Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].CS(O[CH2:17][O:18][C:19](=[O:28])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)(=O)=O.CCCCCC.C(O)C>CC(C)=O>[N:1]1([CH:20]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]([O:18][CH3:17])=[O:28])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CS(=O)(=O)OCOC(=O)Cc1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CCCCCC
Product: COC(=O)C(c1ccc(Cl)cc1)n1cncn1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A suspension of 3.2 g of 1,2,4-triazole and 8.3 g of K2CO3 in 300 ml of anhydrous acetone is refluxed over 1 hour. After cooling to 10° C., 14 g of methyl α-(methanesulphonyloxymethyl-4-chlorophenyl-acetate is added. The temperature is then allowed to spontaneously rise to room temperature, and the reaction mixture is stirred for one hour, is filtered over fritted glass and the filtrate is concentrated under vacuum, 13 g thus being obtained of raw solid product, which is suspended with 10 ml of 1:1 n-hexane+ethanol mixture.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[Cl:13][C:12]1[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccnc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccnc1-n1cccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of 2 g of pyrazole, 4.34 g of 2,3-dichloropyridine, 9.58 g of cesium carbonate and 40 ml N,N-dimethylformamide was stirred at 100° C. for 8 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto. The mixture was extracted with methyl tert-butyl ether three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3.57 g of 3-chloro-2-(1H-pyrazol-1-yl)pyridine of the formula:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][C:21](OCC)=[O:22])([O-:9])=[O:8]>C1COCC1>[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][CH2:21][OH:22])([O-:9])=[O:8]
Reactant: CCOC(=O)CCc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2[nH]cc(CCCO)c2c1
Reaction time: 0.33 h
Yield: 70.1 %

Procedure:
To a suspension of 95% LiAlH4 (2.20 g, 0.058 mol) in 60 mL of dry THF was added a solution of ethyl 5-nitro-3-indolepropionate (7.30 g, 0.028 g mol) in 100 mL of dry THF, at 0° C. under Ar. After stirring for 20 min the mixture was quenched by cautiously adding 3 mL of H2O. The resulting suspension was stirred for 10 min and then it was filtered and the filtercake was washed with additional THF. The filtrate was evaporated and the residue was taken up in ether, dried (Na2SO4) and evaporated, and the resulting solid was triturated with hexane to give the title compound (4.30 g, 70%) as a yellow solid, m.p. 107°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[H-].[Na+].[CH2:14](I)[CH3:15].O>CN(C)C=O.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][N:9]([CH2:14][CH3:15])[N:8]=2)[S:5][CH:6]=1.[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([CH2:14][CH3:15])[N:9]=[CH:10][CH:11]=2)[S:5][CH:6]=1
Reactant: CCI
Reactant: Brc1csc(-c2cc[nH]n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCn1ccc(-c2cc(Br)cs2)n1
Product: CCn1nccc1-c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68 %
Yield: 15 %

