Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([O:12][CH3:13])(OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:14][C:15]1[C:20]([O:21][CH3:22])=[CH:19][C:18]([C:23]2[O:27][CH2:26][C:25]([CH3:29])([CH3:28])[C:24]=2[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17]C=1O.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>S(O)(C1C=CC(C)=CC=1)(=O)=O.O.O>[C:30]([C:24]1[C:25]([CH3:29])([CH3:28])[CH2:26][O:27][C:23]=1[C:18]1[CH:19]=[C:20]([O:21][CH3:22])[C:15]2[N:14]=[C:3]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[O:12][C:13]=2[CH:17]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc(O)c1N
Reactant: COC(OC)(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C2=C(C(C)(C)C)C(C)(C)CO2)cc2oc(-c3ccccc3)nc12
Temperature: 150 °C
Yield: 78.3 %

Procedure:
To 1.00 mL (5.82 mmol) of trimethyl orthobenzoate was added 204 mg (0.70 mmol) of 5-(4-amino-3-hydroxy-5-methoxyphenyl)-4-t-butyl-3,3-dimethyl-2,3-dihydrofuran (Compound [61]), and the mixture was refluxed for 1.5 hours at 150° C. To this reaction mixture, 2.0 ml of ethyl acetate, and 0.2 ml of H2O, and 10.1 mg (0.05 mmol) of TsOH H2O was added and the mixture was refluxed for 1 hours at 97° C. The resulting mixture was poured in saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried with magnesium sulfate anhydride, and concentrated. The residue was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=10:1) to obtain 207 mg of 4-t-butyl-5-(4-methoxy-2-phenylbenzo[d]oxazol-6-yl)-3,3-dimethyl-2,3-dihydrofuran (Compound [62]). Yield 78.4%.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](Br)=[O:9].C(N(CC)CC)C>ClCCl>[Br:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: C1CCNC1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of pyrrolidine (1.7 g, 24 mmol), bromoacetyl bromide (4.6 g, 24 mmol) and triethylamine (2.02 g, 20 mmol) in dichloromethane (40 mL) was stirred at room temperature for 4 hours. The precipitate was filtered off and the residue was concentrated to give 3.1 g of 2-bromo-1-pyrrolidin-1-yl-ethanone as a light brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].S(OOS([O-])(=O)=O)([O-])(=O)=[O:12].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:12])#[N:2]
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: N#Cc1cccc(CN)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 51.2 %

Procedure:
13.2 g of m-cyanobenzylamine, 23.8 g of sodium persulfate and 200 ml of water were mixed and allowed to react at 70° C. for 2 hours while stirring. After cooling the reaction mixture to room temperature, sodium bicarbonate was added to render the solution weakly alkaline. The solution was subjected to separation, column chromatography, and crystallization operations in the same manner as in Example 19 to obtain 6.7 g (yield: 51%) of m-cyanobenzaldehyde. The purity was 98%.
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO.O1CCCC1>[OH:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3[N:21]([CH3:35])[N:22]([C:25]4[CH:34]=[N:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[C:23](=[O:24])[C:17]=3[CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nccc(N2CCc3c(c(=O)n(-c4cnc5ccccc5n4)n3C)C2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of (R)-1-[4-(1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-pyrimidin-2-yl]-ethyl butyrate (prepared according to the method of Example 75, Step D, 248 mg, 0.52 mmol) in a 5:2 mixture of methanol/tetrahydrofuran (7 mL) was added potassium carbonate (218 mg, 1.57 mmol). This mixture was stirred at room temperature overnight and evaporated. The residue was diluted with saturated aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→3% methanol/chloroform) to give 150 mg (71%) of the title compound as a white solid. mp: 217-219° C. (dec); 1H NMR (CDCl3, 250 MHz) δ 9.66 (s, 1H), 8.25 (d, 1H), 8.12 (dd, 1H), 7.99 (m, 1H), 7.68-7.78 (c, 2H), 6.47 (d, 1H), 4.72 (q, 12H), 4.32 (s, 2H), 4.19-4.14 (c, 3H), 3.41 (s, 3H), 2.80 (t, 2H), 1.51 (d, 3H); MS (APCI) 404 (MH+); [α]D+13.4 (c 1.5, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]=[O:13])=[CH:7][N:6]=1)=[O:4].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([CH2:11][CH:12]2[O:16][CH2:15][CH2:14][O:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: OCCO
Reactant: COC(=O)c1cnc(CC=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1cnc(CC2OCCO2)cn1
Yield: 85.7 %

