Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[CH2:6]([NH2:8])[CH3:7].[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([C@@H:27]3[CH:32]4[O:33][C@@H:29]([CH2:30][CH2:31]4)[C@@H:28]3[CH2:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[CH2:42][CH2:43][C:44]([OH:46])=O)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.CN(C)CCCN=C=NCC>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:9]1([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]2[N:23]=[C:24]([CH:27]3[CH:28]([CH2:34][C:35]4[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=4[CH2:42][CH2:43][C:44](=[O:46])[NH:8][CH2:6][CH3:7])[CH:29]4[O:33][CH:32]3[CH2:31][CH2:30]4)[O:25][CH:26]=2)=[O:21])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(O)CCc1ccc(F)cc1C[C@H]1[C@@H]2CCC(O2)[C@H]1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCNC(=O)CCc1ccc(F)cc1CC1C2CCC(O2)C1c1nc(C(=O)NCCCCC2CCCCC2)co1
Reaction time: 23 h
Yield: 20.8 %

Procedure:
DMF (0.22 mL) and ethyl amine (77 μL, 0.15 mmol) were added to 3-(2-{(1S,2R,3S)-3-[4-(4-Cyclohexyl-butylcarbamoyl)-oxazol-2yl]-7-oxa-bicyclo[2.2.1]hept-2-ylmethyl}-4-fluoro-phenyl)-propionic acid (1) (28 mg, 0.053 mmol), EDCI [1-(3-dimehylaminopropyl)-3-ethylcarbodiimide hydrochloride] (17 mg, 0.089 mmol) and DMAP (8 mg, 0.065 mmol). The solution was stirred for 23 h and then was diluted with 15 mL ethyl acetate and washed with HCl (1 M, 3×15 mL). The ethyl acetate solution was then dried (Na2SO4), filtered and evaporated. Flash chromatography on silica gel (ethyl acetate) gave a mixture of the starting acid and the product amide. Purification by preparative thin layer chromatography (4% methanol/dichloromethane) gave the title amide (6 mg, 0.011 mmol, 20%). 1H NMR (300 MHz, ppm) δ 8.06 (s, 1 H) 7.1–7.0 (m, 2 H) 6.8–6.7 (m, 2 H) 5.43 (br s, 1 H) 4.97 (d, J=4.4 Hz, 1 H) 4.82 (d, J=4.4 Hz, 1 H) 3.4–3.3 (m, 3 H) 3.3–3.2 (m, 2 H) 2.9–2.8 (m, 2 H) 2.6–2.5 (m, 1 H) 2.3–2.1 (m, 4 H) 1.8–0.8 (m, 24 H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][NH:23][CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([NH2:35])=[O:34]>CC#N>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][N:22]([CH2:32][C:33]([NH2:35])=[O:34])[CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Yield: 82.9 %

Procedure:
Following the general method as outlined in Example 41, starting from 6-fluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole (Intermediate 5; 250 mg; 0.73 mmol), K2CO3 (274 mg; 1.98 mmol), and 2-bromoacetamide (274 mg; 1.99 mmol) and MeCN (20 mL), 241 mg (83%) of the title compound was obtained as a white solid after filtration and concentration.
Reaction SMILES: N(OCCC(C)C)=O.[CH3:9][O:10][C:11]([C:13]1[S:17][C:16](N)=[N:15][CH:14]=1)=[O:12].C(OCC)(=O)C>O1CCOCC1>[CH3:9][O:10][C:11]([C:13]1[S:17][CH:16]=[N:15][CH:14]=1)=[O:12]
Reactant: COC(=O)c1cnc(N)s1
Agent: CC(C)CCON=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cncs1
Temperature: 80 °C
Yield: 48.5 %

