Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2(O)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])O.[Na+]>FC(CC(O)=O)(F)F>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C(O)CC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Product: FC(F)(F)c1cccc(C2=CCNCC2)c1
Temperature: 80 °C
Yield: 38.8 %

Procedure:
4-[3-(Trifluoromethyl)phenyl]-4-hydroxypiperidine (Aldrich Co., 2.2 g) was suspended in trifluoromethylacetic acid (10 ml) and the mixture was stirred with heating at 80° C. for 5 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to give 4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (791 mg, yield 67%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[N:8]=[C:9]=[S:10].CN(C1C=CC=CN=1)C.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:7][C:4]1[C:3]([N:8]=[C:9]=[S:10])=[C:2]([NH:1][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[S:6][N:5]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nsc(N)c1N=C=S
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1nsc(NC(=O)C(C)(C)C)c1N=C=S
Reaction time: 16 h

Procedure:
16.7 g of 5-amino-4-isothiocyanato-3-methylisothiazole and 0.5 g of dimethylaminopyridine are dissolved in a mixture of 100 ml of toluene and 100 ml of pyridine, and 15.9 g of pivaloyl chloride are added. Stirring is carried out for 16 hours at 80° C., the solution is evaporated to dryness, the residue is taken up in ethyl acetate and the solution is extracted with aqueous sodium bicarbonate solution and 10% strength hydrochloric acid. The organic phase is dried and evaporated down.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:41]([C:46]#[N:47])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([C:46]#[N:47])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: N#Cc1ncccc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5cccnc5C#N)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromopyridine-2-carbonitrile (283 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (421 mg, 79%) as a light yellow oily substance.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[C:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C/c1ccc(C(=C2CCOCC2)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.7 %

Procedure:
tert-Butyl (2E)-3-{4-[(4-hydroxyphenyl)(tetrahydro-4H-pyran-4-ylidene)methyl]phenyl}prop-2-enoate (47) (0.071 g, 0.182 mmol) was dissolved in CH2Cl2 (1 mL) and TFA (1 mL). The solution was stirred at RT for 4 h, then was concentrated. The residue was recrystallized from EtOAc to provide 0.020 g (33%) of compound 48 as a tan solid. 1H NMR (DMSO-d6): δ 12.34 (s, 1H), 9.37 (s, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.07 (d, J=8.2 Hz, 2H), 6.85 (d, J=8.4 Hz, 2H), 6.67 (d, J=8.4 Hz, 2H), 6.45 (d, J=16.0 Hz, 1H), 3.59 (m, 4H), 2.25 (m, 4H). LRMS (ESI): m/z 335 (M−H)−.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][N:11]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:22][C:23]([NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[C:29]([O:33][CH3:34])=[CH:28][C:27]=2[O:35][CH3:36])=[O:24])[C:12]1=[O:37].[C:38](Cl)(=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41].O>C1COCC1.C(N(CC)CC)C>[Cl:32][C:30]1[C:29]([O:33][CH3:34])=[CH:28][C:27]([O:35][CH3:36])=[C:26]([NH:25][C:23]([CH2:22][N:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20](=[O:21])[N:11]([CH2:10][CH2:9][NH:8][C:38](=[O:43])[CH2:39][CH:40]([CH3:42])[CH3:41])[C:12]2=[O:37])=[O:24])[CH:31]=1
Reactant: CC(C)CC(=O)Cl
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCN)c(=O)c3ccccc32)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)CC(C)C)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-[3-(2-amino-ethyl)-2,4-dioxo-3,4-dihydro-2H-quinazolin-1-yl]-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide trifluoroacetate (75 mg, 0.17 mmol) in THF (1 ml), triethylamine is added (0.06 ml, 0.43 mmol) followed by isovaleryl chloride (30 mg, 0.26 mmol). The mixture is stirred overnight at RT and then treated with water (3 ml). The resulting solid is filtered and washed with water to afford the title compound; [M+H]+ 517.3.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.Cl.[NH2:11][CH2:12][CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)([CH3:25])[CH3:24])[CH:18]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([NH:22][CH2:21][CH2:20][CH2:19][N:17]2[CH:18]=[C:14]([CH2:13][CH2:12][NH:11][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:15]=[CH:16]2)([CH3:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride, (0.65 g) in dichloromethane (25 ml) and the resulting solution cooled to 0° C. A solution of benzoyl chloride (0.21 g) in dichloromethane (10 ml) was added over 20 minutes at 0-5° C. with stirring. The mixture was stirred at ambient temperature for 2.5 hours. The solution was washed with sodium bicarbonate solution, then water, then dried, filtered and evaporated to give N-[2-(1-(3-[1-(4-chlorophenyl)-1-methylethylamino]propyl}imidazol-4-yl)ethyl]benzamide as an oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:7][CH:6]=1.[OH-].[Na+].O>CO.O1CCCC1>[C:15]1([C:13](=[O:14])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([OH:26])=[O:2])=[CH:6][CH:7]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C(=O)c1ccc(OCC(=O)c2cccc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCC(=O)c2cccc3ccccc23)cc1
Yield: 51.3 %