Procedure:
A solution of 5-(2-oxo-ethyl)-pyrazine-2-carboxylic acid methyl ester (295 mg, 1.42 mmol) and ethylene glycol (100 μL, 1.79 mmol) in benzene (10 mL) was treated with p-toluenesulfonic acid monohydrate (27 mg, 0.142 mmol), and the mixture was heated under reflux with a Dean-Stark condenser for 20 h. The mixture was cooled, diluted with benzene (15 mL), and then washed with a saturated aqueous sodium bicarbonate solution (10 mL) followed by a saturated aqueous sodium chloride solution (10 mL). Each aqueous phase was extracted with a small portion of benzene. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to dryness to afford 5-[1,3]dioxolan-2-ylmethyl-pyrazine-2-carboxylic acid methyl ester as an orange oil (273 mg, 86%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([Cl:25])=[C:7]([C:21]([Cl:24])=[CH:22][CH:23]=1)[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:16]([Br:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:29].O>CN(C)C=O>[Br:20][C:16]1[N:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][C:7]3[C:21]([Cl:24])=[CH:22][CH:23]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH3:29])[C:6]=3[Cl:25])[C:11]2=[N:18][C:17]=1[CH3:19]
Reactant: CI
Reactant: CC(=O)Nc1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Yield: 58.9 %

Procedure:
To a solution of 8-(3-acetylamino-2,6-dichlorobenzyloxy)-3-bromo-2-methylimidazo[1,2-a]pyridine (222 mg) in N,N-dimethylformamide (2 ml) was added sodium hydride (24 mg, 60% oil dispersion) in one portion at ambient temperature. The mixture was stirred for half an hour at the same temperature and iodomethane (142 mg) was added thereto. After stirring for half an hour, the mixture was poured into water. The separated oil was extracted with ethyl acetate. The extracts were washed with water, dried, and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel to give 3-bromo-8-[2,6-dichloro-3-(N-acetyl-N-methylamino) benzyloxy]-2-methylimidazo[1,2-a]pyridine (135 mg) as a solid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C.C(Cl)(Cl)Cl>[NH2:18][C:14](=[O:17])[CH2:15][CH2:16][N:10]1[CH2:9][CH2:8][N:7]([C:5]([O:4][C:2]([CH3:13])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH2:11]1
Reactant: C=CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCC(N)=O)CC1

Procedure:
A molten mixture of 7.5 (0.04 mole) of 1-(1,1-dimethylethoxycarbonyl)piperazine, 2.9 g (0.04 mole) of acrylamide and 3 drops of acetic acid was stirred and heated at 65° for 18 hours. The mixture which had solidified during the heating period was dissolved in 100 ml of chloroform and washed with dilute aqueous sodium hydroxide solution. The dried (MgSO4) CHCl3 solution was filtered and evaporated in vacuo to yield a white solid. Recrystallization from toluene-hexane returned 8.0 g (78%) of product, m.p. 96°-8°. Calc. for C12H13N3O3 (257.335): C, 56.01; H, 9.01; N, 16.33. Found: C, 56.05; H, 9.04; N, 16.05.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:63]1([NH:69][CH2:70][C@@H:71]2[CH2:75][CH2:74][CH2:73][NH:72]2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[CH2:70][NH:69][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CNc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (S)-2-(phenylaminomethyl)-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl>O1CCOCC1>[CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-N-((R)-Cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.765 mmol), ethanol (2.7 mL), and 4.0 M of hydrogen chloride in dioxane (2.7 mL) were combined and the mixture was stirred at rt overnight. Reaction was concentrated down to an oil and then redissolved and washed with ethanol 3 times, and concentrated. The residue was dried on the high vacuum overnight to obtain a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.Cl[C:7]1[S:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([Cl:12])[N:11]=1>CN1CCCC1=O>[Cl:12][C:10]1[N:11]=[C:7]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[S:8][C:9]=1[N+:13]([O-:15])=[O:14]
Reactant: c1cc[nH]c1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1sc(-n2cccc2)nc1Cl
Temperature: 70 °C
Yield: 71.9 %

Procedure:
6.7 g (0.1 mol) of pyrrole are added to a solution of 10.0 g (0.05 mol) of 2,4-dichloro-5-nitrothiazole in 100 ml of N-methyl-2-pyrrolidinone at room temperature. The mixture is then heated at 70° C. for 5 hours and subsequently cooled to room temperature and stirred into 1 l of ice-water. The precipitate formed is filtered off, washed with water and dried. 8.25 g (72.0% of theory) of 4-chloro-5-nitro-2-(1-pyrrolyl)-thiazole of melting point 138° C. to 139° C. (yellow needles from toluene) are obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)=[CH:5][C:4]=1[Cl:27].[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:27][C:4]1[CH:5]=[C:6]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:7]=[CH:8][C:3]=1[CH2:2][N:32]1[C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]2[C:28]1=[O:38]
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CC(c2ccc(CBr)c(Cl)c2)=NO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1Cl

