Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH:4]=[CH:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:7]=1>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=3)[NH2:21])=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(C2C=CCO2)c2c(-c3cccc([N+](=O)[O-])c3)ncnc21
Agent: [Pd]
Solvent: CO
Product: C[Si](C)(C)CCOCn1cc(C2CCCO2)c2c(-c3cccc(N)c3)ncnc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-(2,5-dihydrofuran-2-yl)-4-(3-nitrophenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 1.14 mmol) in methanol (6.0 mL), was added Pd/C (250 mg, 10 wt. % loading Pd). The atmosphere was purged with hydrogen gas and the resulting solution was stirred for 12 hours at room temperature under hydrogen atmosphere (1 atm). The reaction was then filtered and concentrated in vacuo to afford crude 3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline as a yellow oil. LRMS (ESI) calc'd for C22H31N4O2Si [M+H]+: 411, found 411. 1H NMR (400 MHz, CD3OD) δ 8.79 (d, J 3.2 Hz, 1H), 7.59 (s, 1H), 7.35-7.26 (m, 1H), 6.88-6.98 (m, 3H), 5.71 (s, 2H), 5.07-5.01 (m, 1H), 3.99-3.97 (m, 1H), 3.75-3.72 (m, 1H), 3.63-3.59 (m, 2H), 1.80-1.73 (m, 2H), 1.58-1.53 (m, 1H), 1.41-1.30 (m, 1H), 0.92-0.88 (m, 2H), 0.02 (s, 9H).
Reaction SMILES: [C:1]([C:3]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[C:18]([O:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:17]=1)([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:4][CH2:5][C:6]([O:8]C)=O)#[N:2].[H-].[Na+].Cl>COCCOC>[C:12]([CH:11]1[CH2:10][C:3]([C:1]#[N:2])([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:24])[F:25])=[C:18]([O:26][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:17]=2)[CH2:4][CH2:5][C:6]1=[O:8])([O:14][CH3:15])=[O:13]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccc(OC(F)F)c(OC2CCCC2)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C1CC(C#N)(c2ccc(OC(F)F)c(OC3CCCC3)c2)CCC1=O
Temperature: 0 °C
Yield: 27.8 %

Procedure:
To a solution of dimethyl 4-cyano-4-(3-cyclopentyloxy-4-difluoromethoxyphenyl)pimelate (3.1 g, 6.7 mmol) in dry 1,2-dimethoxyethane (50 mL) under an argon atmosphere was added sodium hydride (80% dispersion in mineral oil, 0.81 g, 27 mmol). The resulting mixture was refluxed for 20 min, additional 1,2-dimethoxyethane (50 mL) was added and the mixture was refluxed for another 70 min. The mixture was cooled to 0° C., was acidified with dilute hydrochloric acid and was concentrated. The mixture was partitioned between ether and dilute hydrochloric acid the organic layer was dried (magnesium sulfate) and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 85:15 hexanes/ethyl acetate, to provide a white solid (0.76 g, 37%): m.p. 109°-110.5° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1.[Li]C(C)(C)C.CCCCC.[CH3:28][S:29]SC>C(OCC)C>[CH3:28][S:29][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CSSC
Reactant: CCCN(CCC)C1Cc2ccc(Br)cc2C1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CCCN(CCC)C1Cc2ccc(SC)cc2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
Distilled (6-bromo-indan-2-yl)-dipropyl-amine (Example 11, 270 mg, 0.91 mmol) was dissolved in dry diethyl ether (20 mL). The solution was kept under argon and cooled to -78° C. A solution of t-BuLi in pentane 1.7M (0.7 mL, 1.20 mmol) was added and the mixture was stired at -78° C. for 1 h. Freshly distilled methyl disulfide (0.14 mL, 1.55 mmol) was added at -78° C. and the mixture was stirred at this temperature for 30 min. The reaction mixture was allowed to reach room temperature and stirred for an additional 1 h. The organic layer was washed with aq. Na2CO3 (5%), the layers separated, dried (Na2CO3) and evaporated to dryness. The crude product was chromatograped (SiO2) using dichloromethane-methanol (45:1) as eluant. The pure fractions were pooled yielding 180 mg (75%) of (6-methylsulfanyl-indan-2-yl)-dipropyl-amine. The free base was converted to the hydrochloride salt and recrystallized from a mixture of 2-propanol and isopropyl ether. m.p. 180-182 (HCl); 1H NMR (300 MHz, CDCl3) δ 0.90 (t, 6H), 1.55 (m, 4H), 2.45-2.60 (m, 7H), 2.80-3.10 (m, 4H), 3.60-3.75. m (1), 7.05-7.20 (m, 3H); 13C NMR (75.4 MHz, CDCl3) δ 12.01, 16.67, 20.21, 36.22, 36.64, 59.43, 63.32, 123.39, 124.81, 125.49, 135.70, 139.38, 142.91; MS m/e 263 (12, M+), 235 (100), 163 (31), 115 (23), 116 (17).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22](O)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][C:41](=[O:52])[CH2:42][CH2:43][C:44]2[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=2)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]([NH:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C@H:34]([NH:40][C:41](=[O:52])[CH2:42][CH2:43][C:44]4[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=4)[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:29][CH:28]=3)=[O:23])=[CH:19][C:18]=2[CH:25]=1)=[NH:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)CCc1ccc(OC)cc1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc2oc(C(=O)O)cc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc(NC(=O)c2cc3cc(C(=N)NC(=O)OCc4ccccc4)ccc3o2)cc1)NC(=O)CCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.2 %