Procedure:
The mixture of 2.15 g of isoamyl nitrite and 10 ml of dioxane was stirred at 80° C. under a nitrogen atmosphere. A solution of 1.23 g of 2-aminothiazole-5-carboxylic acid methyl ester (7-3) in 20 ml of dioxane was added drop wise. The mixture was refluxed for 2 hours. After cooling to room temperature 30 ml of ethyl acetate was added. The mixture was washed with brine and dried and the solvent evaporated under reduced pressure. The crude product is purified on silica, thus yielding 0.54 g (48%) of thiazol 5-carboxylic acid methyl ester (7-4).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[C:5]([C:20]2[N:21](C(OC(C)(C)C)=O)[CH2:22][CH2:23][N:24]=2)[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH:9]=1)#[N:2].O1CCOCC1.Cl>>[C:1]([C:3]1[C:4]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[Cl:39])=[C:5]([C:20]2[NH:21][CH2:22][CH2:23][N:24]=2)[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])[CH:9]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCN=C1c1sc(-c2ccnc(NC(=O)C3CC3)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccnc(NC(=O)C3CC3)c2)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a solution of tert-butyl 2-[4-cyano-5-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}-3-(2,4-dichlorophenyl)-2-thienyl]-4,5-dihydro-1H-imidazole-1-carboxylate (0.315 g, 0.541 mmol) in 1,4-Dioxane (4.00 mL, 51.2 mmol) was added 4.00 M of Hydrochloric acid in 1,4-Dioxane (1.35 mL, 5.41 mmol), stirred at room temperature overnight. Solvent was evaporated, residue was diluted with DCM (50 mL) and washed with 1M NaOH (5 mL). Layers were separated and the aqueous phase was extracted with DCM (3×50 mL). Combined organic extracts were dried with MgSO4, filtered and evaporated. The residue was purified using ISCO chromatography on silica gel, elution 5 to 80% ethyl acetate in hexanes to afford the product (0.197 g, 76%). LCMS: (FA) ES+, 482, 484. 1H NMR (400 MHz, d1-chloroform) δ: 8.66-8.64 (m, 1H) 8.41-8.38 (m, 1H), 8.25 (s, 1H), 7.61-7.59 (m, 1H), 7.48-7.45 (m, 1H), 7.44-7.41 (m, 1H), 7.37-7.34 (m, 1H), 3.97-3.68 (m, 2H), 3.60-3.25 (m, 2H), 1.57-1.52 (m, 1H), 1.17-1.11 (m, 2H), 0.95-0.88 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[N:17]2[N:18]=[C:19]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:16]2[C:15]([CH3:41])=[CH:14][N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5](/[CH:7]=[CH:21]/[C:19]2[N:20]=[C:16]3[N:17]([C:12]([CH3:11])=[N:13][CH:14]=[C:15]3[CH3:41])[N:18]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cn1nc(Br)nc1C=O
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a solution of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (120 mg, 632 μmol, Eq: 1.00) in tetrahydrofuran (25 ml) were added ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (290 mg, 632 μmol, Eq: 1.00) (prepared as described in WO2011150156, pp 123-125, Expl. 24 g) and DBU (106 mg, 105 μl, 695 μmol, Eq: 1.1). The resulting solution was stirred for 18 hours at 25° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate methanol 0-10% as eluent affording 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (154 mg, 73%) as a white solid. MS: m/z=336.63537 (M+H+)
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[CH:19]=2)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:6]([Cl:10])(=[O:8])=[O:7])=[CH:27][CH:28]=1
Reactant: COc1ccc(Cc2cc3ccccc3s2)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1

Procedure:
2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride was prepared by the method of Example 40B with DMF (3.2 mmoles, 0.24 ml), sulfurylchloride (2.7 mmoles, 0.22 ml) and 2-(4-methoxybenzyl)benzo[b]thiophene (1.6 mmoles. 0.4 g). Flash chromatography using 2% ethyl acetate/hexanes provided 0.19 g (33%) of a light yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([CH2:28]Cl)=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][N:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:19]([CH2:28][NH:37][CH2:36][C:35]2[CH:38]=[CH:39][C:32]([O:31][CH3:30])=[CH:33][CH:34]=2)=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][N:22]=[CH:21]2)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1CCl)NC(=O)OCc1ccccc1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C(Cc1cc(Cl)c2[nH]ncc2c1CNCc1ccc(OC)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 83.3 %

Procedure:
To a solution of methyl 2-{[(benzyloxy)carbonyl]amino}-3-(7-chloro-4-{chloromethyl}-1H-indazol-5-yl)propanoate (4.3 g, 9.17 mmol) in acetonitrile (100 mL) was added 4-methoxybenzyl amine (2.4 mL, 2.52 g, 18.34 mmol) and the solution stirred at room temperature for several hours. The reaction was poured into a saturated aqueous solution of sodium bicarbonate (500 mL) and the mixture extracted with ethyl acetate. The combined organic extracts were washed once with brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give 4.1 g of the title compound. MS: m/z=537 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:34]=[C:35]=[O:36])[CH2:32][CH3:33]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35]([NH:34][CH2:31][CH2:32][CH3:33])=[O:36])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCCN=C=O
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CCCNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}3-propyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and n-propyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.33 min (Grad 2); ES-MS: m/eo=484.9.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:23][C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[F:34])[N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH:15]=2)(=O)=O)=CC=1.[CH3:45][O-].[Na+]>CO>[F:34][C:25]1[CH:26]=[C:27]([NH:30][C:31](=[O:33])[CH3:32])[CH:28]=[CH:29][C:24]=1[O:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[NH:16][CH:15]=[C:14]([CH2:13][CH2:12][O:11][CH3:45])[C:22]=12
Reactant: C[O-]
Reactant: CC(=O)Nc1ccc(Oc2ccnc3c2c(CCOS(=O)(=O)c2ccc(C)cc2)cn3S(=O)(=O)c2ccc(C)cc2)c(F)c1
Agent: [Na+]
Solvent: CO
Product: COCCc1c[nH]c2nccc(Oc3ccc(NC(C)=O)cc3F)c12
Temperature: 45 °C
Reaction time: 8 h