Procedure:
To a solution of 34.1 g of 3-(4-bromomethyl-3-chlorophenyl)-5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole in 200 mL of N,N-dimethylformamide, 12.6 g of potassium phthalimide was added and the resultant mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted with 350 mL of ethyl acetate and the diluted reaction mixture was washed with water (80 mL×3). Subsequently, the washed reaction mixture was dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:3) to obtain 24.3 g of the objective substance as a light yellow resinoid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[C:9]([CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:8][CH:7]=[CH:6][C:5]=1[O:13][CH3:14])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc(CCO)c1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCOS(C)(=O)=O)c1CCOS(C)(=O)=O
Yield: 96.1 %

Procedure:
To a slurry of 2,3-bis-(2-hydroxyethyl)-1-methoxybenzene (50.6 g, 0.258 mol, 1 equiv.) and triethylamine (78.3 g, 0.774 mol, 3 equiv.) in DCM (500 mL) at 0° C., add dropwise a solution of methanesulfonyl chloride (65.0 g, 0.567 mol, 2.2 equiv.) in DCM (100 mL) over 45 min. The addition is exothermic and the methanesulfonyl chloride is added at a rate to keep the temperature below 10° C. After the addition is complete, warm the reaction to ambient temperature. Wash the solution with water (2×500 mL), and then brine (750 mL). Dry the organic layer over Na2SO4, filter and concentrate in vacuo to obtain the desired intermediate as a dark yellow oil (87.4 g, 96.2%), which is used in the next reaction without further purification. An analytical sample is obtained by flash column chromatography eluting with 100% diethyl ether. 1H NMR (300 MHz, CDCl3), δ 7.20 (t, 1H, J=7.9), 6.82 (s, 1H, J=7.2), 6.80 (s, 1H, J=8.2), 4.41-4.34 (m, 4H), 3.83 (s, 3H), 3.16-3.09 (m, 4H), 2.91 (s, 3H), 2.87 (s, 3H); 13C NMR (300 MHz, CDCl3), δ 158.07, 136.55, 128.26, 123.34, 122.39, 109.24, 69.88, 69.08, 55.55, 37.35, 37.14, 32.57, 26.47; 13C NMR (300 MHz, DMSO-d6), δ 157.58, 136.79, 127.81, 122.91, 122.00, 109.33, 70.19, 68.88, 55.55, 36.49, 36.47, 31.56, 25.72; IR (KBr): 1586.8, 1469.4, 1358.51, 1267.3, 1173.9, 1105.4, 972.4, 954.6, 914.3 cm−1; MS (ES+) m/z 257 (M+H)+; Anal. Calc'd. for C13H20O7S2: C, 44.31; H, 5.72; N, 0. Found: C, 44.22, H, 5.68; N, 0.13; Rf=0.72 eluting with 95:5 DCM/methanol.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15]([CH3:43])=[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[C:17]4[N:18]([N:20]=[C:21]([NH:23][C:24]([NH:26]C5CCNCC5)=[O:25])[N:22]=4)[CH:19]=3)=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C=O.C(O[BH-](O[C:56](=O)[CH3:57])OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[CH3:13][N:9]1[CH2:57][CH2:56][CH:4]([N:23]([C:21]2[N:22]=[C:17]3[C:16]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=4)=[C:15]([CH3:43])[C:14]([C:13]4[N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=5)[N:10]=[CH:11][CH:12]=4)=[CH:19][N:18]3[N:20]=2)[C:24]([NH2:26])=[O:25])[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)NC3CCNCC3)nc2c1-c1cccc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N(C(N)=O)C3CCN(C)CC3)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.4 %

