Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:11]([OH:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[OH-].[NH4+:16].CC(C)=O>O>[CH2:1]([S:11]([O-:14])(=[O:13])=[O:12])[CH2:2][S:3][S:4][CH2:5][CH2:6][S:7]([O-:10])(=[O:8])=[O:9].[NH4+:16].[NH4+:16]
Reactant: O=S(=O)(O)CCSSCCS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=S(=O)([O-])CCSSCCS(=O)(=O)[O-]
Yield: 82 %

Procedure:
A solution of 2,2′-dithiobis ethane sulfonic acid (2.5 g, containing 9% water, 8.1 mmol) in water (1.0 mL) was titrated with ammonium hydroxide aqueous solution (28-30% concentration, Aldrich) until the pH of the reaction solution was adjusted to 7.0. Overall 2.6 mL of ammonium hydroxide was used. Acetone (200 mL) was added to the reaction solution to precipitate the product. The resulting white solid was isolated by filtration and dried under high vacuum to give 2.10 g of product (82% yield). The purity of the product was 98.2% from HPLC analysis.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][N:20]1[CH:24]=[C:23]([C:25]2[CH:26]=[C:27]([CH:36]=[CH:37][CH:38]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32][C:33]([OH:35])=O)[CH:22]=[N:21]1.[CH3:39][O:40][CH:41]([O:49][CH3:50])[CH2:42][NH:43][C@@H:44]([CH:46]([CH3:48])[CH3:47])[CH3:45].C(N(CC)CC)C>C1COCC1.C(#N)C.C(OCC)(=O)C>[CH3:39][O:40][CH:41]([O:49][CH3:50])[CH2:42][N:43]([C@@H:44]([CH:46]([CH3:47])[CH3:48])[CH3:45])[C:33](=[O:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28][C:27]1[CH:36]=[CH:37][CH:38]=[C:25]([C:23]2[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=2)[CH:26]=1
Reactant: COC(CN[C@H](C)C(C)C)OC
Reactant: Cn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC#N
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C)c2)c1)[C@H](C)C(C)C)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of T3P (1.86 mL) dissolved in THF (1.57M) was added in one portion to a stirred solution of 3-(3-(1-methyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 2a, Step i)] (567 mg), (R)—N-(2,2-dimethoxyethyl)-3-methylbutan-2-amine [Preparation 4] (307 mg), and triethylamine (2.44 mL) in acetonitrile (6 mL) at 25° C. The resulting solution was stirred at 25° C. for 15 min. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with saturated sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0-100% ethyl acetate in isohexane, then elution gradient 5-10% methanol in ethyl acetate to afford the subtitled compound as a gum (210 mg). 1H NMR (400 MHz, CD3OD) δ 7.92 and 7.91 (2×s, 1H), 7.77 (s, 1H), 7.40-7.37 (m, 1H), 7.36-7.32 (m, 1H), 7.23 and 7.22 (2×t, J=7.7 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.59 and 4.43 (2×t, J=5.4 Hz, 1H), 3.90 (s, 3H), 3.75-3.45 (m, 5H), 3.36 (d, J=1.5 Hz, 2H), 3.35, 3.34, 3.33, 3.32 (4×s, 6H), 2.84 and 2.84 (2×t, J=7.0 Hz, 2H), 2.76-2.61 (m, 2H), 1.98-1.86 and 1.79-1.66 (2×m, 1H), 1.16 and 1.14 (2×d, J=7.0 Hz, 3H), 0.90 and 0.88 (2×d, J=6.8 Hz, 3H), 0.79 and 0.75 (2×d, J=6.8 Hz, 3H), a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[S:10][C:11]=2[C:12]2[N:16]=[CH:15][N:14](C3CCCCO3)[N:13]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>O1CCCC1.CO>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3ncn(C4CCCCO4)n3)s2)ccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nc(Cc3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
To a 20 mL vial was added a solution of 4-{4-(4-chlorobenzyl)-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-1,3-thiazol-2-yl}-2-methylpyridine (0.1654 g, 0.365 mmol) in anhydrous tetrahydrofuran (2.000 mL) and methanol (2.000 mL). 4.0 M hydrochloric acid in 1,4-dioxane (1.0 mL, 4.0 mmol) was added and the reaction mixture was allowed to stir at 50° C. for 18 hours. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10 mL) then was extracted with EtOAc (10 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by HPLC to afford the product (0.0351 g, 39.9%) as a white solid. LC/MS (AA) ES+ 368, 370. 1H NMR (400 MHz, d6-DMSO) δ: 8.73 (s, 1H), 8.56 (d, J=5.2 Hz, 1H), 7.75 (s, 1H), 7.67 (dd, J=5.2, 1.6 Hz, 1H), 7.37-7.32 (m, 4H), 4.65 (s, 2H) 2.55 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1>C(Cl)(Cl)Cl.CN(C=O)C>[CH3:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([S:17]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2o1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
Piperidine (2.2 g, 26 mmol) was added drop wise to a solution of Compound 8 (3.0 g, 10 mmol) in chloroform (30 ml) and DMF (10 ml). The combined mixture was stirred at room temperature for 1 hour, and then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was then dried over sodium sulfate and evaporated to provide 2.76 g (76%) of Compound 9 as a sticky white solid. TLC analysis showed Rf=0.25 (30% ethyl acetate in hexane). The structure of this compound is given below:
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([CH3:23])([C:21]#[CH:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCN(CC)CC.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]([CH3:23])([CH3:13])[C:21]#[C:22][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4])[CH3:20]
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and ethyl 3,3-dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added Pd(PPh3)2Cl2 (13.8 g, 0.02 mol) and CuI (3.6 g, 0.02 mol) under N2. The reaction mixture was stirred at 70° C. for 8 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and 1500 mL of water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (500 mL×3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give ethyl-5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 57%). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1H), 6.36 (d, J=13.2 Hz, 1H), 5.60 (brs, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.51 (s, 2H), 1.40 (s, 6H), 1.28 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1](/[C:14]1[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=1)=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(OCC)C.[Pd]>[CH2:1]([C:14]1[CH:15]=[C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])[O:17][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCC/C=C\c1coc([Si](C)(C)C)c1
Agent: [Pd]
Solvent: CCOCC
Product: CCCCCCCCCCCCCc1coc([Si](C)(C)C)c1
Reaction time: 7 h

