Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=S)=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH2:18])=[C:13]([NH2:19])[CH:12]=1>>[ClH:10].[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]2[N:18]=[C:8]([NH:7][C:3]3[C:2]([CH3:1])=[CH:6][S:5][CH:4]=3)[NH:19][C:13]=2[CH:12]=1
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1N
Product: Cc1cscc1Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Product: Cl

Procedure:
N-(2-Amino-4,5-dichlorophenyl)-N′-(4-methyl-3-thienyl)thiourea is obtained analogously to the reaction described in example 1b) from 4-methyl-3-thienyl isothiocyanate and 4,5-dichloro-1,2-diaminobenzene. Crystalline solid, m.p. 310-320° C. b) 3N-(5,6-Dichloro-2-benzimidazolyl)-4-methyl-3-thienylamine hydrochloride is obtained analogously to the procedure described in example 1c) from N-(2-amino-4,5-dichlorophenyl)-N′-(4-methyl-3-thienyl)thiourea and methyl iodide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:6][CH:7]=1.NC1C(C(OCC)=[O:31])=NC=CC=1.C1C=CC(CC(Cl)=O)=CC=1.CC1(C(F)(F)F)OO1.FC(F)(F)C(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[N+:6]([O-:31])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([NH:13][C:14](=[O:22])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: CCOC(=O)c1ncc(Cl)cc1NC(=O)Cc1ccccc1
Reactant: CCOC(=O)c1ncccc1N
Agent: CC(=O)C(F)(F)F
Agent: CC1(C(F)(F)F)OO1
Agent: O=C(Cl)Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)Cc2ccccc2)cc(Cl)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 4 %

Procedure:
Ethyl 5-chloro-3-(phenylacetamido)picolinate (153) was formed by reacting ethyl 3-aminopicolinate and phenacetyl chloride under the conditions described in Example 3. The amide (153) (10.0 mg, 0.0324 mmol) was added to a CH2Cl2 solution (10 mL) of methyl(trifluoromethyl)dioxirane, generated from 2.5 mL of 1,1,1-trifluoroacetone using the procedure of Mello et al. (Mello et al., J. Amer. Chem. Soc. 111:6749-6757 (1989)). The solution was stirred at rt in a bomb protected from light. After 4 days, the solvent was removed and the residue chromatographed by prep TLC (silica GF). Eluting with hexanes-EtOAc (1:4), the band at Rf =0.45 was removed and triturated with MeOH (40 mL) overnight. The mixture was filtered and the filtrate rota-evaporated to dryness, leaving a white residue (0.4 mg, 4%). 1H NMR (CDCl3): δ1.26 (t, J=7.2, 3, CH3CH2), 3.75 (s, 2, benzylic), 4.10 (q, J=7.2, 2, CH3CH2O), 7.37 (m, 5, phenyl), 7.98 (d, J=0.9, 1, py), 8.44 (s, 1, py); LRMS (m/z):336 (5), 335 (5), 334 (M+, 20), 274 (15), 273 (10), 272 (55), 260 (10), 226 (10), 180 (10), 156 (10), 154 (30), 126 (10), 117 (20), 91 (100), 65 (15); HRMS Calcd for C16H15ClN2O4 : 334.0720, Found: 334.0729; HPLC: 77%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[N:17][N:18]([CH2:21][CH3:22])[C:19]=3[CH3:20])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]([NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:31])[CH3:30].O>CN(C)C(=O)C.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>[ClH:1].[CH2:21]([N:18]1[C:19]([CH3:20])=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:3]3[C:2]([C:37]4[CH:38]=[CH:39][C:34]([CH2:33][NH:32][C:29](=[O:31])[CH3:30])=[CH:35][CH:36]=4)=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:9][CH2:10]2)[CH:16]=[N:17]1)[CH3:22]
Reactant: CCn1ncc(CN2CCN(c3nccnc3Cl)CC2)c1C
Reactant: CC(=O)NCc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1ncc(CN2CCN(c3nccnc3-c3ccc(CNC(C)=O)cc3)CC2)c1C
Product: Cl
Yield: 87.4 %

