Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)[O:6][C@H:5]([C:7]([N:9]2[CH2:14][CH2:13][C:12]([C:15]3[C:20]([F:21])=[CH:19][C:18]([N:22]4[CH2:26][C@H:25]([CH2:27][N:28]([C:36]5[O:40][N:39]=[C:38]([CH3:41])[CH:37]=5)C(OC(C)(C)C)=O)[O:24][C:23]4=[O:42])=[CH:17][C:16]=3[F:43])=[CH:11][CH2:10]2)=[O:8])[CH2:4][O:3]1.FC(F)(F)C(O)=O.O>ClCCl>[OH:6][C@@H:5]([CH2:4][OH:3])[C:7]([N:9]1[CH2:14][CH2:13][C:12]([C:15]2[C:20]([F:21])=[CH:19][C:18]([N:22]3[CH2:26][C@H:25]([CH2:27][NH:28][C:36]4[O:40][N:39]=[C:38]([CH3:41])[CH:37]=4)[O:24][C:23]3=[O:42])=[CH:17][C:16]=2[F:43])=[CH:11][CH2:10]1)=[O:8]
Reactant: Cc1cc(N(C[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H]5COC(C)(C)O5)CC4)c(F)c3)C(=O)O2)C(=O)OC(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(NC[C@H]2CN(c3cc(F)c(C4=CCN(C(=O)[C@@H](O)CO)CC4)c(F)c3)C(=O)O2)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
3-(4-(1-(2,2-Dimethyl-1,3-dioxolan-4(S)-ylcarbonyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)-3-methylisoxazol-5-ylaminomethyl)oxazolidin-2-one (400 mg, 0.65 mM) was dissolved in dichloromethane (6 ml) and treated with trifluoroacetic acid (6 ml) at 0°. After stirring for 30 minutes at ambient temperature, water (1.2 ml) was added, and stirring continued for 1 hour. Solvent was removed, the residue dissolved in methanol (20 ml), and treated with aqueous ammonia to bring the pH to 7-8; solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (181 mg ). NMR (DMSO-d6) δ: 2.02 (s, 3H); 2.29 (m, 1H); 2.35 (m, 1H); 3.41 (t, 2H); 3.47 (m, 1H); 3.54 (m, 1H); 3.71 (m, 1H); 3.75 (dd, 1H); 4.04 (dd, 1H); 4.08 (m, 1H); 4.13 (t, 1H); 4.24 (m, 1H); 4.36 (t, 1H); 4.66 (t, 1H); 4.82 (m, 1H); 4.95 (t, 1H); 4.99 (s, 1H); 5.85 (s, 1H); 7.30 (d, 2H); 7.36 (t, 1H). MS (ESP): 479 (MH+) for C22H24F2N4O6
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:16][C@@:17]12[C:25](=[O:26])[CH2:24][CH2:23][C@H:22]1[C@@H:21]1[CH2:27][CH:28]=[C:29]3[CH2:34][C@@H:33]([OH:35])[CH2:32][CH2:31][C@:30]3([CH3:36])[C@H:20]1[CH2:19][CH2:18]2.O>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:35][C@H:33]1[CH2:32][CH2:31][C@@:30]2([CH3:36])[C:29](=[CH:28][CH2:27][C@@H:21]3[C@@H:20]2[CH2:19][CH2:18][C@@:17]2([CH3:16])[C@H:22]3[CH2:23][CH2:24][C:25]2=[O:26])[CH2:34]1)([CH3:7])[CH3:6]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 88.3 %

Procedure:
Add t-butyldimethylsilyl chloride (10.97 g, 72.8 mmol), 4-dimethylaminopyridine (0.42 g, 3.47 mmol) and triethylamine (10.63 mL, 76.27 mmol) to a stirred solution of dehydroepiandrosterone (A1, 20.00 g, 69.3 mmol) in anhydrous DMF (350 mL) under nitrogen. Stir the resultant suspension at room temperature for 3 days and then pour into rapidly stirred water (1.5 L). Filter the resultant suspension and recrystallize the white solid from aqueous acetone to give A2 (24.64 g, 88%) as a white crystalline solid: mp 146-148° C. TLC Rf 0.78, ethyl acetate/hexane (1:1); 1H NMR δ 5.38-5.32 (m, 1H), 3.55-3.43 (m, 1H), 1.03 (s, 3H), 0.89 (s, 9H), 0.88(s, 3H), 0.06 (s, 6H); MS (CI, CH4) m/z (rel intensity) 403 (MH+, 3), 401 (5), 387 (9), 345 (18), 271 (100). Analysis Calculated for C25H42SiO2: C, 74.57; H, 10.51. Found: C, 74.89; H, 10.84.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:29]([F:32])([F:31])[F:30])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[O:16])=[C:10]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:9]=[CH:8]2.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCCC1>[CH2:20]([O:19][C:18]([N:17]([C:15]([C:11]1[C:12]2[C:7](=[C:6]([C:29]([F:31])([F:30])[F:32])[C:5]([O:4][CH3:3])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[O:16])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:22])[CH3:21]
