CH3:2]>[OH-].[OH-].[Pd+2].CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C@H:10]([NH:14][C:15]([NH:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=1[CH:20]=[N:21][N:22]3[C:27]([O:29][CH2:30][P:31](=[O:32])([OH:41])[OH:33])=[O:28])=[O:16])[CH2:9][CH2:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCP(=O)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc2c(c1)CC[C@H]2NC(=O)Nc1cccc2c1cnn2C(=O)OCP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
1.5 g (2.25 mmol) of the compound from Example 21C was added to a mixture of 0.3 g 20% Pd(OH)2/C and 150 mL methanol in a stainless steel autoclave. The reactor was sealed and flushed with nitrogen, and then it was pressurized with hydrogen (60 psi). The mixture was stirred at ambient temperature for 90 minutes. Product precipitated, added 150 mL tetrahydrofuran to redissolve, catalyst was filtered off, washed with methanol and tetrahydrofuran, and the filtrate was concentrated to provide 1.08 g (99%) of the title compound. MS (ESI) m/z: 485.21 [M−H]− 1H NMR (DMSO-d6) δ: 1.28 (s, 9H), 1.81-1.88 (m, 1H), 2.42-2.48 (m, 1H), 2.79-2.87 (m, 1H), 2.91-3.01 (m, 1H), 4.56 (d, 2H), 5.16 (q, 1H), 6.69 (d, 1H), 7.27 (s, 2H), 7.31 (s, 1H), 7.50 (t, 1H), 7.72 (d, 1H), 7.89 (d, 1H), 8.43 (s, 1H), 8.85 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21]C)([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26]C)([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[N+](C1C=CC([Cl:38])=CC=1N=NC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)([O-])=O>>[Cl:38][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:11]([C:12]3[CH:17]=[C:16]([C:18]([CH3:21])([CH3:19])[CH3:20])[CH:15]=[C:14]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:13]=3[OH:28])[N:10]=[C:5]2[CH:6]=1
Reactant: CC(C)(C)c1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 68.2 %

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene was replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3',5'-di-tert-butylazobenzene, the above noted product was obtained in a yield of 68.2%.
Reaction SMILES: [C:1]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].Cl[CH2:23][C:24]1[S:28][CH:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[C:12]([O:11][C:9]([N:8]([CH2:23][C:24]1[S:28][CH:27]=[C:26]([C:29]([O:31][CH3:32])=[O:30])[CH:25]=1)[C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)c1csc(CCl)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
To a solution of 3.69 g of di-tert-butyl imidodicarbonate in 54 ml of DMF was added 1.91 g of potassium tert-butoxide at 0° C. under argon, followed by stirring at room temperature for 1 hour. A solution of 2.7 g of methyl 5-(chloromethyl)thiophene-3-carboxylate in 8.1 ml of DMF was slowly added thereto, followed by stirring at room temperature overnight. Water and ethyl acetate were added to the reaction solution, followed by carrying out an extraction operation, and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain 4.394 g of methyl 5-{[bis(tert-butoxycarbonyl)amino]methyl}thiophene-3-carboxylate.
Reaction SMILES: [C:1]([O:11][CH2:12][CH3:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:14]([N:21]([CH2:25][Si](C)(C)C)[CH2:22]OC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([O:11][C:1]([CH:2]1[CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25][N:21]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:22]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccccc1

Procedure:
103.1 In analogy to example 101.1 ethyl cinnamate and N-benzyl-N-(methoxymethyl)tri-methylsilylmethylamine (CAS 93102-05-7) were reacted to give (3RS,4SR)-1-benzyl-4-phenyl-pyrrolidine-3-carboxylic acid ethyl ester. Light yellow liquid. MS 310.1 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(F)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(F)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Ethyl 5-fluorosalicylate (191 mg), 4-chloro-6,7-dimethoxyquinoline (125 mg), and 4-dimethylaminopyridine (205 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (64 mg, yield 22%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[CH:16]([C:19]1([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[N:28]=[CH:27][CH:26]=[CH:25]3)[CH2:21][CH2:20]1)[CH:17]=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:16]([C:19]4([C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[N:28]=[CH:27][CH:26]=[CH:25]6)[CH2:21][CH2:20]4)=[CH:17][N:14]=3)[N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1ncc(-c2ccc(Br)cc2)nn1
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Product: Brc1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1