Procedure:
Combine 3′-chloro-4-(1-ethyl-5-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.300 g, 0.935 mmol), potassium carbonate (0.310 g, 2.24 mmol), (4-acetamidomethylphenyl)boronic acid (0.216 g, 1.12 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.009 mmol) in N,N-dimethylacetamide (1.9 mL). Add water (940 μL), and reflux reaction for 6 hr. Add DCM and wash with water. Extract water layer three times with DCM. Dry combined organics (magnesium sulfate) and purify (silica gel chromatography, eluting with 50:50 to 100:0 ethyl acetate:hexanes then 10:90 to 20:80 methanol:ethyl acetate), to give the free base of the title compound (384 mg, 95%). Dissolve the free base (0.381 g, 0.880 mmol) in acetonitrile (1.06 mL) and add aq. 1 N HCl solution (1.06 mL, 1.06 mmol). Shake for 15 min. at ambient temperature. Freeze dry to give the title compound (416 mg, 100%). MS (ES): m/z=434 [M+H]+.
Reaction SMILES: [C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:31]2)=CC=1>C1(C)C=CC=CC=1.CO>[C:1]1([CH2:11][CH:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][C:13]2=[S:31])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: S=C1N=C2C=CC=CN2C1Cc1cccc2ccccc12
Temperature: 160 °C

Procedure:
A suspension of 200 mg (0.73 mmol) of 3-naphthalen-1-ylmethyl-imidazo[1,2-a]pyridin-2-one and 250 mg (0.62 mmol) of 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's reagent) in 20 mL of toluene is heated at 160° C. for 1 h under microwave condition. The resulting mixture is dissolved in methanol and absorbed on silica gel. The slurry is dried under reduced pressure and is purified by flash chromatography on silica gel. The compound is eluted 5˜10% methanol in dichloromethane solution to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([O:31]C)=[O:30])[N:19]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:28][C:29]([OH:31])=[O:30])[N:19]=1
Reactant: COC(=O)Cc1ccccc1OCc1csc(CCc2nc(-c3ccccc3)oc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCc1nc(COc2ccccc2CC(=O)O)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.1 %

Procedure:
To a mixture of methyl 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate (0.49 g), tetrahydrofuran (3 mL) and methanol (3 mL) was added a 1N aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid (3 mL) and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (0.38 g, 79%) of 2-[2-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 152-153° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:19][C:18]=2[F:29])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]>C(O)C.[Pd]>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:28])([CH3:27])[CH3:26])=[CH:19][C:18]=2[F:29])=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CC(C)(O)C#Cc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)CCc1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)c(F)c1
Yield: 99 %