Procedure:
To a hot solution of 4-[2-(1-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid methyl ester (0.128 g) in methanol (3 mL) and tetrahydrofuran (0.5 mL) was added 1N sodium hydroxide (0.8 mL) followed by water (15 mL). The solvents were removed under reduced pressure, then the solution was acidified with 1N hydrochloric acid (1 mL) and extracted with dichloromethane (1×20 mL, 1×10 mL). The combined organic layers were washed with water, dried (MgSO4) and evaporated and the resulting yellow solid (0.107 g) was crystallized from ethyl acetate-hexane to provide 0.063 g of 4-[2-(1-naphthalenyl)-2-oxoethoxy]-alpha-oxobenzeneacetic acid, mp 141°-143° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[F:13][CH2:14][CH2:15][O:16][NH2:17]>CS(C)=O>[F:13][CH2:14][CH2:15][O:16][N:17]=[C:4]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[NH:1][C:2]1=[O:3]
Reactant: NOCCF
Reactant: O=C1Nc2ncccc2C1=O
Agent: Cl
Solvent: CS(C)=O
Product: O=C1Nc2ncccc2C1=NOCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of compound 134a (300 mg, 1.03 mmol) in DMSO (25 mL) was heated at 95° C. at 15 torr for 6.5 hours. The solution containing the corresponding 7-aza isatin was cooled to room temperature, followed by the addition O-(2-Fluoro-ethyl)-hydroxylamine hydrochloride (131 mg, 1.13 mmol). After stirring for 1 hour at room temperature the mixture was quenched with water and extracted with ethyl acetate (6×25 mL). The combined organic phases were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography (gradient, 2% MeOH in methylene chloride to 3%) to give 1H-Pyrrolo[2,3-b]pyridine-2,3-dione 3-[O-(2-fluoro-ethyl)-oxime] (200 mg, 93%) as an orange solid that was further purified by trituration from diethyl ether-methylene chloride (1:1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#N.C(O)(=[O:33])C>N1C=CC=CC=1.[Ni].O>[CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(C#N)c2)NC(=O)OC(C)(C)C)cc1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(C=O)c2)NC(=O)OC(C)(C)C)cc1
Temperature: 46 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 3-(3-cyanophenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (2.7 g, 6.60 mmole) was dissolved in pyridine (18.6 ml) and acetic acid (9.3 ml). Raney Nickel (2.7 g of a slurry in H2O) was added and the resulting suspension was stirred at 46° C. overnight. The reaction was confirmed complete by reverse phase HPLC/MS. The reaction was cooled to room temperature and then filtered through celite. The filtrate was concentrated under reduced pressure and then partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×). The combined organics were washed with H2O (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The crude produce was dried under high vacuum overnight and used without further purification. Yield was 2.70 g. MS (m/z) 413 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:14]([OH:15])[C@H:13]([OH:16])[C@@H:12]([CH2:17][O:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[OH-].[K+].[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1(C)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([OH:15])[C@H:13]([O:16][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:12]([CH2:17][O:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CCOC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Yield: 88 %