Procedure:
This compound was prepared from the condensation of 6-(4-bromophenyl)-1,2,4-triazin-3-amine and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde using a procedure analogous to that described for the synthesis of Example 7, Step 8. LCMS: (M+H)=442.3/444.2.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[Br:6][C:7]1[C:8]([O:18][CH3:19])=[C:9]([C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]>C(Cl)(Cl)Cl>[Br:6][C:7]1[C:8]([O:18][CH3:19])=[C:9]([C:13]([O:16][CH3:17])=[C:14]([Cl:4])[CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(Br)c(OC)c1C(=O)O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1c(Cl)cc(Br)c(OC)c1C(=O)O
Temperature: 25 °C

Procedure:
A solution of 40 ml (0.5 mol) of sulphuryl chloride in 100 ml of chloroform is added dropwise to a solution of 26.1 g (0.1 mol) of 3-bromo-2,6-dimethoxybenzoic acid in 150 ml of chloroform. After a night at room temperature the solution is refluxed for 45 minutes. The solvent is evaporated and the residue recrystallized from isopropyl ether - light petroleum. Yield: 23.5 g, m.p. 98.5°-100° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([O-:8])=[O:7])(=[O:3])[CH3:2].[K+].[C:10](=[O:17])([S:14][CH2:15][CH3:16])[O:11][CH2:12]I>>[C:10](=[O:17])([S:14][CH2:15][CH3:16])[O:11][CH2:12][O:7][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CCSC(=O)OCI
Reactant: CC(=O)NCC(=O)[O-]
Agent: [K+]
Product: CCSC(=O)OCOC(=O)CNC(C)=O
Reaction time: 48 h

Procedure:
Finely powdered potassium N-acetylglycinate (5.8 g, 37 mmol) and TBA I (1.2 g, 3.4 mmol) are thoroughly mixed and shaken for 5 min with 5b (8.3 g, 34 mmol). The mixture is left for 48 h at room temperature and then extracted with Et2O (4×40 mL). The combined extracts are filtered and evaporated. The residue (6.4 g) is thoroughly extracted with pentane (4×25 mL) to remove unreacted 5b. The residue is freed from remaining traces of pentane by evaporation leaving 3.7 g of 6tb (46%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].C(=[O:10])CC(C)C.N1CCC[C@H]1C(O)=O.[CH:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>>[OH:23][C@@H:19]([CH:2]([CH3:3])[CH3:1])[C@H:20]([CH3:22])[CH:21]=[O:10]
Reactant: CC(C)C=O
Reactant: CCC=O
Reactant: CC(C)CC=O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(C)[C@H](O)[C@H](C)C=O
Yield: 82 %

Procedure:
Entry 2, representing the addition of propionaldehyde to isovaleraldehyde, indicates that the reaction product was obtained in 88% yield and 97% ee. This indicates that the method of the invention is able to provide a single regioisomer despite the fact that both the aldol donor and accept bear enolizable α-methylene protons. Entries 5-7, corresponding to Examples 5-7, indicate that the aldol reaction can tolerate a range of structural variation in the aldehyde donor (R1=Me, n-Bu, Bn, 19:1 to 24:1 anti:syn, 91 to >99% ee). In contrast to proline mediated ketone additions, lower catalyst loadings (10 mol %) and shorter reaction times (11 to 26 hours) were possible without loss in reaction efficiency (Hajos et al. (1974) Org. Chem. 39:1615; Eder et al. (1971) Angew. Chem. 10:496; Agami et al. (1987) Bull. Chim. Soc. Fr. 2:358). Entry 5 also illustrates the preparative utility of the reaction, insofar as the addition of propionaldehyde to isobutyraldehyde was performed on a 25 mmol scale to afford 2.65 g (82% yield) of (2S,3S)-3-hydroxy-2,4-dimethylpentanal in >99% ee with 24:1 antidiastereoselectivity.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[N:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][N:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]cc(-c2ccccc2)nc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1nc(-c2ccccc2)cnc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-5-phenylpyrazin-2(1H)-one (0.16 g), silver carbonate (0.18 g), benzyl bromide (0.080 mL) and toluene (6.0 mL) was heated under reflux for 3 hr. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:7]=1
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 31.2 %