Procedure:
The product of Example 12, 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methyl-1-butynyl)anilino]-N-(2-hydroxyethoxy)benzamide was hydrogenated in absolute ethanol in the presence of 5% Pd/C by the general procedure of Example 1, Step D. The resulting crude solid was purified by filtration through a plug of silica (MeOH as eluant) to give 3,4-difluoro-2-[2-fluoro-4-(3-hydroxy-3-methylbutyl)anilino]-N-(2-hydroxyethoxy)benzamide (99%) as a cream foam (hygroscopic). 1H NMR [400 MHz, (CD3)2SO] δ 10.09 (br s, 1 H), 7.60–7.55 (m, 1 H), 7.03–6.91 (m, 2 H), 6.86 (dd, J=8.2, 1.4 Hz, 1 H), 6.71 (ddd, J=8.6, 8.6, 5.8 Hz, 1 H), 4.22 (br s, 1 H), 3.79 (t, J=4.9 Hz, 2 H), 3.55 (t, J=4.9 Hz, 2 H), 2.60–2.49 (m, 2 H), 1.65–1.59 (m, 2 H), 1.13 (s, 6 H). HRMS (EI+) calcd for C20H23F3N2O4 412.1610 (M+), found 412.1617.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:13])=[O:12].[CH:14]([C:17]1[N:18]=[C:19]([C:22](Cl)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]>O1CCOCC1>[CH:14]([C:17]1[N:18]=[C:19]([C:22]([NH:1][C:2]2[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=2[C:11](=[O:12])[CH3:13])=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1csc(C(=O)Cl)n1
Reactant: COc1ccc(C(C)=O)c(N)c1C
Solvent: C1COCCO1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of the compound 4 (18.6 g, 104 mmol) in dioxane (50 mL) was added under nitrogen to a suspension of 4-isopropylthiazole-2-carbonyl chloride in dioxane (250 mL). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCO3 and AcOEt, organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropyl ether, filtered off and washed with diisopropyl ether to give 30.8 g (90%) of the title product 5.
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].CS(C)=O.[CH3:14][N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]2=[CH:26][S:27][CH:28]=[C:17]2[C:16]1=[O:29]>Cl.CCOCC>[CH3:4][N:5]([CH3:6])[CH2:7][CH2:8][N:19]1[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:15]([CH3:14])[C:16](=[O:29])[C:17]2=[CH:28][S:27][CH:26]=[C:18]12
Reactant: CN1C(=O)c2cscc2Nc2ccccc21
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CN(C)CCN1c2cscc2C(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
A mixture of 0.72 g. of 55% sodium hydride-mineral oil dispersion and 0.60 g. of dimethylaminoethylchloride hydrochloride in 25 ml. of dimethylsulfoxide is stirred at room temperature for 0.5 hours. To the mixture is added 0.46 g. of 4,9-dihydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and stirring is continued for 3 hours. The reaction mixture is quenched by dropwise addition of water, diluted with about 200 ml. of water, acidified, filtered, made alkaline with 5N sodium hydroxide and extracted several times with chloroform. The chloroform extracts are dried over magnesium sulfate and concentrated under reduced pressure to give an amber oil. The oil is dissolved in a minimal volume of ethanolic hydrogen chloride solution and diluted with ether to give an oily semi-solid which slowly crystallizes. Recrystallization from ethanol-ether gives tan crystals, m.p. 245°-248° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.[F:26][C:27]([F:34])([F:33])[CH2:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[F:26][C:27]([F:34])([F:33])[CH2:28][S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:31])=[O:30]
Reactant: Cn1cc(-c2cc(N)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2OC2CCOCC2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.7 %

Procedure:
To a solution of Example 99b (43.2 mg, 0.127 mmol) in dichloromethane (2 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.015 mL, 0.140 mmol) and triethylamine (0.053 mL, 0.382 mmol). The mixture was stirred for 18 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by flash column chromatography (silica gel, 0.5-5% methanol in dichloromethane) to provide the title compound (20.8 mg, 33.7% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.00 (s, 1H), 10.16 (s, 1H), 7.25-7.32 (m, 3H), 7.14-7.20 (m, 2H), 6.18-6.24 (m, 1H), 4.36-4.55 (m, 3H), 3.52-3.68 (m, 5H), 3.33-3.45 (m, 2H), 1.79-1.94 (m, 2H), 1.39-1.57 (m, 2H). MS (ESI+) m/z 486.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][NH2:15])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[CH3:18][C:19]([CH3:21])=O>>[CH2:1]([O:3][C:4]([N:6]1[CH2:17][CH2:16][C:9]2[N:10]=[N:11][C:12]([NH:14][N:15]=[C:19]([CH3:21])[CH3:18])=[CH:13][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2nnc(NN)cc2C1
Reactant: CC(C)=O
Product: CCOC(=O)N1CCc2nnc(NN=C(C)C)cc2C1