Reactant: CCOC(=O)NC(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 0.346 g, 1.1 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, ethyl ester (4.60 g, 10.5 mmol) in anhydrous tetrahydrofuran (125 mL) at room temperature under a dry nitrogen atmosphere. After 1 hour, the t-butyl bromoacetate (2.54 mL, 1.5 eq) was added. The reaction was heated to 65° C. for 1 hour, cooled to room temperature, and the THF was removed. The residue was dissolved in ether (200 mL), washed with water (2×50 mL) and saturated aqueous NaCl (1×50 mL). The ether phase was dried with magnesium sulfate and the ether was removed. The crude product was flash chromatographed (17:3 petroleum ether:ethyl acetate, silica) and triturated with petroleum ether to provide the title compound as a white powder (4.60 g, 79%), m.p. 84°-86° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=Cc1cn(S(=O)(=O)c2ccccc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1H-indole-3-carboxaldehyde (0.290 g, 2.00 mmol) in methylene chloride (4 mL) was added with 2-chlorophenylsulfonyl chloride (0.507 g, 2.40 mmol) and diisopropylethylamine (0.310 g, 2.40 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate to terminate the reaction, and then extracted three times with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain 1-(2-chlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.580 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 0.25 h

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.7 grams), anhydrous stannous chloride (3.8 grams), and 4.0 milliliters of concentrated hydrochloric acid were mixed in 20 milliliters of acetic acid. The mixture was cooled to temperatures of 0°-10°C. and maintained thereat for 15 minutes. Water (50 milliliters) was then added to the reaction mixture, and the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)imidazo(4,5-b)-pyridine product precipitated. It was separated and dried. The yield was 1.3 grams, 55 percent. The product so obtained melted at 264°-66°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[CH:5]2.[CH3:19]I.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:19])[C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[Cl:18])=[CH:5]2
Reactant: CI
Reactant: Clc1ccc(-c2cc3cc(Cl)ccc3[nH]2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccc(Cl)cc2Cl)cc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-2-(2,4-dichlorophenyl)-1H-indole (160 mg, 0.54 mmol) and methyl iodide (124 μL, 2.0 mmol) in tetrahydrofuran is treated with NaH (60% dispersion in mineral oil, 160 mg, 4.0 mmol), shaken at room temperature for 16 h, quenched with water and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford the title product which is used as is in Example 128.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:31])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:32][CH:33]([CH3:36])[CH:34]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:32]([N:28]1[CH2:29][CH2:30][CH:25]([C:15]2[C:14]([CH2:13][N:12]([CH3:31])[CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:18][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH2:26][CH2:27]1)[CH:33]([CH3:36])[CH3:34]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1C1CCNCC1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)CN1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