Procedure:
To a solution of 1-[6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-piperidin-4-yl-urea (Ex. 50, 53 mg, 0.09 mmol) in DCM (2 mL) was added 37% aqueous formaldehyde solution (75 μL.) and 2 drops of MeOH, followed by sodium triacetoxyborohydride (160 mg, 0.75 mmol), and the solution was stirred at RT for 18 hrs. The reaction mixture was partitioned between DCM (15 ml) and aqueous 2 M Na2CO3, and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (19 mg).
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[CH3:41][N:42]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[N:43]1>C(Cl)Cl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:47]([C:44]2[CH:45]=[CH:46][N:42]([CH3:41])[N:43]=2)(=[O:49])=[O:48])[CH2:6][CH2:5]1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.21 g, 0.48 mmol) and DIPEA (0.26 mL, 0.0015 mol) in DCM (5 mL) was added 1-methyl-1H-pyrazole-3-sulfonyl chloride (0.14 g, 0.78 mmol) in portions at 0° C. The reaction mixture was stirred at RT overnight, quenched with water, and extracted with DCM. The organic layers were dried over MgSO4, concentrated and purified on silica gel (eluting with 0-5% MeOH in DCM) to give the desired product. LCMS calculated for C26H40N9O3SSi(M+H)+: m/z=586.3; Found: 586.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].C1C(=O)N([Cl:28])C(=O)C1>C1COCC1>[Cl:28][C:16]1[C:17]2[C:12](=[CH:11][C:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([OH:8])=[C:6]([F:9])[CH:5]=3)=[CH:19][CH:18]=2)[CH:13]=[CH:14][C:15]=1[OH:20]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1
Solvent: C1CCOC1
Product: Oc1ccc2cc(-c3cc(F)c(O)c(F)c3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-(3,5-difluoro-4-hydroxyphenyl)-2-naphthol (300 mg, 1.10 mmol) and NCS (155 mg, 1.16 mmol) in THF (30 mL) according to method C to yield 264 mg (78%) of grey solid: mp 209-210° C.; 1H NMR (DMSO-d6): δ 7.32 (1H, d, J=8.89 Hz), 7.50-7.61 (2H, m), 7.83 (1H, d, J=8.96 Hz), 7.92 (1H, dd. J=8.94 Hz, J=1.59 Hz), 8.05 (1H, d, J=8.88 Hz), 8.22 (1H, d, J=1.19 Hz), 10.36 (1H, s), 10.54 (1H, s); MS (ESI) m/z305/307 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C@@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[OH:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH2:17](I)[CH:18]=[CH2:19]>>[CH2:19]([O:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=1)[CH:18]=[CH2:17]
Reactant: C=CCI
Reactant: N#Cc1ccc(O[C@@H]2CCC[C@@H]2O)cc1Cl
Product: C=CCO[C@H]1CCC[C@H]1Oc1ccc(C#N)c(Cl)c1
Yield: 11.8 %

Procedure:
The product of Example 34, Step A (87 mg) was alkylated with allyl iodide (73.6 mg) according to the procedure of Example 34, Step B to give 12 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([N:26]4[CH2:27][CH2:28][CH:29]([N:32]([CH3:33])[CH3:34])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(Cl)cc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2C#N)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N(C)C)CC3)c(C#N)c2)cnn1-c1ccc(Cl)cc1
Yield: 30.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(4-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (3.3 g) and 5-amino-2-[4-(N,N-dimethylamino)piperidin-1-yl]benzonitrile (2.9 g), the title compound (1.7 g) was obtained, melting point: 210–213° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:55])[CH:30]([NH:38][C:39](=[O:54])[CH:40]([N:42]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH3:43])[CH3:41])[CH:31]([O:33]C(C)(C)C)[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]2[C:24]3[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:13]2[N:26]([C:29](=[O:55])[CH:30]([NH:38][C:39](=[O:54])[CH:40]([N:42]([C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[CH3:43])[CH3:41])[CH:31]([OH:33])[CH3:32])[CH2:27][CH2:28][CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OC(C)(C)C)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)C(NC(=O)C(C)N(C)C(=O)OCc1ccccc1)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution containing crude 45 (330 mg, 0.44 mmol) in DCM (10 mL) was treated with TFA (3 mL) at ambient temperature. After 2 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the resultant organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 300 mg of 46 as a pale brown-colored foam which was used without further purification. 1H NMR (CDCl3, 300 MHz) mixture of rotamers: δ8.38 (s, 0.5H), 8.34 (s, 0.5H), 8.12 (dd, J=5.1, 8.7 Hz, 0.5H), 8.03 (dd, J=5.4, 8.4 Hz, 0.5H), 7.35-7.26 (m, 5H), 7.05-6.87 (m, 2H), 6.77 (s, 0.5H), 6.62 (s, 0.5H), 5.29-5.12 (m, 3H), 4.76-4.52 (m, 1.5H), 4.34-4.30 (m, 1H), 4.22-4.19 (m, 0.5H), 3.89 (app t, J=5.4 Hz, 1H), 3.57-3.42 (m, 2H), 2.82 (s, 3H), 2.45-2.39 (m, 0.5H), 2.27-2.21 (m, 0.5H), 1.90 (br s, 1H), 1.38 (d, J=7.5 Hz, 3H), 1.16 (d, J=6.3 Hz, 3H) ppm. Mass spectrum, m/z [700.3] (M+H)+.