Procedure:
5-(Benzyloxycarbonylamidino)-2-benzofurancarboxylic acid (151 mg, 0.447 mmol) and ethyl (S)-3-(4-aminophenyl)-2-[3-(4-methoxyphenyl)propionylamino]propionate (165 mg, 0.445 mmol) were dissolved in N,N-dimethylformamide (10 ml), and PyBOP (benzotriazol-1-yl-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate) (225 mg, 0.490 mmol) and N-methylmorpholine (0.05 ml, 0.455 mmol) were added. The mixture was stirred at room temperature for 15 hours. Water (20 ml) was added to the reaction mixture, and the resulting precipitate was collected by filtration and washed with water to give 271 mg of ethyl (S)-3-[4-[[5-(benzyloxycarbonylamidino)-2-benzofuranyl]carbonylamino]phenyl]-2-[3-(4-methoxyphenyl)propionylamino]propionate as a colorless solid (88%).
Reaction SMILES: I[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[CH:7][N:6]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ncc(I)c(OC)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: COc1ncc(-c2ccccc2C)c(OC)n1
Yield: 46.3 %

Procedure:
5-Iodo-2,4-dimethoxy-pyrimidine (1 g, 3.75 mmol) was dissolved in degassed n-PrOH (25 mL) and then 2-methylphenyl boronic acid (766 mg, 3.8 mmol), Na2CO3 (865 mg, 8.16 mmol), PPh3 (215 mg, 0.8 mmol) and Pd(OAc)2 (50 mg, 5.67 mmol) were added. The suspension was stirred at reflux for 3 hours. The solvent was evaporated and the crude was partitioned between water and DCM. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (1-9) to give 400 mg of the title compound (46% yield).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]([CH2:16][CH:17]1[CH2:19][CH2:18]1)[C:12](OC)=[O:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO>[CH:17]1([CH2:16][C@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])[CH2:12][OH:13])[CH2:19][CH2:18]1
Reactant: COC(=O)[C@H](CC1CC1)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H](CO)CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
NaBH4 (1.5 g, 39 mmol) was added in portions to a solution of (S)-methyl 2-(tert-butoxycarbonylamino)-3-cyclopropylpropanoate (Example 135 a, 3.15 g, 13 mmol) in MeOH (30 mL) at room temperature. The mixture was stirred at room temperature for 2 h. H2O (50 mL) was added and a white precipitate formed. The precipitate was collected by filtration and dried to give the title product (1.84 g, 66%) as white solid which was used in the next step without further purification; MS (EI): m/e=238.1 [M+Na]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH2:25][CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[N:21]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+].O1[CH2:54][CH2:53][O:52][CH2:51]C1>O>[Si:29]([O:28][CH2:27][CH2:26][CH2:25][N:24]1[C:23]2[CH:36]=[CH:37][CH:38]=[CH:39][C:22]=2[N:21]=[C:20]1[NH:19][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:4]3[CH:8]=[N:7][CH:11]=[CH:54][C:53]=3[O:52][CH3:51])[CH:3]=2)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=1)([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: C1COCCO1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1c(Nc2nn(COCC[Si](C)(C)C)c3ccc(Br)cc23)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccncc1-c1ccc2c(c1)c(Nc1nc3ccccc3n1CCCO[Si](C)(C)C(C)(C)C)nn2COCC[Si](C)(C)C