To a solution of (R/S) tert-butyl N-methyl-N-[2-[methyl([[1-(oxan-2-yl)-3-(piperidin-4-yl)-1H-pyrazol-4-yl]methyl])amino]ethyl]carbamate (250 mg, 0.57 mmol, 1.00 equiv) and 2-methylpropanal (62 mg, 0.86 mmol, 1.50 equiv) in 1,2-dichloroethane (15 mL) was added NaBH(OAc)3 (364 mg, 3.00 equiv). The resulting solution was stirred at room temperature overnight and then concentrated under vacuum to give 160 mg of crude (R/S) tert-butyl 2-(((3-(1-isobutylpiperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)(methyl)amino)ethyl(methyl)carbamate as a light yellow oil. LCMS (method A, ESI): RT=1.52 min, m/z=492.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([OH:11])=O.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH2:22])[CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]1[O:21][N:20]=[C:19]([NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: O=C(O)C=Cc1ccccn1
Reactant: Nc1cc(-c2ccco2)on1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(C=Cc1ccccn1)Nc1cc(-c2ccco2)on1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.6 %

Procedure:
To a solution of 6 mg of 3-pyridin-2-yl-acrylic acid and 6 mg of 5-furan-2-yl-isoxazol-3-ylamine in DMF were added 8 mg of HOBt, 9 mg of EDC and 0.014 mL of TEA. The reaction solution was stirred for 18 hrs at room temperature, followed by concentration under reduced pressure. The concentrate was purified by preparative HPLC to provide 4 mg of N-(5-furan-2-yl-isoxazol-3-yl)-3-pyridin-2-yl-acrylamide. (Yield: 36%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][O:8][CH:9]1[CH2:12][NH:11][CH2:10]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:34]([N:37]([CH:40]([CH3:42])C)[CH2:38][CH3:39])(C)C.Cl.[O:44]=[C:45]1[NH:54][C:53]2[N:52]=[CH:51][C:50](/[CH:55]=[CH:56]/[C:57](O)=[O:58])=[CH:49][C:48]=2[CH2:47][CH2:46]1>CN(C)C=O.O.C(OCC)(=O)C>[CH3:34][N:37]1[CH2:38][CH2:39][C:46]2([CH2:47][C:48]3[C:53](=[N:52][CH:51]=[C:50](/[CH:55]=[CH:56]/[C:57](=[O:58])[N:11]4[CH2:12][CH:9]([O:8][CH2:7][C:3]5[S:2][CH:6]=[CH:5][CH:4]=5)[CH2:10]4)[CH:49]=3)[NH:54][C:45]2=[O:44])[CH2:42][CH2:40]1
Reactant: CCN(C(C)C)C(C)C
Reactant: c1csc(COC2CNC2)c1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC(OCc4cccs4)C3)cnc1NC2=O
Reaction time: 8 h

Procedure:
3-(Thiophen-2-ylmethoxy)-azetidine hydrochloride (45.8 mg, 0.22 mmol), EDCI (40.26 mg, 0.21 mmol), HOBt (28.5 mg, 0.21 mmol) and diisopropylethylamine (62 μL, 0.35 mmol) were successively added to a solution of (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-acrylic acid hydrochloride (47.0 mg, 0.14 mmol) in dimethylformamide (5 mL) at room temperature. The reaction mixture was stirred overnight and then diluted by addition of ethyl acetate (20 ml) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×20 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol (95:5 to 0:1) as eluent. After precipitation in a mixture dichloromethane/diethylether/pentane, the title product was obtained as a white solid (12 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:8][C:9]1[C:18](Br)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:30][C:31](=[O:50])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:50])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([C:18]2[C:9]([CH2:8][N:7]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:27])=[N:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:34]=1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)Cc1nc2ccccc2cc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(Cc2ccccc2)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using the following starting materials: benzyl-(3-bromo-quinolin-2-ylmethyl)-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][CH2:41][N:42]([CH2:45]C)[CH2:43]C>O1CCOCC1.CCOC(C)=O>[CH3:43][N:42]([CH3:45])[CH2:41][CH2:40][CH2:39][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:37])(=[O:36])=[N:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([C:17]#[C:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([C:28]4[N:32]([CH3:33])[N:31]=[C:30]([CH3:34])[CH:29]=4)=[O:27])[CH:20]=3)[CH:14]=[N:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CCCCl
