Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(O)(=O)C>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:7])=[O:6])(=[O:22])=[O:21])=[CH:18][CH:19]=1)([O-:13])=[O:12]
Reactant: NC(=O)c1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: NC(=O)c1cccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C

Procedure:
A solution containing 44 g (0.32 m) of 3-aminobenzamide, 71.6 g (0.32 m) of p-nitrobenzenesulfonyl chloride and 700 ml of pyridine was stirred and heated on a steam bath for 2.5 hours, then poured into ice water. Acetic acid was added to a pH 5.0-6.0 and the resulting solid collected by filtration, washed with water and air-dried to give 105 g, m.p. 240°-244°.
Reaction SMILES: [H][H].[CH3:3][NH:4][CH3:5].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.CNC.C1(=O)CCCCC1>O>[CH3:3][N:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:5]
Reactant: CNC
Reactant: [H][H]
Reactant: O=C1CCCCC1
Solvent: O
Product: CN(C)C1CCCCC1

Procedure:
Under atmospheric pressure (1 bar absolute), the fresh gas flow was set to a constant 100 standard l/h (standard l=standard liters=volume at STP) by means of hydrogen. Dimethylamine and cyclohexanone were vaporized separately and, after mixing, introduced into the hot fresh gas stream. The laden gas stream was reacted isothermally at 150° C. (+/−2° C.) and 1 bar absolute over the catalyst in a tube reactor. The synthesis was carried out at a space velocity over the catalyst of 0.10 lalcohol/lcat·h, a molar ratio of dimethylamine/cyclohexanone of 3:1, an amount of circulating gas of 8.4 standard m3/h (standard m3 =standard cubic meters=volume at STP) and an amount of fresh gas/H2 of 100 standard liters/lcat·h. The cyclohexanone was completely reacted in the reaction and a selectivity of 88% based on the cyclohexanone used was achieved. The product was condensed in a water-cooled condenser and collected for purification by distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].[OH-].[Na+].O.Cl[CH2:15][CH2:16][OH:17]>C(O)CCC>[OH:17][CH2:16][CH2:15][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: OCCCl
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCO
Product: O=[N+]([O-])c1ccccc1OCCO
Temperature: 100 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
10 g (71.88 mmol) 2-nitrophenol A1 and 3.59 g (89.86 mmol) sodium hydroxide were dissolved in 55 ml n-butanol and 5 ml water at 70° C., 6.26 ml (7.52 g, 93.44 mmol) 2-chloroethanol were slowly added drop by drop. This was followed by three days of vigorous stirring at 100° C. After cooling, the reaction mixture was filtrated, the precipitate washed with chloroform and the filtrate reduced. The residue was taken up in chloroform and washed three times with aqueous 10% sodium hydroxide solution. Then the organic phase was dried over sodium sulfate and was concentrated in vacuo. 10.8 g of bright yellow crystals were obtained; yield 82%.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:16]=[C:15]([CH2:17][N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:29](Cl)(=[O:33])[C:30](Cl)=[O:31].[OH:35][N:36]1[C:40](=[O:41])[CH2:39][CH2:38][C:37]1=[O:42].N1C=CC=CC=1>ClCCl>[O:42]=[C:37]1[CH2:38][CH2:39][C:40](=[O:41])[N:36]1[O:35][C:29](=[O:33])[C:30]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[C:15]([CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[N:16]=2)[CH:2]=1)=[O:31]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(Cn2ccc3ccccc32)n1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(ON1C(=O)CCC1=O)C(=O)c1cn(Cc2cccc(CN3C(=O)c4ccccc4C3=O)n2)c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
2-(6-Indol-1-ylmethyl-pyridin-2-ylmethyl)-isoindole-1,3-dione (2.70 g, 7.35 mmol) was dissolved in dichloromethane (50 ml) and cooled to 0° C. Oxalylchloride (0.63 ml, 7.35 mmol) was added and the reaction kept at 0° C. for 30 minutes before the addition of N-hydroxysuccinimide (0.85 g, 7.35 mmol) followed by careful addition of pyridine (1.19 ml, 14.7 mmol). The reaction was kept at 0° C. for 30 minutes before it was allowed to slowly regain room temperature during 3 hours and then washed with water (40 ml) and brine (2×50 ml). The organic layer was dried over MgSO4 followed by removal of the solvent in vacuo to obtain the sub-title product (3.34 g, 85%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[C@@H:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@H:12]([C:19]([O:21][CH3:22])=[O:20])[CH2:11][C@@H:10]1[C:23]([OH:25])=[O:24])=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:33]CCl>>[ClH:33].[NH2:8][C@H:9]1[C@@H:13]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C@H:12]([C:19]([O:21][CH3:22])=[O:20])[CH2:11][C@@H:10]1[C:23]([OH:25])=[O:24]
Reactant: ClCCl
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](NC(=O)OC(C)(C)C)[C@H]1CNC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)[C@@H](N)[C@H]1CNC(C)=O
Product: Cl

