Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4](Cl)=[O:5].FC(F)(F)C1C=C(C(F)(F)F)C=CC=1C(OC)=O.[CH3:37][C:38]([N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1)([CH3:47])[CH:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:3]=1[C:4]([NH:46][CH:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:38]([CH3:47])([N:48]1[CH2:49][CH2:50][CH2:51][CH2:52]1)[CH3:37])=[O:5]
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Agent: COC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of 2-methyl-4,6-bis(trifluoromethyl)benzoyl chloride and methyl 2,4-bis(trifluoromethyl)benzoate (approximately 0.5 mmol) prepared as described in D53 was dissolved in dry DCM (3 ml) and treated with (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (109 mg, 0.50 mmol) and triethylamine (140 ul, 1.00 mmol) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product as an gum (127 mg, ca.54%). 1H NMR (CDCl3) δ: 0.90 (3H, s), 1.01 (3H, s), 1.70 (4H, overlapping m), 2.47 (3H, s), 2.63 (4H, overlapping m), 4.84 (1H, d, J=2.8 Hz), 7.16 (1H, br s), 7.26-7.38 (5H, overlapping m) 7.67 (1H, s), 7.77 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 473 (MH+) C24H26F6N2O requires 472. Ret time 2.24 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]CC)=[O:14])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12].[Li+].[OH-]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[C:8]2[CH3:12]
Reactant: CCOC(=O)c1cc(OC)c2[nH]nc(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)cc2c(C)n[nH]c12
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of ethyl 7-methoxy-3-methyl-1H-indazole-5-carboxylate (294 mg, 1.26 mmol) in EtOH (11 mL) was added 1 M LiOH (2.5 mL). The mixture was heated at reflux for 4 hours, cooled to room temperature and concentrated. The crude material was triturated with 1 N HCl, the solids were isolated by filtration and washed with water. The solid was air dried overnight to provide the title compound (235 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH2:23])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(CCc1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1N)NC(=O)OC(C)(C)C

Procedure:
A solution of ethyl 2-t-butyloxycarbonylamino-4-(o-nitrophenyl)butyrate (13.0 g) in ethanol (300 ml) is hydrogenated at room temperature and atmospheric pressure, using 10% palladium on charcoal (1 g) as catalyst, until uptake ceases. The catalyst is filtered off. Evaporation of the solvent gives ethyl t-butyloxycarbonylamino-4-(o-aminophenyl)butyrate which is used without further purification for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(S)cc1
Reactant: ClCCCN1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1ccc(SCCCN2CCOCC2)cc1

Procedure:
A mixture was prepared containing 55.5 grams (0.440 mole) of 4-hydroxybenzenethiol, 88.0 grams (0.440 mole) of 20% sodium hydroxide, and 160 ml of water. To this 72.0 grams of 4-(3-chloropropyl)morpholine was added. The reaction mass was heated to reflux with stirring and immediately cooled and diluted with water. The product separated out as an oil, but crystallized upon standing. Recrystallization from methylcyclohexane and ethanol gave white crystals of 4-(3-(4-hydroxyphenylthio)propyl)morpholine having a melting point of 130.5°-131° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1.[F:16][C:17]1[C:22]([OH:23])=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([S:11]([O:23][C:22]3[C:21]([F:24])=[C:20]([F:25])[C:19]([F:26])=[C:18]([F:27])[C:17]=3[F:16])(=[O:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH3:15])[CH:3]=1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cn1cc(Br)c2ccc(S(=O)(=O)Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c2ccc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)cc21
Reaction time: 0.75 h
Yield: 95.4 %

Procedure:
A vial was charged with 3-bromo-1-methyl-1H-indole-6-sulfonyl chloride (505.0 mg, 1.637 mmol), pentafluorophenol (452 mg, 2.455 mmol), and DCM (8.1 mL) to give a clear, light-yellow solution. Triethylamine (342 μl, 2.455 mmol) was added dropwise, and the resulting mixture was stirred for 45 min before being concentrated in vacuo. The crude product was purified by chromatography on silica gel (40% EtOAc/Heptane) to give perfluorophenyl 3-bromo-1-methyl-1H-indole-6-sulfonate (712.3 mg, 1.561 mmol, 95% yield) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.04 (t, J=1.1 Hz, 1 H), 7.82-7.67 (m, 2 H), 7.41 (s, 1 H), 3.91 (s, 3 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=1)[NH2:14].C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[C:13]([CH:15]=2)[NH2:14])[CH2:4][CH2:3]1
Reactant: CC1CCNCC1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 100 °C
Yield: 110 %

