Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11])[C:2]([CH3:5])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[CH2:10][OH:11])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COC(=O)c1cccc(OCC(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a solution of methyl 3-(neopentyloxy)benzoate (4.51 g, 20.3 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (1.93 g, 50.75 mmol) by small portions under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the mixture were successively added slowly water (2 ml), 15% aqueous sodium hydroxide solution (2 ml) and water (6 ml) under ice-cooling. The obtained solid was filtered with celite, washed thoroughly with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give 3-(neopentyloxy)benzyl alcohol (3.81 g, 97%) as a colorless transparent oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:12])=[O:11].C1C=C(Cl)C=C(C(OO)=[O:36])C=1>C(Cl)Cl.CCOC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:36])(=[O:11])=[O:12]
Reactant: COC(=O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (181 mg, 0.43 mmol) in CH2Cl2 (4 ml) was added mCPBA (153 mg, ˜0.64 mmol). The reaction was stirred at room temperature for 1 hour, diluted with EtOAc, extracted with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane, then 10% MeOH in CH2Cl2) to yield the title compound (87 mg, 46%).
Reaction SMILES: Cl.[NH2:2]O.C([O-])(=O)C.[NH4+].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH:18]=O)[CH:11]=[CH:10]1>C(O)C.O.[Zn].[OH-].[NH4+]>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:18][NH2:2])[CH:11]=[CH:10]1
Reactant: O=Cc1cccc2cc[nH]c12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: NCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Add hydroxylamine hydrochloride (2.87 g, 41.37 mmol) and ammonium acetate (4.78 g, 62.06 mmol) to a solution of indole-7-carboxaldehyde (3.0 g, 20.68 mmol) in ethanol: H2O (3:1) (120 ml). Stir at room temperature for 2 hours. Add ammonium hydroxide (25 ml, 0.72 mmol) and zinc (11.0 g, 8.1 mmol) in portions. Filter the reaction mixture, dilute with ethyl acetate, and wash with water. Extract the organic layer with 1N HCl. Make the aqueous layer basic by adding 1N NaOH and extract with ethyl acetate. Wash the organic layer with water followed by saturated aqueous sodium chloride, dry over magnesium sulfate, and concentrate under reduced pressure to provide the desired compound (2.69 g, 89%) as a white solid.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:77][C:78]([C:81]3[CH:82]=[C:83]4[C:88](=[CH:89][CH:90]=3)[CH:87]=[C:86]([C:91]3[CH:92]=[C:93]5[C:120](=[CH:121][CH:122]=3)[C:97]3[NH:98][C:99]([C@@H:101]6[CH2:105][CH2:104][CH2:103][N:102]6[C:106](=[O:119])[C@@H:107]([NH:114][C:115](=[O:118])[O:116][CH3:117])[CH:108]6[CH2:113][CH2:112][O:111][CH2:110][CH2:109]6)=[N:100][C:96]=3[CH:95]=[CH:94]5)[CH:85]=[CH:84]4)=[CH:79][N:80]=1)[NH:70]2>>[CH3:117][O:116][C:115](=[O:118])[NH:114][C@@H:107]([CH:108]1[CH2:109][CH2:110][O:111][CH2:112][CH2:113]1)[C:106]([N:102]1[CH2:103][CH2:104][CH2:105][C@H:101]1[C:99]1[NH:98][C:97]2[C:120]3[C:93]([CH:94]=[CH:95][C:96]=2[N:100]=1)=[CH:92][C:91]([C:86]1[CH:85]=[CH:84][C:83]2[C:88](=[CH:89][CH:90]=[C:81]([C:78]4[NH:77][C:76]([C@@H:71]5[C@@H:72]6[CH2:75][C@@H:69]([CH2:74][CH2:73]6)[N:70]5[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[N:80][CH:79]=4)[CH:82]=2)[CH:87]=1)=[CH:122][CH:121]=3)=[O:119]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@H]7N[C@@H]8CC[C@H]7C8)[nH]6)ccc5c4)ccc3c2[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(7-(6-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.83 [M+H]+. (44 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]([CH3:20])[CH3:19])[N:10]=[C:11]3[C:17]=2[CH2:16][CH2:15][N:14]([CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCNCC2
Reactant: O=CCc1ccccc1
Product: CC(C)n1nc2c(c1-c1ccc(F)cc1)CCN(CCc1ccccc1)CC2