Procedure:
A solution of (±)-(1S,2S,3R,4R)-2-(t-butyloxycarbonylamino)-3-(acetamidomethyl)-4-(methoxycarbonyl)-cyclopentane-1-carboxylic acid (66 mg, 0.18 mmole) in 3 mL of dichloromethane was reacted with trifluoroacetic acid (1.0 mL) for 1 hr, at room temperature. The solution was concentrated in vacuo at 25° C. The crude product was treated with 1 N HCl and concentrated in vacuo to provide the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10]>>[C:8]([NH:1][C:2]1[N:3]=[C:4]([Br:7])[S:5][CH:6]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: Nc1csc(Br)n1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)Nc1csc(Br)n1

Procedure:
4-Amino-2-bromothiazole is treated with acryloylchloride to give 4-acrylamido-2-bromothiazole which is refluxed with sodium in absolute methanol for sufficient time to produce the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][N:41]([C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:42](=[O:57])[C@H:43]([NH:55][CH3:56])[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][O:11][CH2:12][C:13](=[O:15])[N:55]([CH3:56])[C@@H:43]([C:42](=[O:57])[N:41]([CH3:40])[C@@H:58]([C:66](=[O:74])[NH:67][CH2:68][CH:69]1[CH2:73][CH2:72][CH2:71][O:70]1)[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[CH2:44][C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(COCC(=O)O)NC(=O)OC(C)(C)C
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C(=O)COCC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC1CCCO1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
(2-tert Butoxycarbonylamino-2-methylpropoxy)acetic acid (0.5 g; 2.06 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.2 g; 1.51 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.30 g; 1.58 mmol) were added. The reaction mixture was stirred for 15 min at room temperature. (2R)-N-Methyl-2-methylamino-3-(2-naphthyl)-N-((1R)-2-phenyl-1-(((tetrahydrofuran-2-yl)methyl)carbamoyl)ethyl)propionamide (0.65 g; 1.37 mmol) and diisopropylethylamine (0.26 mL; 1.51 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (100 mL) was added. The reaction mixture was washed with an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate (sat; 50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was filtered through silica to afford 0.76 g of (1,1-dimethyl-2-((N-methyl-N-((1R)-1-(N-methyl-N-((1R)-2-phenyl-1-((tetrahydrofuran-2-ylmethyl)carbamoyl)ethyl)-carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)methoxy)ethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:15])=[O:14]
Reactant: CCCSc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Reaction time: 1 h

Procedure:
The product of step i) (2 g) was added to ice-cooled fuming nitric acid (10 ml) over 1 hour and stirred at 0° for a further 1 hour. Pouring into ice followed by drying afforded the sub-title compound as a beige solid (1.7 g).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cu][C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:2]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:19]
Reactant: N#C[Cu]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Br)c1
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(C#N)c1
Temperature: 140 °C
Yield: 73.9 %