Procedure:
A mixture of (E), (Z)-4-(1-tridecenyl)-2-trimethylsilylfuran (2.0 g, 6.25 mmol) and 10% palladium or carbon (20 mg) in ethyl ether (10 ml) was hydrogenated at room temperature for 7 h. The mixture was filtered through celite and the filtrate upon evaporation gave essentially pure 4-tridecyl-2-trimethylsilylfuran. The silylfuran was redissolved in tetrahydrofuran (8 ml) and was exposed to singlet oxygen, in the presence of Rose Bengal (5 mg), for 2 h at 0°. The residue, after solvent removal, was purified by a silica column using 60% ethyl ether/hexane to give the titled furanone.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2N=N1.C(N(CC)CC)C.[C:30]([O:34][C:35]([NH:37][CH2:38][C:39](O)=[O:40])=[O:36])([CH3:33])([CH3:32])[CH3:31]>ClCCl.C(OCC)(=O)C>[C:18]1([NH:14][C:39]([CH2:38][NH:37][C:35](=[O:36])[O:34][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:40])[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.27 g (1.19 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 681 mg (5.04 mmol) of 1-hydroxybenzotriazole and 0.95 ml (6.82 mmol) of triethylamine were added to 1.15 g (6.56 mmol) of t-butoxycarbonylglycine in 20 ml of dichloromethane under cooling in an ice bath, and they were stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the product was washed with 0.1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[Si]([CH:14]=[N+:15]=[N-:16])(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[NH:16]1[CH:2]([C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:3][CH:14]=[N:15]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)C1CC=NN1
Yield: 41.1 %

Procedure:
To a solution of t-butyl acrylate (17 g, 133 mmol) dissolved in toluene (200 mL) and n-hexanes (200 mL) was added TMS-diazomethane (99 mL, 199 mmol) over 10 minutes. After 1 h the reaction mixture was concentrated and the residue diluted with DCM (300 mL) and TFA (20.44 mL, 265 mmol) was added slowly over 15 minutes. After 30 minutes the reaction mixture was concentrated, basified with 1N NaOH and extracted into DCM (400 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by filtration through a pad of silica gel eluting the product with 50% ethyl acetate/hexanes to afford 10 g (54.6 mmol) of 1,1-dimethylethyl 4,5-dihydro-1H-pyrazole-5-carboxylate as a yellow oil. LC-MS (ES) m/e 170.91 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH:7]=[CH:6]2.[CH3:19][S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:32][C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])=[C:27]([CH:31]=1)[C:28](O)=[O:29])(=[O:22])=[O:21].C(OCC)(=O)C>C(#N)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([N:13]1[CH2:14][CH2:15][N:16]([C:28]([C:27]3[CH:31]=[C:23]([S:20]([CH3:19])(=[O:21])=[O:22])[CH:24]=[CH:25][C:26]=3[O:32][C@@H:33]([CH3:38])[C:34]([F:36])([F:37])[F:35])=[O:29])[CH2:17][CH2:18]1)[CH:7]=[CH:6]2
Reactant: Clc1ccc2nc(N3CCNCC3)ccc2c1
Reactant: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[C@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1)C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 b) from 6-chloro-2-piperazin-1-yl-quinoline hydrochloride (Example 1.20b) and 5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example 2.7) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][C:11]([N+:16]([O-])=O)=[CH:10][CH:9]=3>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:15]=[C:14]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:16])=[CH:12][C:13]2=1
Reactant: COc1ccc2[nH]c3ccc([N+](=O)[O-])cc3c2c1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2[nH]c3ccc(N)cc3c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.9 %