Procedure:
A suspension of 23.7 g of 3-hydrazino-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid ethyl ester in 100 cc of acetone is heated at reflux for 4 hours while stirring. The title compound has a M.P. of 171°-174° (decomp., from methanol).
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[OH:9].C(N(CC)CC)C.[C:17]([C:23]([O:25][CH3:26])=[O:24])#[C:18][C:19]([O:21][CH3:22])=[O:20]>C(Cl)(Cl)Cl>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:17]1([C:23]([O:25][CH3:26])=[O:24])[O:9][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:3]2=[N:2]1
Reactant: N=C1CCCCN1O
Reactant: COC(=O)C#CC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1(C(=O)OC)N=C2CCCCN2O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-iminopiperidin-1-ol hydrochloride in chloroform was added triethylamine. The mixture was stirred for 5 min. at room temperature, then cooled to 0° C. and 1.2 eq. of dimethyl acetylenedicarboxylate were added dropwise under stirring. The cooling bath was removed and the mixture was stirred at room temperature for one hour. The solvent was removed under reduced pressure and the solution was partitioned between ethyl acetate and half saturated aq. ammonium chloride. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered through silica gel. The solvent was removed under vacuum to afford methyl 2-(2-methoxy-2-oxoethyl)-5,6,7,8-tetrahydro-2H-[1,2,4]oxadiazolo[2,3-a]pyridine-2-carboxylate as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:14]1([CH2:13][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][OH:11])[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC(CC1CCCC1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CO)CC1CCCC1
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 72.2 %

Procedure:
To a solution of 2-((tert-butoxycarbonyl)amino)-3-cyclopentylpropanoic acid (730 mg, 2.84 mmol) in THF (7.5 mL) cooled to −10° C. was added N-methylmorpholine (0.312 mL, 2.84 mmol) followed by isobutyl chloroformate (0.373 mL, 2.84 mmol). The reaction mixture was then stirred for 5 min. The solid obtained was removed by filtration and washed with THF (5 mL). The filtrate was cooled to −10° C. and treated with NaBH4 (161 mg, 4.26 mmol) in water (5 mL) dropwise. The reaction mixture was stirred at −10° C. for 10 min and allowed to warm to room temperature and stirred for another 30 min. The reaction mixture was then quenched with cold water (5 mL). The aqueous layer extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure to afford a residue which was purified by column chromatography (pet ether: ethyl acetate) to afford tert-butyl 1-cyclopentyl-3-hydroxypropan-2-ylcarbamate (500 mg, 2.05 mmol, 72% yield). 1H NMR (400 MHz, DMSO-d6) δ 6.38 (m, 1 H), 4.51 (m, 1 H), 3.85-3.65 (m, 1 H), 3.42 (m, 1 H), 3.25 (m, 1 H), 3.8 (m, 1 H), 2.75 (m, 1 H), 1.85-1.65 (m, 4H), 1.6-1.25 (m, 12 H), 1.15 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[N+:34]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[OH:22])=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:40]2[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)NC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)ccc1O
Yield: 50 %

Procedure:
The resin-bound 3-(4-bromo-phenyl)-(2S)-[(4′-trifluoromethyl-4-hydroxy-biphenyl-3-carbonyl)-amino]-propionic acid methyl ester (50 mg, 0.1 mmol) prepared as generally described in Example 37 was reacted with 4-nitro-phenyl boronic acid (50.1 mg, 0.3 mmol) by adapting the procedure as described in Example 43 to give title compound (28.2 mg, 50%). LC/MS (m/z): 565 (M+1)+.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:7]1)[CH2:2][CH:3]([CH3:5])[CH3:4].[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][NH:28][CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[F:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([NH:27][N:28]([C:17](=[O:19])/[CH:16]=[CH:15]/[C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH:7]=2)[CH:29]([CH3:30])[CH3:31])=[O:26])=[CH:23][CH:22]=1
Reactant: CC(C)CCn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CCn1cc(/C=C/C(=O)N(NC(=O)c2ccc(F)cc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-isopentyl-1H-indol-3-yl)acrylic acid (170 mg, 0.66 mmol), 4-fluoro-N′-isopropylbenzohydrazide (194.3 mg, 0.99 mmol) and HATU (376.4 mg, 0.99 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.17 ml, 0.99 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that ivory (E)-4-fluoro-N′-(3-(1-isopentyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained (160.0 mg, 55.7%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.S(O[CH2:22][CH2:23][O:24][C@H:25]1[CH2:42][CH2:41][C@@:40]2([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@:31]3([OH:49])[CH2:32][CH2:33][C@@H:34]2[C:44]2[CH:48]=[CH:47][O:46][CH:45]=2)[CH2:26]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:6]1([CH2:5][CH2:4][O:3][CH2:22][CH2:23][O:24][C@H:25]2[CH2:42][CH2:41][C@@:40]3([CH3:43])[C@H:27]([CH2:28][CH2:29][C@@H:30]4[C@@H:39]3[CH2:38][CH2:37][C@@:35]3([CH3:36])[C@:31]4([OH:49])[CH2:32][CH2:33][C@@H:34]3[C:44]3[CH:48]=[CH:47][O:46][CH:45]=3)[CH2:26]2)[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: OCCN1CCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CC[C@H](OCCOCCN3CCCC3)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 86.7 %