Procedure:
1-(5-Chloro-2-hydroxyphenyl)ethanone (20 mg, 0.117 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.5 mg, 0.117 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (16 mg) as a solid. 1H NMR (400 MHz, CD3OD): δ 8.26 (m, 1H), 8.17 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.72 (t, 1H, J=8.0 Hz), 7.48 (d, 1H, J=2.0 Hz), 7.22 (m, 1H), 6.91 (d, 1H, J=8.8 Hz), 3.72 (m, 4H), 3.01 (m, 4H), 2.43 (s, 3H). ESI-MS: 438.1 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[S:15][C:8]2[C:9](=[O:14])[NH:10][CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1)=O.O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[Cl:1][CH2:2][CH2:3][C:5]1[S:15][C:8]2[C:9](=[O:14])[NH:10][CH2:11][CH2:12][CH2:13][C:7]=2[CH:6]=1
Reactant: O=C(CCl)c1cc2c(s1)C(=O)NCCC2
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCCc2cc(CCCl)sc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 47.5 %

Procedure:
A mixture of 1.9 g of 2-chloroacetyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one in 5.4 ml of triethylsilane and 15 ml of trifluoroacetic acid was stirred at 50° C. for 12 hours. The mixture was poured into water, alkali fled and extracted with ethyl acetate. The exract was washed with water, dried and concentrated. The residue was purified by column chromatography on a silica gel to give 0.85 g of 2-chloroethyl-4,5,6,7-tetrahydro-8H-thieno[2,3-c]azepin-8-one as white crystals, m.p. 156°-158° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>C(OCC)(=O)C>[N+:8]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(COc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 15.5 h
Yield: 90.6 %

Procedure:
A mixture of phenol (11.3 g), 4-nitrobenzyl bromide (25.9 g), potassium carbonate (16.6 g) and methyl ethyl ketone (100 ml) was stirred for 15.5 hours at 80° C. Ethyl acetate was added thereto, the insoluble material was removed by filtration, the solvent was evaporated in vacuo, and the resulting residue was recrystallized from hexane-ethyl acetate to provide the title compound (pale yellow powder) (24.9 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:12][NH2:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[C:14](=S)=[S:15].C(N(CC)CC)C.Cl>C(O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[O:11][C:14]([SH:15])=[N:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NNC(=O)c1ccc2[nH]ncc2c1
Reactant: S=C=S
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: Sc1nnc(-c2ccc3[nH]ncc3c2)o1
Yield: 96.6 %

Procedure:
A suspension of 1H-indazole-5-carbohydrazide (4.40 g, 25.0 mmol), carbon disulfide (3.76 mL, 62.5 mmol) and triethylamine (4.18 mL, 30.0 mmol) in ethanol (100 mL) was heated under reflux for 7 hr. After cooling, the reaction mixture was poured into water, and acidified with 1M hydrochloric acid. The precipitate was collected by filtration, dried and recrystallized from tetrahydrofuran to give the title compound (5.27 g, yield 97%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:34])([CH3:33])[CH2:22][O:23]/[CH:24]=[CH:25]/[C:26](=[CH2:32])[O:27][Si](C)(C)C.[OH-].[Na+]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:24]([O:23][CH2:22][C:21]([CH3:34])([CH3:33])[CH3:20])[CH2:25][C:26](=[O:27])[CH2:32][CH:12]3[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: C=C(/C=C/OCC(C)(C)C)O[Si](C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)COC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (0.50 g, 1.72 mmol) and [(E)-3-(2,2-Dimethylpropoxy)-1-methyleneallyloxy]trimethylsilane (1.1 g, 5.5 mmole) in a sealed tube was heated to 150° C. for 1.5 hrs. The reaction mixture was diluted with MeOH (10 mL) and treated with 2.0 mL of 4 N NaOH at rt for 1 h. The mixture was then diluted with AcOEt and washed with Sat NH4Cl, brine, dried over Na2SO4. After concentration the residue was purified by flash column (2%-25% AcOEt in Hex) to give rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(2,2-dimethylpropoxy)-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (310.4 mg, 43.1%) and rac-(1R,2S)-6′-chloro-2-(3-chlorophenyl)spiro[5-cyclohexene-1,3′-[3H]indole]-2′,4(1′H)-dione (201.2 mg, 32.3%).
Reaction SMILES: CO.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:9]=[C:10]([C:13](OCC)=[O:14])[S:11][CH:12]=1.[BH4-].[Na+].Cl>O1CCCC1.O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[N:9]=[C:10]([CH2:13][OH:14])[S:11][CH:12]=1
Reactant: CCOC(=O)c1nc(-c2cccs2)cs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OCc1nc(-c2cccs2)cs1
Yield: 82.1 %