Temperature: 110 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of 5-bromo-N-(1-(3-(tert-butyldimethylsilyloxy)propyl)-1H-benzo[d]imidazol-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-amine (from Step 1: 191 mg, 0.000303 mol), 4-methoxypyridin-3-yl-3-boronic acid (64 mg, 0.00042 mol) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloropalladium(II), complexed with dichloromethane (1:1) (41 mg, 0.000050 mol), was dissolved in 1,4-dioxane (3.04 mL). To this mixture was added 2.0 M sodium carbonate in water (0.76 mL) with stirring. The mixture was flushed with argon sealed and heated at 110° C. After 3 hours, the mixture was diluted with methylene chloride, washed with water and brine, the organic phase dried over magnesium sulfate, filtered, and concentrated. The residue was dissolved in methylene chloride and purified by flash chromatography (50-100% ethyl acetate-0.3% triethylamine in hexanes) to give 132 mg (66%) of the title compound.
Reaction SMILES: [CH2:1]([N:4]([C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1Br)[S:5]([CH3:8])(=[O:7])=[O:6])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][S:5]([N:4]1[C:9]2[C:10](=[CH:11][CH:12]=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=2)[C:2]([CH3:3])=[CH:1]1)(=[O:7])=[O:6]
Reactant: C=CCN(c1cc([N+](=O)[O-])ccc1Br)S(C)(=O)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cn(S(C)(=O)=O)c2cc([N+](=O)[O-])ccc12
Yield: 62.9 %

Procedure:
According to the method of Martin, Helv. Chem. Acta. (1989) 72:1554, a mixture of N-allyl-N-(2-bromo-5-nitrophenyl)methanesulfonamide (2.45 g, 7.31 mmol), palladium acetate (83 mg, 0.37 mmol), tri-o-tolyl phoshpine (222 mg, 0.73 mmol) and diisopropylethylamine (1.42 g, 11.0 mmol) in 10 ml of toluene was heated to reflux for 18 hr. The reaction was cooled and filtered through a fine Whatman glass fiber filter to remove the palladium. The mixture was diluted with 100 ml of ethyl acetate, then washed successively with 1M HCl (50 ml) and brine. The extracts were dried (anhydrous MgSO4) and concentrated. The crude product was dissolved in acetone. Silica gel (10 g) was added then the solvent was removed at reduced pressure. The resultant powder was applied to silica gel column (110 g) and eluted with 25% ethyl acetate/hexane to give 1.17 g of 1-methanesulfonyl-3-methyl-6-nitro-1H-indole (63% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].[C:15]([CH:18]=[C:19]=[O:20])(=[O:17])[CH3:16]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:19](=[O:20])[CH2:18][C:15](=[O:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CC(=O)C=C=O
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(Cl)c1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
To a solution of 3-chloro-4-morpholinoaniline (2.05 g, 9.64 mmol) in EtOAc (30 mL) was added acetyl ketene (1.62 g, 19.3 mmol) with stirring and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=3:1) to give the title compound as a pale yellow solid (2.59 g, 91%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCOCC1.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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH:18]=[CH2:19])[CH2:12][CH2:13]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A mixture of 1-(2-bromo-4-nitrophenyl)-4-methylpiperazine (0.900 g, 3.00 mmol), tetrakis(triphenylphosphine)palladium(0) (0.104 g, 0.090 mmol), and tributyl(vinyl)tin (0.964 mL, 3.30 mmol) in 1,4-dioxane (30 mL) was degassed and heated at 105° C. overnight. After cooling, the suspension was filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:10])[CH:9]=1)[C:5]#[N:6].C1C(=O)N([Br:18])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][Br:18])[CH:9]=1)[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(C#N)c1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 101 %