Procedure:
10 g of (c), 12 g of KOH and 7 ml of benzyl bromide in 340 ml of toluene were heated under reflux for 3 h. The suspension obtained was then hot filtered through Celite and the solid residues were washed with hot toluene. The filtrates were then combined and washed. After washing and evaporating off the solvents, a yellow-white solid was obtained: 12 g (yield: 88%).
Reaction SMILES: [CH2:1]([C@@H:5]1[C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH2:1]([C@:5]1([CH3:16])[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCC[C@@H]1OC(=O)[C@]1(C)CCCC
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of β-lactone 3a (36.3 mg, 0.1835 mmol) in 1.9 mL THF was cooled to −78° C. and 370 μL of LiHMDS (0.367 mmol, 2.0 equiv, 1.0 M solution in THF) was added under a nitrogen atmosphere. After 1.5 h, 23 μL (0.367 mmol, 2.0 equiv) of iodomethane was added and the reaction warmed to −40° C. and stirred for an additional 45 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0→15% Et2O:hexanes) to give β-lactone 8a (28.4 mg, 73%) as a colorless oil and as a mixture of cis/trans diastereomers (dr, 6:1). Data provided for major diastereomer: Rf (15% Et2O:hexanes) 0.64; IR (thin film) 1824 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd (major diast.), J=6.0, 8.5 Hz, 1H), 1.63-1.78 (m, 2H), 1.45-1.53 (m, 2H), 1.39 (s, 3H), 1.24-1.39 (m, 10H), 0.89-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) 14.1, 14.2, 20.0, 22.1, 25.5, 25.6, 26.5, 30.3, 31.7, 35.9, 56.8, 84.5, 175.5; ESI LRMS Calcd. for C13H24O2Li [M+Li]: 219. Found: 219.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].S(=O)(=O)(O)O.[N+]([C:20]1[CH:21]=C(S([O-])(=O)=O)C=C[CH:25]=1)([O-])=O.[Na+].[OH-].[Na+]>OCC(CO)O>[CH3:4][C:2]([C:5]1[CH:11]=[C:10]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:21][CH:20]=[CH:25]2)([CH3:1])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: CC(C)(C)c1ccc2ncccc2c1
Temperature: 0 °C

Procedure:
4-(1,1-Dimethylethyl)aniline (185 g.) is added dropwise, with stirring, to 500 ml. of 75% sulfuric acid, followed by 376 g. of sodium 3-nitrobenzenesulfonate in one portion, then 212 g. of glycerol over a 10 minute period. The mixture is stirred for 10 minutes, heated slowly to reflux temperature over a 2.5 hour period, then stirred and heated at reflux for 9 hours. The mixture is cooled, diluted with 400 ml. of ice water, basified with 855 ml. of 50% aqueous sodium hydroxide and warmed to 70° C. The supernatant solution is decanted and extracted with toluene. The toluene extract is in turn extracted with three 800 ml. portions of 2 N hydrochloric acid. The combined acid extract is basified with excess 50% aqueous sodium hydroxide and extracted with toluene. The toluene extract is evaporated at reduced pressure to give a residue of 6-(1,1-dimethylethyl)quinoline which is purified by distillation; b.p. 90°-94° C./ 0.18 mm.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:44]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:44]([NH:47][C:48]2[CH:49]=[CH:50][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([OH:67])=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[CH:52][CH:53]=2)(=[O:46])=[O:45])[CH:39]=[CH:40][C:41]=1[O:42][CH3:43]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2)cc1OC
Yield: 89 %

Procedure:
The compound of example 86 was prepared analogous to compound of example 78 by hydrolysis of compound of example 85.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]2[CH2:24][CH2:23][C@H:22]3[CH2:25][N:26](C(OCC)=O)[CH2:27][C@@H:21]23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](I)(C)C.CO>C(Cl)(Cl)Cl>[N:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:8])=[O:9])=[CH:19]3)[CH2:24][CH2:23][C@H:22]2[CH2:25][NH:26][CH2:27][C@@H:21]12
Reactant: CCOC(=O)N1C[C@@H]2CCN(c3cccc4cc(S(=O)(=O)c5ccccc5)cnc34)[C@@H]2C1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(=O)(c1ccccc1)c1cnc2c(N3CC[C@H]4CNC[C@H]43)cccc2c1
Yield: 21.8 %