Procedure:
3-(4-Bromo-2-thienyl)-1H-pyrazole (10.0 mmol) was dissolved in 25 mL dry N,N-dimethylformamide and cooled to 0° C. under argon atmosphere. Sodium hydride (15.0 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 15 min. After cooling to 0° C. again, ethyl iodide (20.0 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature overnight. Water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 1.76 g 3-(4-bromo-2-thienyl)-1-ethyl-1H-pyrazole (68% yield) and 403 mg of 5-(4-bromo-2-thienyl)-1-ethyl-1H-pyrazole (15% yield).
Reaction SMILES: N1[N:10]2[C:4](=[CH:5][NH:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH:3]=[CH:2]1.[CH2:15](N(CC)CC)C.S(Cl)(Cl)=O.[CH3:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:26][C:27]1[CH:42]=[CH:41][C:30]([O:31][C:32]2[CH:40]=[CH:39][C:35]([C:36]([N:6]3[C:7]4[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=4[CH2:9][N:10]4[CH:15]=[CH:2][CH:3]=[C:4]4[CH2:5]3)=[O:37])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(Oc2ccc(C(=O)Cl)cc2)cc1
Reactant: CCN(CC)CC
Reactant: C1=CC2=CNc3ccccc3CN2N1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(Oc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1.0 g of 10,11-dihydro-5H-pyrazolo[5,1-c][1,4]benzodiazepine in 30 ml of methylene chloride, under nitrogen, while cooling to 0° C. is added dropwise 30 ml of triethylamine followed by a solution of 1.2 equivalents of 4-(4-methylphenoxy)benzoyl chloride in 10 ml of CH2Cl2 (Reference Example 53) prepared from Reference Example 52 and thionyl chloride. The reactants are stirred at room temperature for 16 hours and concentrated in vacuo to a residue. The residue is dissolved in methylene chloride, washed with water, 2N HCl, water, saturated aqueous NaHCO3, water and dried (MgSO4) and evaporated in vacuo to give 2.2 g of the desired product. MS(M+H=395.1)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([Br:18])[N:3]=1.N[CH2:20][CH2:21][CH2:22][OH:23].O1CCOC[CH2:25]1>>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([S:8]([C:6]2[CH:7]=[C:2]([NH:3][CH2:20][CH2:21][CH2:22][OH:23])[CH:25]=[C:4]([Br:18])[CH:5]=2)(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: C1COCCO1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Reactant: NCCCO
Product: Nc1ccc(S(=O)(=O)c2cc(Br)cc(NCCCO)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
0.20 g (0.00051 mol) of 4-(2,6-dibromopyridine-4-sulphonyl)-phenylamine was dissolved in 10 ml dioxane and treated with 3.8 ml of 3-amino-1-propanol. The mixture was stirred at room temperature for 18 hrs., the solvent was removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:1 and finally with pure ethyl acetate. There was obtained 0.158 g (80%) of 3-[3-(4-aminobenzenesulphonyl)-5-bromophenylamino]-propan-1-ol as a brownish oil. MS (ISP): me/e=388, 386 (C14H17BrN3O3S+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]#N)=[C:7]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:8]2.[OH-:19].[Na+].[OH:21]O.Cl>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:17]([OH:21])=[O:19])=[C:7]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[CH:8]2
Reactant: COc1ccc(C#N)c2cc(C3CCCC3)oc12
Reactant: [OH-]
Reactant: OO
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccc(C(=O)O)c2cc(C3CCCC3)oc12
Temperature: 0 °C

Procedure:
0.5 g of 7-methoxy-2-cyclopentylbenzofuran-4carbonitrile is heated to reflux for 5 h in a solution of 10 ml of n-butanol, 30 ml of sodium hydroxide solution (50% strength) and 2.5 ml of hydrogen peroxide (30% strength). The mixture is then diluted with ice water, acidified to pH 1-2 with 2 N hydrochloric acid and the precipitate formed is filtered off with suction, washed with water until acid-free and dried in vacuo: m.p. 170-171° C.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[S:6])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCN=C=S
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCNC(=S)NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 6.6 %

Procedure:
A solution of propyl isothiocyanate (0.78 g, 7.72 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.256 g, 7.72 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide a pale orange syrup. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-propylthiourea as a white solid, m.p. 113-116° C. Mass spec M+1=433.2.
Reaction SMILES: [CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[N:21]=[CH:22][S:23][C:24]=1C=C>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:24]2[S:23][CH:22]=[N:21][C:20]=2[CH3:19])[C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1scnc1C
Reactant: C=CCCCCC(OC1CCCCC1)C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)C(CCCC/C=C/c1scnc1C)OC1CCCCC1
Temperature: 100 °C