Procedure:
To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate (0.5 g, 1.77 mmol) in DMF (20 mL) was added copper(I) cyanide (CuCN; 0.23 g, 2.65 mmol), and the reaction mixture was heated at 140° C. for 3 h. The reaction mixture was cooled to 25° C., diluted with H2O, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; eluting with 15% EtOAc in n-hexane) to afford the title compound as a white solid (0.3 g, 72%): mp 51-53° C.; 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.93 (d, J=17.6 Hz, 1H), 5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 229.84 ([M+H]+); IR (thin film) 2370, 1709, 1142 cm−1.
Reaction SMILES: C=CC.[CH2:4]=[C:5]([CH3:7])[CH3:6].C[C:9]1([CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]1)C=C.[CH2:17]1[C:25]2C(=CC=C[CH:24]=2)[CH2:19][CH2:18]1.[Cl:26][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:28]>[Cl-].[Zn+2].[Cl-].ClCCl>[C:27]([Cl:26])([C:9]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:28]1[CH:24]=[CH:25][CH:17]=[CH:18][CH:19]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH2:4]=[C:5]([CH3:7])[CH3:6]
Reactant: c1ccc2c(c1)CCC2
Reactant: CC(Cl)c1ccccc1
Reactant: C=CC1(C)C=CC=CC1
Agent: C=C(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: C=CC
Product: ClC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The reaction of substituted benzyl halides with olefins such as propene, isobutene and 1-methylstyrene in the presence of zinc chloride or zinc chloride etherate in dichloromethane as solvent is described in J. Org. Chem., 48 (1983), 1159-65. In general the 1:1 addition. product is obtained not only at -78° C. but also at from 0° to +80° C. (see also J. Org. Chem. 29 (1964), 2685-7). The subsequent cyclization to the indane is only found when reacting 1-chloro-1-phenylethane with 1-methylstyrene at +50° C. and trityl chloride with isobutene at 0° C., in yields of 80 and 21% respectively. W. Striepe, Thesis, Erlangen University (1984), 28, 29 and 119, reveals that indanes can be obtained by first reacting p-methylcumyl chloride with an alkyl-substituted olefin at a low temperature in the presence of zinc chloride etherate and then warming the reaction mixture to room temperature in the course of 10 h. However, this method is industrially of little use because of the low temperature and a low space-time yield.
Reaction SMILES: C1COCC1.[Li+].[BH4-].[CH3:8][CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][N:10]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CO>[CH2:19]([O:18][C:16]([N:10]1[CH2:11][CH:12]([OH:15])[CH2:13][CH2:14][CH:9]1[CH3:8])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1CCC(=O)CN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(O)CN1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of THF (200 mL) and MeOH (11 mL) was added LiBH4 (2 M, 89 mL, 0.18 mol). Some gas evolution and a small exotherm were observed. The reaction was aged at room temperature for 30 min before being cooled to −10° C.±benzyl 2-methyl-5-oxopiperidine-1-carboxylate (22.0 g, 0.089 mol) was then added dropwise, keeping the temperature below −5° C. The reaction was then aged at −10° C. for 30 min. The reaction was quenched by adding half-saturated, aqueous NaHCO3, then extracted with EtOAc. The layers were separated and the organics dried with MgSO4. The organics were concentrated to give crude ±benzyl-5-hydroxy-2-methylpiperidine-1-carboxylate as a crude, colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH3:26])=[O:11])=[N:6][CH:7]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:27][C:4]1[C:5]([O:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH3:26])=[O:11])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: [H][H]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ncc(Cl)cc1N
Yield: 86.3 %

Procedure:
To a solution of 2-(5-chloro-3-nitro-pyridin-2-yloxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.96 g, 2.3 mmol) in ethanol (25 mL) was added platinum dioxide on carbon (0.90 mg, 5% on carbon). The reaction was subject to 35 psi hydrogen gas for 20 minutes. The reaction was filtered through celite, concentrated in vacuo and chromatographed on silica gel to give the title compound (0.78 g).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH2:11](O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(I)nc1
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1ccc(I)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11 g of 2-iodopyridine-5-carboxylic acid were suspended in 300 ml of dichloromethane and 4 8 g of benzyl alcohol, 10 g of dicyclohexylcarbodiimide and 100 mg of 4-dimethylaminopyridine were added. The mixture was stirred at room temperature and, after 2 hours, filtered. The filtrate was evaporated and the residue was chromatographed on silica gel using firstly ethyl acetate/petroleum ether (1:9) and then ethyl acetate/petroleum ether (1:6) for the elution. There were obtained 12.2 g of benzyl 2-iodopyridine-5-carboxylate which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])([O-:3])=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([N:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[CH2:14][CH2:15]2)=[CH:6][C:5]=1[O:29][CH2:30][C:31]([F:34])([F:33])[F:32])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(c3ccc([N+](=O)[O-])c(OCC(F)(F)F)c3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCNCC3)CC2)cc1OCC(F)(F)F
Temperature: 0 °C
Yield: 82 %

Procedure:
1,1-Dimethylethyl 4-(1-{4-nitro-3-[(2,2,2-trifluoroethyl)oxy]phenyl}-4-piperidinyl)-1-piperazinecarboxylate (1.35 g, 2.76 mmol) was dissolved in 40 mL of DCM with stirring. TFA (10.0 mL, 130 mmol) was added via syringe, and the reaction was stirred for 3 h and cooled to 0° C. The reaction was quenched with 20 mL of 6N NaOH (aqueous). Saturated NaHCO3 (aqueous) was added until the pH was approximately 9. The mixture was poured into H2O and DCM. The layers were separated, and the aqueous layer was washed with 4:1 DCM/iPrOH (2×) and 4:1 EtOAc/iPrOH. The combined organic layers was dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 0.879 g (82%) of the title compound of step E. 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.5 Hz, 1H), 6.63 (dd, J=9.5, 2.4 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.88 (q, J=8.7 Hz, 2H), 4.02 (d, J=13.6 Hz, 2H), 2.84-2.98 (m, 2H), 2.56-2.67 (m, 4H), 2.26-2.49 (m, 5H), 1.96 (br. s., 1H), 1.70-1.84 (m, 2H), 1.38 (d, J=8.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH2:18]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[C:8]([OH:13])=[O:18]
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Product: O=C(O)c1cc(F)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 5-fluoro-2-nitrotoluene (25.0 g, 161 mmol), potassium permanganate (102 g, 645 mmol) and water (500 mL) was heated and stirred at 100° C. for 3 hours. The solution was cooled to room temperature, and insoluble matter derived from potassium permanganate was removed by celite filtration. The filtrate was washed with diethylether, made acidic by the addition of conc. hydrochloric acid, and organic matter was extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5-fluoro-2-nitrobenzoic acid. To a solution of 5-fluoro-2-nitro benzoic acid thus obtained in ethanol (100 mL) was added 10% palladium-carbon (0.5 g, 50% hydrate), and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give the title compound (6.25 g, 25% yield).
Reaction SMILES: C=O.[CH3:3][NH:4][CH3:5].[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=2)[CH:10]=[N:9][N:8]=[N:7]1.[C:18](=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:3][N:4]([CH2:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[CH:10]=[N:9][N:8]=[N:7]2)=[CH:16][CH:15]=1)[CH3:5]
Reactant: Sc1ccc(-n2cnnn2)cc1
Reactant: CNC
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)CSc1ccc(-n2cnnn2)cc1