Procedure:
A mixture of 3-bromo-5-methylbenzonitrile (9.80 g, 45.0 mmol), NBS (8.90 g, 45.0 mmol) and BPO (0.40 g) in CCl4 (250 mL) was heated for 10 h at reflux. The reaction mixture was cooled to room temperature and filtered, and the organic phase was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuum to give 12.5 g of crude 3-bromo-5-(bromomethyl)benzonitrile.
Reaction SMILES: [CH3:1][C:2]([S@:5](/[N:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:11][N:10]=1)=[O:6])([CH3:4])[CH3:3].[CH3:22][Mg]Br.C1COCC1>C(Cl)Cl>[CH3:4][C:2]([S@:5]([NH:7][CH:8]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:11][N:10]=1)[CH3:22])=[O:6])([CH3:1])[CH3:3]
Reactant: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ncc1OCC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of (R,E)-2-methyl-N-((4-methyl-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylene)propane-2-sulfinamide (1.1 g, 3.4 mmol, Step-6) in DCM (50 mL) is added dropwise a solution of methylmagnesium bromide in THF (0.97 M, 7.0 mL, 6.8 mmol) at −78° C. After stirring at −78° C. for 1 h, the reaction is quenched with saturated aqueous ammonium chloride solution (100 mL). The aqueous layer is extracted with DCM (100 mL×2). The combined organic layer is washed with water (100 mL), and dried over sodium sulfate. After filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (1:3) to give 1.09 g (94% yield) of the title compound as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Si](C)(C)C)=[CH:27][C:26]=2[F:35])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[N:9]=[CH:8]2)=[O:4].[I:36]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:36])=[CH:27][C:26]=2[F:35])=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[N:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc([Si](C)(C)C)cc1F
Reactant: ClI
Solvent: ClCCl
Product: COC(=O)c1ccc2c(cnn2S(=O)(=O)c2ccc(C)cc2)c1Nc1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 4-(2-fluoro-4-trimethylsilanylphenylamino)-1-(toluene-4-sulfonyl)-1H-indazole-5-carboxylic acid methyl ester (0.56 g, 1.1 mmol) in DCM (3 mL) at 0° C. was added a solution of iodine monochloride in DCM (2.2 mL, 1M, 2.2 mmol). The reaction mixture was stirred at 0° C. for 30 minutes. The reaction was quenched by the addition of water (10 mL) then diluted with saturated aqueous sodium thiosulfate solution (10 mL). The resultant mixture was extracted with ethyl acetate (3×20 mL) and the combined organic fractions washed with brine (20 mL), dried (MgSO4) then concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-100% DCM in cyclohexane) to yield the title compound as a light brown solid (0.51 g, 83%). LCMS (Method B): RT=4.87 min, [M+H]+=566.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:4].[N-:21]=[N+:22]=[N-:23].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[N:21]([C:2]1[C:3](=[O:4])[NH:5][C:6]2[C:7]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CBr)Nc1ccccc1C(=O)c1ccccc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=Nc1c(-c2ccccc2Cl)c2ccccc2[nH]c1=O

Procedure:
To a warm solution of 5.0 g. of 2-bromo-2'-(2-chlorobenzoyl)acetanilide in 100 ml. of methanol was added 1.8 g. of sodium azide. The solution was heated to reflux for 15 minutes. On addition of 0.77 ml. of a 35 percent solution of benzyltrimethylammonium hydroxide in methanol, and standing at room temperature overnight, 1.8 g. of pure (tlc) 3-azido-4-(2-chlorophenyl)carbostyril crystallized and was collected and washed with methanol. On recrystallization from dimethylformamide-methanol, pale yellow needles were obtained, having a melting point of 152°-155° dec.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1[C:20]([NH2:22])=[O:21].[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33](OC)=O)=[CH:26][C:25]=2[O:24]1.[O-]CC.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:23]1[O:31][C:30]2[CH:29]=[CH:28][C:27]([CH2:32][C:33]3[NH:22][C:20](=[O:21])[C:3]4[C:4]([CH2:17][CH2:18][CH3:19])=[N:5][N:6]([CH:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH3:10])[C:2]=4[N:1]=3)=[CH:26][C:25]=2[O:24]1
Reactant: CCCCCCC(CCC)n1nc(CCC)c(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCC(CCC)n1nc(CCC)c2c(=O)[nH]c(Cc3ccc4c(c3)OCO4)nc21
Yield: 47.7 %