Procedure:
A mixture of methyl 2-hydroxyoct-7-enoate (6.88 g, 0.040 mmol), dichloromethane (40 mL), 3,4-dihydro-2H-pyran (7.4 mL, 0.082 mol), and 6 drops of trifluoroacetic acid was stirred at room temperature overnight. The resulting mixture was concentrated in vacuo to yield methyl 2-(cyclohexyloxy)oct-7-enoate, which was used in the next step without further purification. A solution of methyl 2-(cyclohexyloxy)oct-7-enoate (500.0 mg, 1.95 mmol) dissolved in toluene (33 mL) containing 4-methyl-5-vinylthiazole (1.11 mL, 19.5 mmol) and Grubb's 2nd generation catalyst (166 mg, 0.195 mmol) was flushed with argon and heated in a sealed tube at 100° C. for 20 h. After cooling to room temperature, the solvent was removed in vacuo and the resulting residue was purified via flash silica gel chromatography (Analogix IF-280, SF25-115 g column, gradient 90:10-80:20 Heptane:EtOAc) to yield (E)-methyl 2-(cyclohexyloxy)-8-(4-methylthiazol-5-yl)oct-7-enoate. MS (ES+) 354 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:63][C@@H:64]1[C:67](=[O:68])[NH:66][C@@H:65]1[CH2:69][N:70]1[C:74]([CH2:75][NH:76][C:77](=[O:83])[O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[N:73][N:72]=[N:71]1>C(Cl)Cl.CN(C=O)C>[C:79]([O:78][C:77]([NH:76][CH2:75][C:74]1[N:70]([CH2:69][C@@H:65]2[C@H:64]([NH:63][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:8])([CH3:9])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:29])/[C:16]3[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[S:19][CH:20]=3)[C:67](=[O:68])[NH:66]2)[N:71]=[N:72][N:73]=1)=[O:83])([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1nnnn1C[C@H]1NC(=O)[C@H]1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1nnnn1C[C@H]1NC(=O)[C@H]1NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
Prepared in an analogous manner to example 4, step 3 using (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (214 mg, 0.498 mmol), DIPEA (953 μL, 5.46 mmol) and HATU (830 mg, 2.18 mmol) in DCM:DMF (5:1, 3.6 mL) at 0° C. followed by a solution of tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-tetrazol-5-yl)methyl)carbamate (123 mg, 0.415 mmol) in DCM:DMF (4.3:1, 3.7 mL). After stirring at rt for 1 h it was subjected to an identical workup then purified via silica gel chromatography (Acetone-DCM), affording the title compound (174 mg, 59%) as a light purple solid. LCMS: Rt=1.03 min, m/z=709.2 (M+1) Method 2m_acidic.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[I:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([I:12])=[C:14]([N+:22]([O-:24])=[O:23])[CH:15]=1)[CH2:5]2
Reactant: O=C(Cl)c1ccc(I)c([N+](=O)[O-])c1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CN2CCC1CC2)c1ccc(I)c([N+](=O)[O-])c1
Yield: 22.5 %

Procedure:
A solution of 3.08 g (24.4 mmol) of 3-aminoquinuclidine dihydrochloride, 7.60 g (24.4 mmol) of 4-iodo-3-nitrobenzoyl chloride, 9.88 g (97.6 mmol) of triethylamine in 150 ml of DMF was stirred at room temperature overnight. The solvent was distilled off in a rotary evaporator, the residue was taken up in 200 ml of dichloromethane, and 200 ml of a saturated sodium bicarbonate solution were added. The organic phase was dried over sodium sulfate, and the solvent was distilled off in vacuo. 2.20 g (22.5%) of the desired title compound were obtained.
Reaction SMILES: CN1CCOCC1.[OH2:8].[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[C:19]([NH:29][S:30]([C:33]2([CH2:36][CH:37]=[CH2:38])[CH2:35][CH2:34]2)(=[O:32])=[O:31])=[C:20]2[O:28][CH2:27][CH2:26][N:21]2[C:22](=[O:25])[C:23]=1[CH3:24].C[OH:40]>C1COCC1.C(Cl)Cl.[Os](=O)(=O)(=O)=O>[F:9][C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:11]=1[NH:17][C:18]1[C:19]([NH:29][S:30]([C:33]2([CH2:36][CH:37]([OH:40])[CH2:38][OH:8])[CH2:34][CH2:35]2)(=[O:32])=[O:31])=[C:20]2[O:28][CH2:27][CH2:26][N:21]2[C:22](=[O:25])[C:23]=1[CH3:24]
Reactant: O
Reactant: CO
Reactant: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(I)cc3F)c(C)c(=O)n3c2OCC3)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CC(O)CO)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
Osmium tetra oxide (8 mg, 0.003 mmol), N-methyl morpholine (8 mg, 0.068 mmol) and water (0.5 mL) were added to a stirred solution of 1-allyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (I-9a: 0.04 g, 0.073 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by TLC (5% MeOH in DCM). The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by thin layer chromatography on silica gel (5% MeOH in DCM) afforded 0.005 g of the product (11% yield).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:12]2=[O:35])=[CH:2]1.CN(C)[C:38](=O)[CH3:39]>C(O)CCC.[Zn]>[CH:30]([OH:32])=[O:31].[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[O:15][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])=[CH:19][C:18]=3[CH3:29])=[C:13]([C:30]([O:32][CH2:33][CH2:34][CH2:38][CH3:39])=[O:31])[C:12]2=[O:35])=[CH:2]1
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Agent: [Zn]
Solvent: CCCCO
Product: CCCCOC(=O)C1=C(Nc2ccc(OCCN(C)C)cc2C)OC(=Cc2c[nH]c3ncccc23)C1=O
Product: O=CO
Temperature: 25 °C
Yield: 31 %