Procedure:
150 mg (0.24 mmol) of 2-{4-[4-(acetylamino)-2-fluorophenoxy]-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl 4-methylbenzenesulfonate are dissolved in 6 ml of methanol. 0.17 ml (0.94 mmol) of a 5.4M sodium methoxide solution is added, and the mixture is stirred at 45° C. overnight. The reaction solution is partitioned between 1N aqueous sodium hydroxide solution and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried over magnesium sulfate. The solvent is removed under reduced pressure. The product obtained is reacted without further purification.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[N:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:11]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[N:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:11]1
Reactant: CC(C)(C)OC(=O)NN1C[C@@H](COCc2ccccc2)OC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NN1C[C@@H](CO)OC1=O
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 5-(benzyloxymethyl)-2-oxooxazolidin-3-ylcarbamate (1.537 g, 4.77 mmol) in ethanol (25 mL), with 10% Pd/C (0.761 g, 0.715 mmol), was hydrogenated for 18 h at 40 psi. Conversion was about 40%. Catalyst was filtered away and replaced with fresh 10% Pd/C (0.254 g, 0.238 mmol); ammonium formate (0.752 g, 11.92 mmol) was added and the reaction was refluxed, under nitrogen, while stirring for 5 h. Conversion was complete. Catalyst was filtered away and the solvent evaporated. The residue was triturated with hot diisopropyl ether/MeOH (10:1) and left to precipitate on standing at r.t. The title compound was obtained as a white solid (802 mg, 3.45 mmol). Yield=72%.
Reaction SMILES: O[N:2]=[C:3]([CH2:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[NH:12][CH:11]=1)[C:4]([O:6]CC)=[O:5].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C.[Zn]>[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:10]([CH2:9][C@@H:3]([C:4]([OH:6])=[O:5])[NH2:2])=[CH:11][NH:12]2
Reactant: CCOC(=O)C(Cc1c[nH]c2cc(Cl)cc(Cl)c12)=NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1c[nH]c2cc(Cl)cc(Cl)c12)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 102.3 %

Procedure:
Dissolve ethyl 2-(hydroxyimino)-3-(4,6-dichloro-3-indolyl)propanoate (1.10 g, 3.65 mmol) in acetic acid (200 mL) and add activated zinc dust (1.25 g, 19.2 mmol). Stir at room temperature for 72 hours. Evaporate the acetic acid in vacuo to give a white oil. Take the white oil up in ethyl acetate (200 mL) and treat with saturated sodium hydrogen carbonate (500 mL). Filter the resulting white precipitate and separate the organic phase. Wash with saturated sodium hydrogen carbonate (100 mL) and brine (100 mL). Dry (MgSO4) and evaporate the solvent in vacuo to give the title compound as an amber oil (1.02 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=1[O:40][CH3:41]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][NH:12][CH2:13][CH:14]3[CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:30][C:29]=3[O:40][CH3:41])=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CCCC(=O)Cc1ccc(OCCCBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCC(=O)Cc1ccc(OCCCC2CNCCC2c2noc3cc(F)ccc23)c(OC)c1
Yield: 68.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)-3-methoxyphenyl]pentanone (3.7 g, 11.3 mmol) in acetonitrile (140 ml) was heated at reflux for 4 hours. At the end of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to an oil. Purification was performed by flash chromatography over a silica gel column (SiO2, 55 g; eluted with 1% methanol in dichloromethane, 600 ml; 3% methanol: 97% dichloromethane, 400 ml). The fractions containing pure product were pooled and concentrated to a solid (4.3 g, 91%). Recrystallization from ethanol (10 ml) gave a powdery solid of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-3-piperidinyl]propoxy]-3-methoxyphenyl]pentanone (3.22 g), m.p.=79°-80° C.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:55]([O:59][C:60]([NH:62][C@H:63]([C:68]([O:70]C(C)(C)C)=O)[CH2:64][C:65]([OH:67])=[O:66])=[O:61])([CH3:58])([CH3:57])[CH3:56]>ClCCl>[C:55]([O:59][C:60]([NH:62][C@H:63]([C:68]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:54])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:70])[CH2:64][C:65](=[O:66])[O:67][C:6]([CH3:11])([CH3:7])[CH3:4])=[O:61])([CH3:56])([CH3:57])[CH3:58]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 27 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-octadecyl-oleamide and N-tert-butyloxycarbonyl-O-tert-butyl-L-aspartic acid. Yield 27%. [α]D =-1.5° (c=0.55, dichloromethane).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].Cl[C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.CN(C=O)C>O>[CH2:1]([S:3][C:6]1[C:7]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=2)=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC[S-]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncccc1Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
0.89 g of sodium ethanethiolate was added to a mixture of 1.56 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide and 3 mL of DMF, and the mixture was stirred at 60° C. for 2 hours. The reaction mixture cooled to room temperature was poured to water, and the precipitated solid was taken by filtration. The resulting solid was dissolved in ethyl acetate, and the mixture was extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.64 g of 3-ethylsulfanyl-N-(3,5-bistrifluoromethylphenyl)picolinamide (hereinafter, referred to as Compound of Present Invention 10).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:29]1([S:35]([C:38]2[CH:39]=[C:40]([NH2:44])[CH:41]=[CH:42][CH:43]=2)(=[O:37])=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([NH:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:44][C:40]5[CH:41]=[CH:42][CH:43]=[C:38]([S:35]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)(=[O:37])=[O:36])[CH:39]=5)[N:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc(Nc3ccnc(Cl)n3)ccc21
Product: Cn1c(Nc2cc(C(C)(C)C)on2)nc2cc(Nc3ccnc(Nc4cccc(S(=O)(=O)N5CCOCC5)c4)n3)ccc21