Procedure:
To 3-methoxy-6-nitro-9H-carbazole (100 mg, 0.41 mmol) in 40 mL MeOH was added Palladium on activated carbon (50 mg). The mixture was stirred at rt under H2 atmosphere for 5 h. Solid was filtered off and the filtrate was concentrated to afford 6-methoxy-9H-carbazol-3-amine as a brown solid (80 mg, 92%). This material was used directly for the next reaction without purification. MS (ESI) m/z 213 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]([N:12]([CH2:8][CH3:6])[CH2:11][CH3:10])=[O:17])=[CH:10][CH:9]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
To a solution of 6.1 g. (0.02 mole) of 5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetic acid in 100 ml. chloroform is added 3.8 ml. (0.03 mole) thionyl chloride. The mixture is stirred and refluxed overnight. The solvent is then evaporated and the residue is added quickly to a solution of 22 ml. diethylamine in 50 ml. water while cooling externally with an ice-bath. A solid precipitates, 5-(p-chlorobenzoyl)-N,N-diethyl-1-methylpyrrole-2-acetamide, which is collected and purified by recrystallization from methylcyclohexane (with charcoal while in solution), m.p. 82°-85°C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=O)[S:29][C:30]=1[Cl:31]>ClCCCl>[Br:25][C:26]1[CH:27]=[C:28]([CH2:32][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:29][C:30]=1[Cl:31]
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)c(Cl)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1sc(CN2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Morpholine (15.2 mL), acetic acid (9.1 mL), and then sodium triacetoxyborohydride (50.3 g) is added to a solution of 4-bromo-5-chloro-2-thiophenecarbaldehyde (Preparation 61, 35.7 g) in 1,2-dichloroethane (600 mL) at 0° C. The mixture is allowed to warm to room temperature, and after 18 h, it is quenched with a 2N NaOH solution (200 mL) with ice bath cooling. The organic layer is separated and washed with 1 N NaOH solution (2×200 mL). The aqueous layers are extracted with CH2Cl2 (2×100 mL). The combined organic layers are extracted with 0.25 M HCl solution (2 L) and the resulting aqueous layer is made basic with 2N NaOH solution. The mixture is then extracted with CH2Cl2 (2 L) and the organic layer is dried (Na2SO4) and concentrated to afford 39.24 g (84%) of the title compound as a light yellow oil. Physical characteristics: 1H NMR (400 MHz, DMSO-d6) δ 7.03, 3.63, 3.57, 2.42; 13C NMR (100 MHz, CDCl3) δ 140.9, 127.3, 125.9, 109.2, 66.9, 57.6, 53.3; MS (ESI+) m/z 296 (72, (M+H)+), 298 (100).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cn1S(C)(=O)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc(N)cn1S(C)(=O)=O
Yield: 98.8 %