Procedure:
6 mg (0.019 mmol) of 5-amino-3-propyl-1-(4-decyl)-1H-pyrazole-4-carboxamide and 20 mg (0.103 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic sodium ethoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 4.1 mg (47%) of a solid, Rf=0.68 (dichloromethane/methanol=15:1).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[S:23]([CH3:26])(=[O:25])=[O:24])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([CH:19]=O)[C:8]=3[CH:21]=2)[CH2:3][CH2:2]1.[CH2:36]([NH2:39])[CH2:37][NH2:38].BrN1C(=O)CCC1=O.CCCCCC.C(OCC)(=O)C>ClCCl>[CH:1]1([C:4]2[C:5]([N:22]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]4[NH:38][CH2:37][CH2:36][N:39]=4)[C:8]=3[CH:21]=2)[CH2:2][CH2:3]1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=O)c3cc2C2CC2)S(C)(=O)=O)cc1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C4=NCCN4)c3cc2C2CC2)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 90.7 %

Procedure:
To a mixture of Example 1L (7.0 g, 14.18 mmol) in dichloromethane (117 mL) under nitrogen was added ethylenediamine (0.938 g/1.043 mL, 15.60 mmol) dissolved in 2 mL of dichloromethane (2 mL) in 200 μL portions over 7 minutes. The mixture was stirred at room temperature for 4.5 hours. The reaction mixture was immersed in an ice bath and N-bromosuccinimide (2.65 g, 14.89 mmol) and powdered 4 Å molecular sieves (3.63 g) were added over ˜1 minute. The reaction mixture was stirred in the ice bath for 10 minutes, then the ice bath was removed and the reaction mixture was stirred at room temperature for a total of 72 hours. Reaction progress was monitored by LCMS. After each 24 hour period, additional ethylenediamine and N-bromosuccinimide were added followed by continued stirring at room temperature for 64 hours. The resulting slurry was filtered through a pad of diatomaceous earth with dichloromethane (2×100 mL) washes. The combined dichloromethane layers were washed with 10% sodium bicarbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the organic layer was concentrated in vacuo to an oily residue. The residue is treated with dichloromethane/acetonitrile (4:1, 100 mL), and the solvent was removed in vacuo leaving a tan foamy solid. The foamy solid was stirred for 20 minutes with hexane/ethyl acetate (4:1, 35 mL), filtered and dried in vacuo giving the title compound as a tan solid (6.86 g, 91%).
Reaction SMILES: [NH2:1][C:2](=[N:14][O:15][C:16](=O)[CH2:17][N:18]([CH:27]1[CH2:30][CH2:29][CH2:28]1)[C:19]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)=[O:20])[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(O)(=O)C>CN(C)C=O>[CH:27]1([N:18]([CH2:17][C:16]2[O:15][N:14]=[C:2]([C:3]3[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[N:1]=2)[C:19]([C:21]2[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=2)=[O:20])[CH2:30][CH2:29][CH2:28]1
Reactant: Cn1cnc(C(=O)N(CC(=O)ON=C(N)c2ccc(OC(F)(F)F)cc2)C2CCC2)c1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cn1cnc(C(=O)N(Cc2nc(-c3ccc(OC(F)(F)F)cc3)no2)C2CCC2)c1
Temperature: 120 °C
Yield: 9.7 %

Procedure:
A mixture of N-{2-[({amino[4-(trifluoromethoxy)phenyl]methylidene}amino)oxy]-2-oxoethyl}-N-cyclobutyl-1-methyl-1H-imidazole-4-carboxamide (75 mg), acetic acid (0.5 mL) and dimethylformamide (0.5 mL) was stirred while heating at 120° C. for 2 hr. After the solvent was distilled off under reduced pressure, the resulting residue was purified by HPLC to afford the title compound (7 mg).