Procedure:
Methanol (1.5 ml) in tetrahydrofuran (2 ml) was added dropwise to a stirred and refluxed mixture of ethyl 4-(2-thienyl)-2-thiazolecarboxylate (1.36 g), sodium borohydride (0.35 g) and tetrahydrofuran (15 ml). After refluxing for 1 h, the reaction mixture was poured into water, acidified with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated to give 4-(2-thienyl)-2-thiazolylmethanol (0.92 g, 82%). Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 113-114° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>C(OCC)(=O)C>[CH:21]([O:20][C:18]([NH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8])=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1sccc1N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NC(=O)OC(C)C
Temperature: 60 °C
Yield: 89.2 %

Procedure:
22.1 g (0.141 mol) of methyl 3-aminothiophene-2-carboxylate was dissolved in 100 ml of ethyl acetate, and to this was added 11.7 g (0.148 mol) of pyridine. 18.1 g (0.148 mol) of isopropyl chloroformate was added dropwise while cooling with ice over 30 minutes. After completion of the addition, the solution was heated to 60° C. and stirred with heating for 3 hours. After completion of the reaction, the reaction solution was washed sequentially with a 5% aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=7/3) to obtain 30.6 g of the intended compound as a crystal (yield: 85%). The crystal herein obtained was not analyzed and used for the next reaction.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].C(N(CC)CC)C.[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19](Cl)=[O:20].O>ClCCl>[Br:13][C:14]1[CH:15]=[N:16][C:17]([Cl:23])=[C:18]([CH:22]=1)[C:19]([N:4]([O:3][CH3:2])[CH3:5])=[O:20]
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cc(Br)cnc1Cl
Reaction time: 8 h
Yield: 71.4 %

Procedure:
5-Bromo-2-chloro-N-methoxy-N-methylnicotinamide. To a mixture of 5-bromo-2-chloronicotinic acid (6 g, 25.5 mmol) in thionyl chloride (30 mL) was added a drop of N,N-dimethylformamide, and the reaction mixture was heated at 80° C. for 2 h. The mixture was cooled to room temperature, and concentrated to give crude 5-bromo-2-chloronicotinoyl chloride. A solution of O,N-dimethyl-hydroxylamine hydrochloride salt (3.45 g, 35.6 mmol) and triethylamine (7.48 g, 74.1 mmol) in dichloromethane (80 mL), and a solution of the above 5-bromo-2-chloronicotinoyl chloride in dichloromethane (20 mL) were added, and the reaction mixture was stirred overnight. The mixture was poured into water, and extracted with dichloromethane (50 mL×3). The combined organic layer was concentrated under reduced pressure, and purified on silica gel column (eluting with 5-10% ethyl acetate in petroleum ether) to give 5-bromo-2-chloro-N-methoxy-N-methylnicotinamide as a solid (6.2 g, 71.4% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 8.39 (s, 1H), 3.49 (s, 3H), 3.30 (s, 3H).