Procedure:
To a solution of 1-methanesulfonyl-4-nitro-1H-pyrrole-2-carboxylic acid ethyl ester (2.4 g, 9.15 mmol) in ethanol (30 mL) was added Pd/C (10%) (120 mg) under nitrogen atmosphere. The reaction flask was charged with hydrogen at 50 psi for 2 hours. The catalyst was removed by filtration through celite. The solvent was evaporated under reduced pressure to afford a sticky syrup that was purified by flash column eluting with 50% EtOAc in hexanes to give the product as sticky oil (2.1 g, 99%). MS (ES+): m/e=233.1 (M+H); LC/Method A/2.36 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([CH2:18][OH:19])=[C:13]([CH2:16][OH:17])[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][O:19][C:16](=[O:17])[C:13]=3[CH:14]=2)[C@H:9]([N:20]([CH2:25][C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(CO)c(CO)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C)COC3=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6,7-bis-hydroxymethyl-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 27A) (100 mg, 0.17 mmol) in 25 ml anhydrous dichloromethane was added pyridinium chloro-chromate (100 mg, 0.46 mmol) and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was poured into a separatory funnel, washed with H2O and sat NaHCO3, dried and concentrated. The crude material was chromatographed on silica gel (30-35% ethyl acetate:hexane) to afford cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-8-oxo-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylic acid ethyl ester (Example 29) MS m/z 574 (M+); 1H NMR (CDCl3) δ3.8 (s, 3H), 7.5 (s, 1H), 7.8 (s, 1H) and cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-6-oxo-3,4,6,8-tetrahydro-2H-furo[3,4-g]quinoline-1-carboxylic acid ethyl ester (Example 30) MS m/z 575 (M+); 1H NMR (CDCl3) δ1.1 (d, 3H), 3.8 (s, 3H), 7.0 (s, 1H), 8.0 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([O:8][CH2:30][CH:29]=[CH2:28])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[C:13]([CH3:16])=[C:12]([C:17]([F:18])([F:20])[F:19])[CH:11]=[N:10]2)=[C:4]([F:21])[CH:3]=1
Reactant: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(-n2ncc(C(F)(F)F)c(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
First, 400 mg (1.2 mmol) of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (intermediate 1) was dissolved in 2.0 ml of N,N-dimethylformamide, to which 257 mg (1.86 mmol) of potassium carbonate and 165 mg (1.36 mmol) of allyl bromide were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography, which afforded 405 mg (1.1 mmol) of 2-{4-chloro-2-fluoro-5-(2-propenyloxy)phenyl}-4-methyl-5-trifluoromethyl-3-oxo-2,3-dihydropyridazine (hereinafter referred to as intermediate 2), m.p. 79.8° C.
Reaction SMILES: [C:1]([N:4]([CH:23]1[C:31]2[C:26](=[C:27]([O:32][CH3:33])[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:5][C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)(=O)[CH3:2].Cl>C1COCC1>[CH2:1]([N:4]([CH:23]1[C:31]2[C:26](=[C:27]([O:32][CH3:33])[CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24]1)[CH2:5][C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:10]=1)[CH3:2]
Reactant: COc1cccc2c1CCC2N(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCN(Cc1nc(-c2ccccc2)c(-c2ccccc2)o1)C1CCc2c(OC)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.4 %

Procedure:
To a solution of 1-[N-acetyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.40 g) in THF (10 ml) was added 1M solution of borane-THF complex in THF (9 ml) at room temperature. The reaction mixture was refluxed for 8 hours and cooled down to room temperature. 1N aqueous HCl solution (25 ml) was added to the reaction mixture. After being stirred for 1 hour at room temperature, the mixture was partitioned between ethyl acetate and 1N aqueous NaOH solution. The organic layer was washed with brine. The dried solvent was evaporated in vacuo to give 1-[N-ethyl-N-[(4,5-diphenyloxazol-2-yl)methyl]amino]-2,3-dihydro-4-methoxy-1H-indene (0.47 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:10]=2[CH2:11][N:12]2[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=3)[C:13]2=[O:32])=[CH:4][CH:3]=1.[F:38]C1C=CC(NC2C=CC=CC=2)=C(C=1)CN1C(C)(C)C(=O)N(C2C=CC(C#N)=C(C(F)(F)F)C=2)C1=O>>[F:37][C:34]1[CH:35]=[CH:36][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:38])=[CH:3][CH:4]=2)=[C:10]([CH:33]=1)[CH2:11][N:12]1[C:16]([CH3:18])([CH3:17])[C:15](=[O:19])[N:14]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=2)[C:13]1=[O:32]
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(F)ccc1Nc1ccccc1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(F)ccc1Nc1ccc(Cl)cc1
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1cc(F)ccc1Nc1ccc(F)cc1

Procedure:
The compounds of example 16, 4-{3-[2-(4-chlorophenylamino)-5-fluorobenzyl]-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl}-2-trifluoromethylbenzonitrile (molecular weight 530.11 (C26H19ClF4N4O2); retention time Rt=2.38 min. [B]; MS (ESI): 531.21 (MH+), and of example 18, 4-[3-(5-fluoro-2-phenylaminobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile (molecular weight 496.15 (C26H20F4N4O2); retention time Rt=2.28 min. [B]; MS (ESI): 497.20 (MH+)