Procedure:
The title compound (104 mg) was prepared from 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 190) and phenylacetaldehyde as in Example 35. MS (ESI): exact mass calculated for C24H28FN3, 377.23; found, m/z 378.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.41-7.27 (m, 9H), 4.39 (m, 1H), 3.88-3.84 (m, 1H), 3.73-3.71 (m, 1H), 3.56-3.52 (m, 3H), 3.45-3.20 (m, 3H), 3.17-3.14 (m, 2H), 2.89-2.84 (m, 2H), 1.41 (t, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12]/[C:13](=N/N(C)C)/[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11].Cl.C1C[O:33]CC1>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12][C:13](=[O:33])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11]
Reactant: C1CCOC1
Reactant: CN(C)/N=C(/CC(CF)(N[S@](=O)C(C)(C)C)c1cccc(F)c1F)C(F)(F)F
Agent: Cl
Product: CC(C)(C)[S@@](=O)NC(CF)(CC(=O)C(F)(F)F)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 26 h

Procedure:
A solution of (R)-N-((Z)-2-(2,3-difluorophenyl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (9.0 g, 20.86 mmol) in THF (10 mL) was treated with hydrogen chloride, 2M aq. solution (10.43 mL, 20.86 mmol). The mixture was stirred at ambient temperature for 26 h. LCMS detected formation of desired product and trace of starting material. The reaction was quenched with saturated NaHCO3 solution and then extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-50% EtOAc/hexane) to afford 5.0 g of (R)-N-(2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide as light yellow solid (91% purity). MS m/z=408.0 [M+H+H2O]+. Calculated for C15H17F6NO2S: 389.4
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][NH:11][C:12]2[N:13]=[C:14]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:15][C:16]=2[C:17]([NH2:19])=[O:18])[CH:7]=[CH:8][CH:9]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28]>O1CCCC1>[Cl:3][C:4]1[C:5]([CH3:26])=[C:6]([CH2:10][N:11]2[C:12]3[N:13]=[C:14]([N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:15][C:16]=3[C:17](=[O:18])[NH:19][C:27]2=[S:28])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(=S)[nH]c(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 98 %

Procedure:
Sodium hydride (0.447 g, 17.71 mmol) was added portionwise to a suspension of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (0.812 g, 2.213 mmol) and 1,1′-thiocarbonyldiimidazole (1.183 g, 6.64 mmol) in Tetrahydrofuran (THF) (20 mL). The mixture was stirred at rt for 2.5 days, then quenched by the dropwise addition of saturated NH4Cl solution. The solvent was evaporated in vacuo and the residue was suspended in water. The pH was adjusted to about 6 by the addition of 1 N HCl. The yellowish orange solid was collected by filtration, washed with water, and dried in a vacuum oven at 65 C to provide 887 mg of the titled compound (98% yield). LC/MS: MS (ES+) m/e 409 (MH+)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][SH:3].[Cl-].[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([N+]#N)[CH:13]=[CH:14][CH:15]=1)[CH3:8].C(OC1C=C(C=CC=1)N)C.Cl>O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:7]([O:9][C:10]1[CH:15]=[C:14]([CH:2]([SH:3])[C:1]([OH:5])=[O:4])[CH:13]=[CH:12][CH:11]=1)[CH3:8]
Reactant: O=C(O)CS
Reactant: CCOc1cccc([N+]#N)c1
Agent: [Cu+2]
Agent: CCOc1cccc(N)c1
Agent: Cl
Solvent: O
Product: CCOc1cccc(C(S)C(=O)O)c1
Reaction time: 0.33 h

Procedure:
32.2 g of thioglycolic acid and 56.4 g of crystalline copper sulphate are stirred for 30 minutes in 250 ml of water. Then an aqueous solution of 3-ethoxyphenyldiazonium chloride, prepared according to Example 1(a) from 34.3 g of 3-ethoxyaniline, is allowed to run in at 25° C. in 20 minutes. After a further 40 minutes' stirring, 64 ml of 36% strength hydrochloric acid are added. The mixture is stirred for 1 hour at 40°-50° C., filtered hot with suction and washed with 5% strength hydrochloric acid. The moist filtered solid is dissolved in 500 ml of water with 30 g of sodium carbonate, and heated to boiling with 5 g of active charcoal for 15 minutes. It is filtered hot and the filtrate is added to 85 ml of 36% strength hydrochloric acid to precipitate the 3-ethoxyphenylthioglycolic acid. It is filtered off with suction, washed with a little water and dried. 40.4 g of 3-ethoxyphenylthioglycolic acid are obtained, which is 75.7% of theory. The acid is 99.5% pure with a melting point of 105°-107° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[C:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: Clc1ncccc1-c1cccnc1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncccc1-c1cccnc1
Temperature: 110 °C