Procedure:
A solution of (3aS,6aS)-ethyl 1-(3-(phenylsulfonyl)quinolin-8-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (60 mg, 0.133 mmol) and trimethylsilyl-iodide (160 mg, 0.797 mmol) in chloroform (1 mL) was stirred at reflux for 1.5 h. Methanol (4 mg) was added and the solution was partitioned between ethyl acetate and aqueous NaOH (1M). The organic extract was dried (MgSO4), filtered and concentrated to yield 11 mg (22%) of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:18])([F:17])[F:16])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8]Br.[C:27]([NH2:30])(=[S:29])[CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][C:13]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:15]([F:16])([F:18])[F:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][NH:30][C:27](=[S:29])[CH3:28]
Reactant: FC(F)(F)C1(c2cc(Cl)cc(Cl)c2)CC(c2ccc(CBr)c(Br)c2)=NO1
Reactant: CC(N)=S
Product: CC(=S)NCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
3-[3-bromo-4-(bromomethyl)phenyl]-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0.3 g) was mixed with thioacetamide (0.04 g), and the mixture was then stirred for one hour at 80° C. The residue was purified by silica gel chromatography to yield N-{2-bromo-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}ethanethioamide (0.09 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: Cc1ccc(OCc2ccc(Cl)cc2C(=O)O)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(4-methylphenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [N+:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([O-:3])=[O:2].[CH2:12]([OH:15])[CH2:13][OH:14].Cl>C1COCC1>[N+:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)([O-:3])=[O:2].[N+:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][CH2:8][C:7]2([O:15][CH2:12][CH2:13][O:14]2)[CH2:6]1)([O-:3])=[O:2]
Reactant: OCCO
Agent: Cl
Agent: O=C1CCC[C@H](C[N+](=O)[O-])C1
Solvent: C1CCOC1
Product: O=[N+]([O-])C[C@H]1CCCC2(C1)OCCO2
Reaction time: 18 h
Yield: 67 %

Procedure:
(S)-3-(nitromethyl)cyclohexanone was synthesized according to the general procedure found in Mei, K.; et al Org. Lett. 2009, 11, 2864-2867. A rt solution containing (3S)-3-(nitromethyl)cyclohexanone (64.6 g, 411 mmol) and ethylene glycol (68.8 mL, 1233 mmol) in THF (741 mL) was treated with HCl (12.5 mL, 411 mmol) under nitrogen. After stirring for 18 h the reaction mixture was concentrated. The residue was dissolved in Et2O and washed with water and saturated aqueous sodium bicarbonate. The combined aqueous layers were washed with Et2O. The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified on two 330 g silica gel columns (0-35% EtOAc/hexanes, 35 min gradient; 100 mL/min elution; 254 nm detection) to provide the title compound (27.7 g, 34% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.29 (dd, J=7.03, 11.80 Hz, 2H), 3.94 (d, J=3.01 Hz, 4H), 2.44-2.57 (m, J=3.51, 7.26, 7.26, 11.18, 14.95 Hz, 1H), 1.68-1.83 (m, 4H), 1.54-1.68 (m, 1H), 1.42-1.53 (m, 1H), 1.34 (t, J=12.17 Hz, 1H), 1.09 (ddd, J=3.76, 12.80, 24.59 Hz, 1H). MS (m/z) 202.1 (M+H+).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:5]([Cl:7])[N:6]=1.C([Li])CCC>C1COCC1>[Cl:7][C:5]1[N:6]=[CH:2][S:3][C:4]=1[CH:8]1[O:12][CH2:11][CH2:10][O:9]1
Reactant: Clc1nc(Cl)c(C2OCCO2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Clc1ncsc1C1OCCO1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
To a −78° C. solution of 2,4-dichloro-5-(1,3-dioxolan-2-yl)-1,3-thiazole (2.9 g, 12.7 mmol) in anhydrous THF (60 mL) was added a solution of butyl lithium (2.5 M in hexanes, 8 mL, 20 mmol). The reaction mixture was stirred at −78° C. for 1.5 hours. The reaction mixture was then quenched with brine (50 mL). The mixture was extracted with EtOAc (3×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo, affording 4-chloro-5-(1,3-dioxolan-2-yl)-1,3-thiazole (2.1 g, 87% yield). The product was used without further purification.