Procedure:
To 1.0 ml. (10 mmol) of formalin at 0°-5° C. was added dropwise, with stirring, 1.1 ml. (10 mmol) of dimethylamine. After 20 minutes stirring, 1.78 g. (10 mmol) of p-(1H-tetrazol-1-yl)benzenethiol was added all at once followed by solid sodium carbonate. The mixture was stoppered, stirred vigorously for 11/2 hours, and dichloromethane added. The dichloromethane layer was washed with water, dried, and evaporated to give white crystals, m.p. 56°-57.5° C.
Reaction SMILES: [OH:1][C@:2]1([C:30]([O:32]C)=[O:31])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[OH-].[Na+].CO>C1COCC1>[OH:1][C@:2]1([C:30]([OH:32])=[O:31])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:7][S:8]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]([CH3:29])[CH:20]=2)=[CH:15][CH:16]=1)(=[O:9])=[O:10]
Reactant: COC(=O)[C@@]1(O)CCC[C@H]1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@]3(O)C(=O)O)cc2)c2ccccc2n1
Reaction time: 5 h
Yield: 438.1 %

Procedure:
To a solution of methyl (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylate (0.19 g, 0.4 mmol ) in THF (2 mL) was added sodium hydroxide solution (5 M, 2 mL) and methanol (2 mL) to make the reaction mixture homogenous. The reaction was stirred for 5 h, and then the MeOH/THF was removed in vacuo. The reaction was quenched with a pH 3 sodium phoshphate buffer. Ethyl acetate was added to this mixture, resulting in the formation of a white precipitate which was isolated by filtration to afford (1R,2R)-1-hydroxy-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid (0.8 g, 42%) as a white solid. MS: 457.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH3:26])[CH:6]=[CH:5][C:4]=1[C:27]1[NH:31][C:30](=[O:32])[O:29][N:28]=1.[Br:33]N1C(=O)CCC1=O>C(#N)C>[Br:33][C:6]1[C:7]([O:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH3:26])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:27]2[NH:31][C:30](=[O:32])[O:29][N:28]=2)[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1-c1noc(=O)[nH]1
Solvent: CC#N
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)c(Br)cc1-c1noc(=O)[nH]1
Temperature: 70 °C
Yield: 29.9 %

Procedure:
To a solution of 100 mg of 3-{2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one in 1 ml of acetonitrile was added 0.08 g of N-bromosuccinimide. The resulting mixture was heated to 70° C. overnight, concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (gradient of dichloromethane/methanol from 100/0 to 94/6) and washed with 94/6 dichloromethane/methanol to give 35 mg of 3-{5-bromo-2-methoxy-4-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-phenyl}-4H-[1,2,4]oxadiazol-5-one.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:19]=2)[NH:15][N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCCc1cc(Nc2nc(-c3ccccc3)nc3ccccc23)[nH]n1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A solution of [5-(3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl]-(2-phenyl-quinazolin-4-yl)-amine (III-80) (250 mg, 0.56 mmol), in dichloromethane (3 mL) at 0° C. was treated with TFA (2 mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane (3×5 mL) and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3 mL) and water (3 mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 80° C. under vacuum to afford III-79 as an off-white powder (122 mg, 63%): mp 205-207° C.; 1H NMR (DMSO) δ 1.68-1.83 (2H, m), 2.65-2.80(4H, m), 6.80 (1H, s), 7.50-7.60 (4H, m), 7.80-7.90 (2H, m), 8.45-8.53 (2H, m), 8.65 (1H, d), 10.45 (1H, br s); IR (solid) 1621, 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 951, 830, 776, 764, 705, 677; MS 345.3(M+H)+.