Procedure:
4-Methylpiperidine (172 mg, 1.738 mmol) was added to a solution of 5-chloro-2-nitroaniline (200 mg, 1.159 mmol) in NMP (5 mL) in the presence of triethylamine (0.404 mL, 2.90 mmol). The reaction mixture was heated via microwave irradiation to 100° C. for 1 h, and. Upon cooling, the solvent was removed by vacuum. Purification by flash column chromatography (5% CH3OH/CH2Cl2) afforded the title compound (300 mg) as a solid. 1H NMR: (400 MHz, CDCl3): δ 7.98 (d, 1H, J=10.0 Hz), 6.26 (dd, 1H, J=2.8 and 10.0 Hz), 6.13 (bs, 2H), 5.92 (d, 1H, J=2.0 Hz), 3.85 (m, 2H), 2.89 (m, 2H), 1.72 (m, 2H), 1.62 (m, 1H), 1.23 (m, 2H), 0.96 (d, 3H, J=6.8 Hz).
Reaction SMILES: [F:1][C:2]1[C:20]([N:21]2[CH2:26][CH2:25][NH:24][CH:23]([CH3:27])[CH2:22]2)=[CH:19][C:5]2=[N:6][C:7]3[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.[CH2:28]=O.[OH-].[K+]>C(O)=O>[CH3:27][CH:23]1[N:24]([CH3:28])[CH2:25][CH2:26][N:21]([C:20]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:19]=2)=[N:6][C:7]2[N:8]([CH3:18])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:22]1
Reactant: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=CO
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)CCN1C

Procedure:
A solution of 1.15 g of 7-fluoro-1-methyl-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid in 1.35 cm3 of 98% formic acid and 3.25 cm3 of a 30% aqueous formaldehyde solution is heated at a temperature close to 100° C. for 2 hours. The reaction mixture is concentrated under reduced pressure (20 kPa) at 50° C. and 5 cm3 of water are then added, the solution obtained is brought to pH 7 by adding 0.5 cm3 of 2 N aqueous potassium hydroxide solution and heated at a temperature close to 100° C. for 2 minutes. The product, which crystallizes, is drained at 20° C. and washed with twice 10 cm3 of water. The crude product obtained is recrystallized twice from 10 cm3 dimethylformamide each time. 0.55 g of 8-(3,4-dimethyl-1-piperazinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydro-benzo [b][1,8]-naphthyridine-3-carboxylic acid is obtained in the form of a yellow solid melting at 306°-308° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH3:13])[CH2:10][C@H:9]1[C:14](=[O:27])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:24])([F:25])[F:26])[CH:17]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C1C[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H]1C[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N(C(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of (S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.29 mmol) in EtOAc (15 mL) was added Pd/C (10%) and the reaction mixture was placed under hydrogen atmosphere overnight. The reaction mixture was filtered on a pad of Celite, the catalyst residue was washed with EtOAc and the solvent was concentrated. The crude material was purified by preparative HPLC (waters SunFire C18-ODB, 5 μm, 30×100 mm, eluent: 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 40 mL/min, loading 150 mg per run) to give after lyophilization of the purified fractions the desired compounds: (2S,4S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: tR (HPLC conditions b): 5.34 min; LC/MS: 387.0 [M−H]−; (2S,4R)-2-(3-trifluoromethoxy-phenylcarbamoyl)-4-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester: tR (HPLC conditions b): 5.53 min; MS (LC/MS): 387.0 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:38])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:27]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:38][C:14]([Cl:13])([Cl:37])[CH2:15][O:16][C:17](=[O:36])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:10][CH2:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:8][CH:7]=2)=[O:34])[CH:27]=1
Reactant: O=C(O)Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(Cc1cccc(SCc2ccccc2C(=O)OCC(Cl)(Cl)Cl)c1)OCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
(4-Trifluoromethyl-phenyl)-methanol (58 mg, 0.332 mmol) was added to a stirred mixture of 2-(3-carboxymethyl-phenylsulfanylmethyl)-benzoic acid 2,2,2-trichloro-ethyl ester (120 mg, 0.277 mmol), EDCxHCl (80 mg, 0.415 mmol), DMAP (3.4 mg, 0.028 mmol) and DCM (4 mL). The reaction mixture was stirred at rt overnight. More DCM was added and the mixture was washed with 0.25M HCl, the organic phase was dried through a phase separator and concentrated. The crude was submitted to flash chromatography using heptane and EtOAc (90/10) as the eluent to yield the titled compound (105 mg, 64%) as a colourless oil; 1H NMR (400 MHz, CDCl3): δ 3.62 (s, 2H), 4.54 (s, 2H), 4.96 (s, 2H), 5.18 (s, 2H), 7.09-7.15 (m, 1H), 7.18-7.24 (m, 4H), 7.30-7.43 (m, 4H), 7.60 (d, 2H), 8.08 (d, 1H); Mass spectrum: M−H+ 590.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.N1C=CC=CC=1.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:22]([O:29][C:30]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Reaction time: 1 h