Procedure:
The title compound was prepared following the procedure of Example I with N2-(5-tert-Butyl-isoxazol-3-yl)-N5-(2-chloro-pyrimidin-4-yl)-1-methyl-1H benzoimidazole-2,5-diamine (35 mg, 0.09 mmol) and 3-(Morpholine-4-sulfonyl)-phenylamine (23 mg, 0.10 mmol) to afford an off white solid (32 mg, 005. mmol). MS (ESI) m/z=605 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([N:12]=[C:13]=[S:14])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].[CH2:16]([NH2:19])[CH2:17][NH2:18]>C(Cl)Cl>[C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH3:15])[C:8]([NH:12][C:13]([NH:18][CH2:17][CH2:16][NH2:19])=[S:14])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2]
Reactant: Cc1c(N=C=S)ccc2c(C#N)c[nH]c12
Reactant: NCCN
Solvent: ClCCl
Product: Cc1c(NC(=S)NCCN)ccc2c(C#N)c[nH]c12
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyano-6-isothiocyanato-7-methylindole (0.152 g, 0.713 mmol) in methylene chloride (30 mL) is added ethylenediamine (0.286 mL, 4.28 mmol). The milky white mixture is stirred for 30 minutes followed by removal of the volatile organics by rotary evaporation. The residue is taken up in 10% methanol/methylene chloride, causing a precipitate to form. This mixture is filtered (solid is saved), and the filtrate is directly applied to a silica gel column. The mixture is separated using 15% methanol (ammonium hydroxide treated)/methylene chloride as eluent. The product containing fractions are combined with the previous precipitate and the solvents removed by rotary evaporation to yield 0.214 g of slightly impure 3-cyano-6-[N'-(2-aminoethyl)thioureido]-7-methylindole as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C1COCC1>[Cl:23][CH2:24][CH2:25][CH2:26][C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)=[O:28]
Reactant: CC1(C)COC(C(C)(C)c2ccc(Br)cc2)=N1
Reactant: O=C(Cl)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(C(C)(C)c2ccc(C(=O)CCCCl)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene (10.0 g. 0.0338 mole), prepared in accordance with Example 2, in 400 mL THF is cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) is added via syringe, and the mixture is stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., 4-chlorobutyryl chloride (14.4 g, 0.102 mole) in 30 mL THF is added dropwise, and the mixture is stirred at −78° C. for 30 minutes. The mixture is allowed to warm to −15° C. and is quenched with water. The product is extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue is cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 4-(4-chloro-1-oxobutyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl) toluene.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23](Br)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:24][CH:25]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc2ccccc2c1
Product: c1ccc2cc(-c3ccc(Cn4ccnc4)cn3)ccc2c1

Procedure:
Synthesized using 2-naphthylboronic acid (217 g, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 118 mg, 0.41 mmol, 66%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.23 (s, 2H), 6.97 (s, 1H), 7.17 (s, 1H), 7.50-7.53 (m, 2H), 7.57 (dd, J=8.2, 2.4 Hz, 1H), 7.85-7.88 (m, 3H), 7.95 (d, J=8.8 Hz, 2H), 8.11 (dd, J=8.5, J=1.8 Hz, 1H), 8.47 (d, J=0.9 Hz, 1H), 8.65 (d, J=1.8 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.4, 119.2, 120.9, 124.3, 126.4, 126.5, 126.8, 127.7, 128.6, 128.7, 129.3, 129.8, 133.4, 133.8, 135.7, 136.0, 137.2, 148.7; MS (ESI): m/z=285.92 [M+H]+.