Procedure:
A 440 mg portion of 2-chloro-3,3'-bipyridine and 0.73 ml of anhydrous hydrazine were dissolved in 15 ml of pyridine and heated at 110° C. for 3 days. The volatiles were removed at reduced pressure, 10 ml of toluene was added and the volatiles again removed. The residue was partitioned between 125 ml of methylene chloride and 25 ml of saturated aqueous sodium carbonate. The organic layer was dried and the solvent removed at reduced pressure, giving an oily solid which was recrystallized from methylene chloride-hexane, giving 2-hydrazino-3,3'-bipyridine as a tan powder, mp 104.5°-107° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([Br:31])[CH:30]=1)[NH:27][C:26](=[O:32])[CH2:25]2>>[Br:31][C:29]1[CH:30]=[C:22]([F:21])[CH:23]=[C:24]2[C:28]=1[NH:27][C:26](=[O:32])[C:25]2=[CH:16][C:13]1[NH:12][C:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:19][CH3:20])[CH2:1][CH3:2])[C:7](=[O:18])[C:8]=2[C:14]=1[CH3:15]
Reactant: O=C1Cc2cc(F)cc(Br)c2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4c(Br)cc(F)cc43)c(C)c2C1=O
Yield: 78.2 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-7-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (62 mg, 78.2%) as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl.O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:33])=[O:32])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1sc2ncnc(N)c2c1-c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A 0° C. solution of Example 1E (0.1 g, 0.39 mmol) in dichloromethane (4 mL) was treated with pyridine (0.038 mL, 0.47 mmol) and benzenesulfonyl chloride (0.05 mL, 0.4 mmol), stirred at 0° C. for 1 hour, then stirred at room temperature overnight. The reaction mixture was diluted with water and extracted twice with dichloromethane. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was triturated from dichloromethane/hexanes to provide 91 mg (59%) of the desired product. MS(ESI(+)) m/e 397 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H); 8.25 (s, 1H); 7.77 (m, 2H); 7.65-7.55 (m, 3H); 7.24 (m, 4H); 1.99 (s, 3H); Anal. Calcd. for C19H16N4O2S2.0.3C2H4O2: C, 57.37; H, 4.39; N, 13.25. Found: C, 57.22; H, 4.48; N, 13.32.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].C([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[C:34]([F:37])([F:36])[F:35])C1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1COCC1>[CH3:17][O:16][C:14](=[O:15])[C:13]([O:12][CH3:11])=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([OH:25])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:28]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(C(F)(F)F)c1
Reactant: COCC(=O)OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ccc(O)c(C(F)(F)F)c1)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide 1N (0.8 mL, 0.8 mmol) in THF (4 mL), was added dropwise methyl methoxyacetate (0.066 mL, 0.66 mmol) at −78° C. After allowing the mixture to stir for 1 hour, 4-Benzyloxy-3-trifluoromethyl-benzaldehyde (185 mL, 0.66 mmol) was added dropwise. When the addition was finished the mixture was warmed to room temperature and stirred for 3 additional hours. Trifluoroacetic anhydride (0.28 mL, 1.98 mmol) was added and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated and the residue dissolved in ethyl acetate (50 mL). 10% palladium on carbon (200 mg) was added to the solution and the mixture stirred under hydrogen pressure (5 atm) for 16 hours, filtered through a pad of celite and concentrated under vacuum. The residue was chromatographed (silica gel, hexanes/ethyl acetate 4:1) to produce 3-(4 hydroxy-3-trifluoromethyl-phenyl)-2-methoxy-acrylic acid methyl ester as a white solid (72 mg, 40%). 1H-NMR ((CD3)2CO, 200.15 MHz): δ 9.65 (b, 1H), 8.02 (d, 1H, J=1.8), 7.87 (dd, 1H, J=8.4, 1.8), 7.08 (d, 1H, J=8.4), 6.90 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5CCC)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:38]([CH:41]1CCCN1)[CH2:39]C>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:35]([NH2:37])=[O:36])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH:28]5[CH:38]([CH3:41])[CH3:39])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCCC1CCCN1Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCCC1CCCN1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5C(C)C)c4)cc23)CC1
Yield: 29.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide, substituting 2-(1-methylethyl)pyrrolidine (113 mg, 1.0 mmol) for 2-propylpyrrolidine to afford 16.0 mg of the title compound (29.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH2:14][CH:13]([N+:15]([O-])=O)[CH2:12][N:11]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>>[NH2:15][CH:13]1[CH2:12][N:11]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14]1
Reactant: COc1ccc(CN2CC([N+](=O)[O-])CN2Cc2ccc(OC)cc2)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Product: COc1ccc(CN2CC(N)CN2Cc2ccc(OC)cc2)cc1
Yield: 99.2 %