Procedure:
A solution of ethyl 5-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-2-({4-[2-(dimethylamino)ethoxy]-2-methylphenyl}amino)-4-oxo-4,5-dihydrofuran-3-carboxylate (0.033 g, 0.070 mmol) which similarly prepared according to the procedure described in the Example 111, and zinc cluster catalyst (Zn4(OCOCF3)6O) (0.0033 g, 0.0035 mmol) in n-butanol (0.5 mL) and N,N-dimethylacetamide (0.5 mL) was stirred with the microwave synthesizer (Biotage Initiator™) at 150° C. for 30 min. Cooled to ambient temperature, the precipitate was removed by filtration. The filtrate was purified by preparative HPLC to afford the titled compound as solid (0.011 g, y. 31%).
Reaction SMILES: [Cl-].[C:2]([O:6][C:7](=[O:10])[CH2:8][Zn+])([CH3:5])([CH3:4])[CH3:3].[Cl:11][C:12]1[CH:40]=[CH:39][C:15]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:19]=2[C:25]2[C:26]([CH3:38])=[N:27][O:28][C:29]=2/[CH:30]=[N:31]/[S@@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])=[O:17])=[CH:14][CH:13]=1.[NH4+].[Cl-].CCOC(C)=O>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:19]=2[C:25]2[C:26]([CH3:38])=[N:27][O:28][C:29]=2[C@H:30]([NH:31][S@@:32]([C:34]([CH3:35])([CH3:36])[CH3:37])=[O:33])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:17])=[CH:39][CH:40]=1.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([C:18]2[C:22]([CH3:23])=[C:21]([CH3:24])[S:20][C:19]=2[C:25]2[C:26]([CH3:38])=[N:27][O:28][C:29]=2[C@@H:30]([NH:31][S@@:32]([C:34]([CH3:35])([CH3:36])[CH3:37])=[O:33])[CH2:8][C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:10])=[O:17])=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1noc(/C=N/[S@](=O)C(C)(C)C)c1-c1sc(C)c(C)c1C(=O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1sc(C)c(C)c1C(=O)c1ccc(Cl)cc1
Product: Cc1noc([C@H](CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1-c1sc(C)c(C)c1C(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 31 %
Yield: 43 %