Procedure:
To a suspension of 0.13 g of NaH (60% dispersion in mineral oil) in 15 ml of anhydrous dimethylformamide, 0.37 g of 1-(2-hydroxyethyl)pyrrolidine were added at room temperature in a nitrogen atmosphere. The mixture was kept at reflux for 2 hrs, then 0.90 g of 3β-(2-tosyloxy-ethoxy)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as an intermediate in Ex. 7, were added. The mixture was kept at reflux temperature for 4 hrs; then 50 ml of water were added cautiously. The residue was extracted with methylene chloride, the organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using acetone/methanol 85/15 as eluant to give 0.70 g of the title compound (I-ah) as a light yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4](=[O:13])[CH2:3]1.Br[CH2:15][CH2:16][Cl:17]>CO.C(Cl)Cl.O>[Cl:17][CH2:16][CH2:15][N:5]1[C:4](=[O:13])[CH2:3][CH:2]([CH3:1])[N:6]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: ClCCBr
Reactant: CC1CC(=O)NN1c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC1CC(=O)N(CCCl)N1c1ccccc1
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
A sodium methylate solution, obtained from 3.9 g sodium and 80 ml methanol is added to a suspension of 26.1 g 5-methyl-1-phenylpyrazolin-3-one in 200 ml methanol. After stirring for 30 minutes, 43.02 g 1-bromo-2-chloroethane are added to the clear solution at ambient temperature. The reaction mixture is heated for 15 hours under reflux. Then the solvent is drawn off under reduced pressure. The residue which remains is dissolved in 250 ml methylene chloride and 100 ml water. The organic phase is separated off, dried over sodium sulphate, filtered, and the solvent is evaporated off under reduced pressure. The residue is dissolved in ethyl ether, and the solution is filtered to remove the remaining initial material. Then the solvent is evaporated and the residue (27 g) is boiled in 100 ml butanol or 8 hours under reflux. Finally, the solvent is evaporated in a vacuum and the residue is purified by column chromatography over silica gel. 20 g 2-(2-chloroethyl)-5-methyl-1-phenylpyrazolin-3-one are obtained as an oil.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[K+].[CH3:7][N:8]1[C:12](Cl)=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1>C1OCCOCCOCCOCCOCCOC1.CS(C)=O.O>[CH3:7][N:8]1[C:12]([S:1][CH2:2][CH2:3][OH:4])=[C:11]([Cl:14])[C:10]([Cl:15])=[N:9]1
Reactant: OCCS
Reactant: Cn1nc(Cl)c(Cl)c1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(Cl)c(Cl)c1SCCO
Temperature: 140 °C
Yield: 38.1 %

Procedure:
To a mixture of 26.5 g (0.34 moles) 2-mercaptoethanol, 19 g of 85% potassium hydroxide, and a few drops of 18-Crown-6 in 250 ml of DMSO, 60 g(0.32 moles) 1-methyl-3,4,5-trichloro pyrazole (product of Example 1 or 1A)were added in portions. When the addition was complete, the reaction mixture was heated to 140° C. for 1 day. The cooled reaction mixture was diluted with water and extracted with ether. The oganic phase was washed four times with 200 ml water per time, dried and stripped. The crude product was chromatographed on a silica gel column. The product, 1-methyl-3,4-dichloro-5-(2-hydroxyethyl) thio pyrazole, was eluted from the column with ethyl acetate, yielding 27.7 g (37.7% yield) of a yellow oil.