Procedure:
To a solution of 1,2-bis(4-methoxyphenylmethyl)-4-nitropyrazolidine (0.88 g) in diethylether anhydride (20 ml) was gradually added lithium aluminum hydride (0.38 g) while being cooled with ice. After being refluxed with heating for two hours, the reaction liquid, with an aqueous sodium potassium tartrate solution added thereto, was extracted with ether. The extract was concentrated under a vacuum, thereby yielding 0.80 g of a raw product of the aimed compound.
Reaction SMILES: C(OC([C:6]1[S:20][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[C:7]=1[O:21][CH3:22])=O)C.C(Cl)(Cl)Cl.[Br:27]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH2:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:8]2[C:7]([O:21][CH3:22])=[C:6]([Br:27])[S:20][C:9]=2[CH2:10][CH2:11]1)=[O:16])[CH3:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc2c(c1OC)CCN(C(=O)OCC)CC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCc2sc(Br)c(OC)c2CC1

Procedure:
The product of step c) (17 mg, 0.067 mmol) was dissolved in 1 mL 1:1 acetic acid:CHCl3 and treated with N-bromosuccinimide (12 mg, 0.068 mmol). After 30. minutes, the reaction solution was added dropwise to a solution of saturated sodium bicarbonate and extracted with ethyl acetate. The organic extracts were concentrated to give the subtitle compound, which was used without further purification.
Reaction SMILES: O.[P].[Cl:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-])=O>[Pt].O[PH2]=O.C1(C)C=CC=CC=1>[NH2:17][C:5]1[CH:6]=[C:7]([C:13]([F:16])([F:14])[F:15])[CH:8]=[C:9]([NH2:10])[C:4]=1[Cl:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Agent: [Pt]
Agent: O=[PH2]O
Agent: [P]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(C(F)(F)F)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
0.48 g of Pt/C catalyst (5%) and 1.5 g of water are placed in a beaker and mixed with 103 mg of aqueous H3PO2 solution (50% by weight, corresponding to 5% by weight phosphorus, based on the catalyst). The mixture is stirred for 10 minutes at room temperature, then 77 mg of vanadylacetyl acetonate VO(acac)2 are added and stirred for a further 5 minutes. 40 g of 4-chloro-3,5-dinitro-benzotrifluoride and 47 g of toluene are placed in an agitator autoclave, and the catalyst suspension is flushed in with 4 g of water. Hydrogenation subsequently takes place at a temperature of 100° C. and at a hydrogen pressure of 5 bar. When the hydrogen uptake is complete, the autoclave is cooled and rendered inert with nitrogen. The catalyst is filtered off and washed with toluene. After working up by distillation, 29.8 g of 3,5-diamino-4-chloro-benzotrifluoride (yield 95.8% of theory) are obtained. Elementary analysis:
Reaction SMILES: [Na].[C:2]([O:8]CC)(=O)[CH2:3][C:4]([CH3:6])=O.Cl.[C:12]([NH2:15])(=[NH:14])[CH3:13].Cl>C(O)C>[CH3:13][C:12]1[N:15]=[C:2]([OH:8])[CH:3]=[C:4]([CH3:6])[N:14]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc(O)nc(C)n1
Temperature: 25 °C

Procedure:
Sodium (3.6 g) was added by portions to ethanol (92 ml) over 2 hours, while the solution was stirred at room temperature. Thereafter, ethyl acetoacetate (10 ml) and acetamidine hydrochloride (7.42 g) were added to the reaction solution, and the obtained mixture was stirred at 70° C. for 16 hours. Thereafter, the reaction mixture was stirred at 100° C. for 9 hours, and the temperature of the reaction solution was returned to room temperature. Concentrated hydrochloric acid was added to the reaction solution, so that the pH value was adjusted to around 5. The obtained mixture was concentrated under reduced pressure, so as to obtain a crude title compound (25.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9](=[CH:17][N:18]([CH3:20])C)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[I:22][C:23]1[CH:29]=[CH:28]C(N)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9](=[CH:17][NH:18][C:20]1[CH:28]=[CH:29][C:23]([I:22])=[CH:24][CH:25]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: Nc1ccc(I)cc1
Reactant: CN(C)C=C(C(=O)OC(C)(C)C)C(=O)c1ccccc1Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C(=CNc1ccc(I)cc1)C(=O)c1ccccc1Cl
Reaction time: 8 h

Procedure:
A solution of 1,1-dimethylethyl 2-chloro-α-[(dimethylamino)methylene]-β-oxo-benzenepropanoate (25.5 mg, 0.082 mmol) in 1 mL of toluene was treated with 4-iodoaniline (17.9 mg, 0.082 mmol) added as a solid in one portion. After stirring overnight, the reaction was concentrated in vacuo and the residue was adsorbed onto silica gel and added to 19.5 cm of flash silica in a 2 cm dia. column. Elution with 5:1 hexanes/EtOAc gave the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Product: Cc1cc(C)cc(OCC(=O)c2ccccc2)c1
Yield: 86 %

Procedure:
Using 3,5-dimethylphenol and phenacyl bromide, the title compound was synthesized in the same manner as in Reference Example 177. Yield 86%. Melting point: 104-105° C. (methanol).