Procedure:
To a cooled (0° C.) solution of (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.200 mL, 0.100 mmol) was added a solution of (R,E)-N-((4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)methylene)-2-methylpropane-2-sulfinamide (0.039 g, 0.084 mmol) in THF (0.5 mL). Additional THF (2×0.5 mL) was used to aid in complete transfer of the sulfinamide. After 1.5 h, additional (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (1.00 mL, 0.500 mmol) was added and the reaction temperature was allowed to reach to ambient temperatures. After several hours, the reaction mixture was diluted aqueous saturated NH4Cl and EtOAc. The aqueous layer was extracted with EtOAc (2×), the combined organic phase was washed with water (2×), dried over Na2SO4 and concentrated in vacuo to give a thick oil. The resultant oil was purified on Biotage system (gradient elution, 12% MTBE:95% Hexanes to 100% MTBE) to deliver the (3R)-tert-butyl 3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.016 g, 0.027 mmol, 31% yield) as a light white foam and (3S)-tert-butyl 3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate (0.021 g, 0.036 mmol, 43% yield) as a light white foam. (3R)-tert-butyl 3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate: LC/MS m/z 579 [(M (35Cl)+H]+ and m/z 581 [(M (37Cl)+H]+ and (3S)-tert-butyl 3-(4-(3-(4-chlorobenzoyl)-4,5-dimethylthiophen-2-yl)-3-methylisoxazol-5-yl)-3-((R)-1,1-dimethylethylsulfinamido)propanoate: LC/MS m/z 579 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:18]=[C:17]([C:19]3[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=3)[O:16][C:4]=2[N:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]=1.[CH:29]([Mg]Br)([CH3:31])[CH3:30]>>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][C:6]2[N:7]=[C:2]([CH:29]([CH3:31])[CH3:30])[C:3]3[N:18]=[C:17]([C:19]4[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH3:27])=[C:21]([CH3:28])[CH:20]=4)[O:16][C:4]=3[N:5]=2)=[CH:14][CH:13]=1
Reactant: COc1c(C)cc(-c2nc3c(Cl)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Reactant: CC(C)[Mg]Br
Product: COc1c(C)cc(-c2nc3c(C(C)C)nc(Cc4ccc(Cl)cc4)nc3o2)cc1C
Yield: 11 %

Procedure:
Analogously to example 7 (d), the reaction of 1.5 g of 7-chloro-5-(4-chlorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)oxazolo[5,4-d]pyrimidine with isopropylmagnesium bromide gave 165 mg (11%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[N:8]([CH3:11])[N:9]=[CH:10][C:3]=12.[CH3:12]B1OB(C)OB(C)O1.[C:21](=O)([O-])[O-].[Na+].[Na+]>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>[CH3:11][N:8]1[C:4]2[CH2:5][NH:6][CH2:7][C@@H:2]([CH3:12])[C:3]=2[CH:10]=[N:9]1.[CH3:11][N:8]1[C:4]2=[CH:5][N:6]=[CH:7][C:2]([CH3:21])=[C:3]2[CH:10]=[N:9]1
Reactant: Cn1ncc2c(Br)cncc21
Reactant: O=C([O-])[O-]
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Product: C[C@@H]1CNCc2c1cnn2C
Product: Cc1cncc2c1cnn2C

Procedure:
The requisite (4S)-1,4-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine was prepared in the following manner. Reaction of C8 at elevated temperature with trimethylboroxin in the presence of sodium carbonate and tetrakis(triphenylphosphine)palladium(0) afforded 1,4-dimethyl-1H-pyrazolo[3,4-c]pyridine. This material was reduced using the method described for synthesis of C9 from C8 in Example 2; the product was subjected to supercritical fluid chromatography to separate the enantiomers (Column: Chiral Technologies, Chiralpak IC, 5 μm; Eluent: 4:1 carbon dioxide/methanol). The second-eluting enantiomer was collected and used for synthesis of Example 20. The absolute stereochemistry was arbitrarily assigned.
Reaction SMILES: [F:1][CH:2]([F:14])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>CO.[Pd]>[F:1][CH:2]([F:14])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1NCC(F)F
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1NCC(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of 3.6 g (18 mM) of N-(2,2-difluoroethyl)-2-nitroaniline in 25 ml of methanol, were added 470 mg of palladium on carbon at 5%. The reaction mixture was stirred for 3 h at room temperature under hydrogen atmosphere, at room pressure and room temperature. The catalyst was filtrated on Celite and the filtrate was evaporated under vacuum to give 3 g of N-(2,2-difluoroethyl)benzene-1,2-diamine as an oil. Yield: 97.5%.