Procedure:
Ethyl 5-aminoindole-2-carboxylate [J. Am. Chem. Soc. 80, 4621 (1958) JCS Perkin I 53 (1977), 0.50 g] is dissolved in 49 ml of methylene chloride and pyridine (0.20 g) is added. The reaction is cooled to 0° and benzylchloroformate (0.36 ml) is added dropwise over 10 min. The reaction is stirred for 1 hr, diluted with chloroform, washed with saturated aqueous sodium bicarbonate, water, saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (150 g silica gel) eluting with hexane/ethyl acetate (3/1). The appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CDCl3) 8.90, 7.79, 7.41-7.33, 7.24, 7.16, 5.22, 4.40 and 1.41 δ.
Reaction SMILES: N1C=CC=CC=1.Cl.[C:8]([O:13][CH2:14][CH2:15][NH2:16])(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>CN(C)C=O>[C:8]([O:13][CH2:14][CH2:15][NH:16][C:20](=[O:21])[CH2:19][C:18]([CH3:17])=[O:22])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C1CC(=O)O1
Reactant: C=C(C)C(=O)OCCN
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)CC(C)=O
Temperature: 20 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Pyridine (16 g, 0.2 mole) was added dropwise at 0° C. to a solution of 2-aminoethyl methacrylate hydrochloride (33 g, 0.2 mole) and diketene (16.8 g, 0.2 mole) in N,N-dimethylformamide (600 ml). After the addition, the solution was stirred at 20° C. for 20 hours. The solvent was then removed at low vacuum. The residue was dissolved in chloroform (1200 ml), washed with water (twice with 200 ml), dried over anhydrous magnesium sulfate and filtered. Excess solvent was then removed. Distillation of the residue gave acetoacetamidoethyl methacrylate (b.p.=113°-132° C./5μ) at a yield of 60%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]([O:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1)([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1
Yield: 85.9 %

Procedure:
3-Nitrophenol (50.0 g, 360 mmol), isopropyl iodide (76.19 g, 450 mmol), and potassium carbonate (60 g) were combined and refluxed under nitrogen overnight in 400 ml of acetone. The reaction mixture was cooled, and the solvent was removed in vacuo . The reaction was combined with about 300 ml of water and thereafter extracted with four 100 ml portions of ethyl acetate. The ethyl acetate extracts were combined and washed twice with lN sodium hydroxide and brine, dried over anhydrous sodium sulfate, and evaporated to provide 56 g (86%) of 3-isopropoxynitrobenzene as a clear yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].[C:18]1([CH3:27])[C:19]([N:24]=[C:25]=[O:26])=[CH:20][CH:21]=[CH:22][CH:23]=1>C(Cl)Cl>[CH3:17][O:16][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH3:27])=[O:26]
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: ClCCl
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of t-butyl 4-amino-3-methoxyphenylacetate (0.024 g, 0.10 mmol) in methylene chloride (2.0 mL) was added o-tolyl isocyanate (15 μL, 0.12 mmol). The reaction was stirred for 2 h then concentrated to afford t-Butyl 3-methoxy-4-o-tolylureidophenylacetate (0.036 g, 97%) as a tan foam:
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH:19]=[CH:20]2)[CH:15]=[CH:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[K].C(OC(C)=C)(=O)C>C(OCCCC)(=O)C>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][CH:18]([OH:28])[CH:19]=[CH:20]2)=[CH:15][CH:14]=3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: C=C(C)OC(C)=O
Agent: [K]
Solvent: CCCCOC(C)=O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4CC(O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 58 %

Procedure:
To a mixture of 19 g (0.05 mol) of cholesta-1,4,6-trien-3-one (I), 6.8 g (0.05 mol) of potassium acid sulphate and 200 g (2 mol) of isopropenyl acetate were added 200 ml of butyl acetate, and the resulting mixture was heated under reflux for 7 hours. After completion of the reaction, the same treatment as in Example 1 was carried out to yield 11.1 g of cholesta-1,5,7-trien-3-ol (IV). The yield was 58%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45](O)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1.[NH2:55][C:56]1[S:57][CH:58]=[CH:59][N:60]=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31](/[C:44](=[CH:48]\[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]2)/[C:45]([NH:55][C:56]2[S:57][CH:58]=[CH:59][N:60]=2)=[O:46])[CH:32]=[CH:33][C:34]=1[N:35]1[C:39]([C:40]([F:43])([F:42])[F:41])=[N:38][N:37]=[N:36]1
Reactant: O=C(O)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nccs1)/C(=C/C1CCCCC1)c1ccc(-n2nnnc2C(F)(F)F)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11.5 %

Procedure:
A solution of triphenylphosphine (772 mg, 2.96 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (526 mg, 2.96 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with a solution of (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-acrylic acid (594 mg, 1.48 mmol) in methylene chloride (5 mL). The reaction mixture was then stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (444 mg, 4.44 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (70 mL) and a 1N aqueous hydrochloric acid solution (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 5/1 to 3/2 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-trifluoromethyl-tetrazol-1-yl)-phenyl]-3-cyclohexyl-N-thiazol-2-yl-acrylamide (82 mg, 11 %) as an amorphous solid: EI-HRMS m/e calcd for C20H18ClF3N6OS (M+) 482.0903, found 482.0906.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[C:4]([CH2:19][N:20]2[C@@H:24]([CH3:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:22][C:21]2=[O:32])[CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>>[CH3:25][C@H:24]1[C@@H:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:22][C:21](=[O:32])[N:20]1[CH2:19][C:4]1[CH:3]=[C:2]([C:37]2[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=2)[CH:18]=[CH:17][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(Br)ccc1Oc1cccc(CC(=O)O)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(-c2cnn(C)c2)ccc1Oc1cccc(CC(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: {3-[4-bromo-2-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid and 1-methylpyrazole-4-boronic acid pinacol ester.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.[CH4:13]>C1C=CC=CC=1.[Rh]>[CH:5]([C:6]([CH2:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])=[CH2:13])=[O:4]
Reactant: C
Reactant: CC(=O)OCC=CCOC(C)=O
Agent: [Rh]
Solvent: c1ccccc1
Product: C=C(C=O)CCOC(C)=O
Reaction time: 6 h
Yield: 54 %

Procedure:
The procedure of Example 7 was repeated using 1,4-diacetoxy-2-butene (170 g.) and 5% by weight rhodium on 95% by weight charcoal (1.12 g.) in benzene (340 g.). The reaction took 6 hours to go to completion. Work-up in the manner of Example 7 gave a 54% yield of 2-formyl-4-acetoxybutene.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26](Br)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)#[CH:32]>CN(C=O)C>[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([C:32]#[C:31][C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)=[CH:27][CH:28]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Br)o3)cc2)C1
Reactant: C#Cc1ccc(C)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C#Cc2ccc(C(=O)Nc3ccc(N4CCC(N(C)C)C4)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.042 ml of diisopropylamine was added under argon to 3.8 mg of Pd(tBu)2Cl2 and 0.95 mg of Cul in 0.2 ml of DMF. A solution of 94.6 mg of 5-bromofuran-2-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]-amide in 0.3 ml of DMF and a solution of 4-ethynyltoluene in 0.3 ml of DMF were then added dropwise. The solution was stirred at room temperature overnight. The precipitate which had separated out was filtered off with suction and the filtrate purified by preparative HPLC. The desired product with the molecular weight of 413.52; MS (ESI): 414 was obtained as hydrotrifluoroacetate.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.[I:13]C1C=CC(C(O)=O)=CN=1.C(C(CC)(CC)C([O-])([O-])[O-])C>>[I:13][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCOC(=O)c1ccc(Cl)nc1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(=O)c1ccc(I)nc1
Yield: 92.4 %

Procedure:
Using the same procedure for ethyl 6-chloronicotinate but instead using 6-iodonicotinic acid (7.14 g, 28.67 mmol) and triethylorthoacetate (13.96 g, 86.02 mmol) gave the titled compound as a white solid (7.340 g, 26.49 mmol, 92.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6]2.[CH3:16][O:17]C1C=CC(CC(F)(F)F)=CC=1C=O>>[CH:16]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[C:12]([F:13])([F:14])[F:15])=[CH:4][C:3]=1[O:2][CH3:1])=[O:17]
Reactant: COc1ccc2c(c1)CCC2C(F)(F)F
Reactant: COc1ccc(CC(F)(F)F)cc1C=O
Product: COc1cc2c(cc1C=O)C(C(F)(F)F)CC2

Procedure:
This compound was prepared from Compound 64 in the same manner of Compound 46.