Reactant: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(N)cc4)c3)c2)n(C)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C#Cc3cncc(C(=O)N=S(C)(=O)c4ccc(NCCCN(C)C)cc4)c3)c2)n(C)n1
Temperature: 100 °C
Yield: 4 %

Procedure:
N-[(4-{amino}phenyl)(methyl)oxido--sulfanylidene]-5-[(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}phenyl)ethynyl]nicotinamide (0.085 g, 0.168 mmol) was dissolved in dioxane (1.7 mL) then treated with (3-Chloro-propyl)-diethyl-amine (0.047 g, 0.252 mmol) and TEA (0.070 mL, 0.504 mmol). The reaction mixture was then heated to 100° C. for 48 h then cooled to room temperature. The cooled mixture was dissolved in EtOAc (5 mL) and then extracted with water (3×5 mL) and with brine (5 mL). The organic layer was dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude mixture was purified via column chromatography (gradient eluant mixture of MeOH in EtOAc: 0% to 20% MeOH) to give the title compound (4 mg, 3.5%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C(OCC)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH2:30][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:24]=[CH:23]2
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CCOC(=O)Cc1ccc2cc(Br)ccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of diisopropylamine (19.2 g, 0.19 mole) in diethyl ether (200 mL) was added 2.5 M n-butyllithium in hexane (74 mL, 0.185 mole) at −78° C. The clear solution was mixed for 30 min, and followed by addition of 6-bromo-2-methyl-quinoline (13.32 g, 0.060 mole) in ether (200 mL) slowly at −78° C. The brown solution was stirred for 0.5 hour, and ethyl chloroformate (7.45 g, 0.069 mole) in ether (50 mL) was syringed into the mixture slowly so that the internal temperature did not exceed −70° C. The yellow reaction mixture was quenched by addition of 50 mL water, allowed to warm up to rt, and diluted with ethyl acetate (300 mL). The solution was washed with 5% sodium bicarbonate aq. solution (700 mL×3), 25% brine (700 mL), dried over MgSO4, and filtered. The organic was concentrated to ˜50 mL volume, and the slurry diluted with heptane (50 mL). The slurry was stirred at 0° C. for 2 h, and the solid was collected by filtration, rinsed with a ice-cold heptane: ethyl acetate (10 mL, 2:1), dried at 50° C. under vacuum to give a yellow solid (12.0 g). Concentration of the mother liquid afforded a 2nd crop of the product (3.6 g). Total yield: 88%; mp: 100–101° C. (uncorrected); MS (ESI): 294, 296 (M+H)+; 1H-NMR (CDCl3) δ 8.02 (1H, d, J=8.5 Hz), 7.94 (1H, d, J=2.2 Hz), 7.91 (1H, d, J=8.9 Hz), 7.74 (1H, dd, J=8.9, 2.2 Hz), 7.44 (1H, d, J=8.5 Hz), 4.20 (2H, q, J=7.1 Hz), 4.01 (2H, s), 1.27 (3H, t, J=7.1 Hz); 13C-NMR (CDCl3) δ 169.7, 154.9, 146.0, 135.1, 132.6, 130.5, 128.9, 127.8, 122.3, 119.9, 61.2, 44.9, 14.5.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].O[CH2:13][CH:14]([OH:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C(O)C>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[O:21][CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][O:4]1
Reactant: OCC(O)c1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: c1ccccc1
Product: Clc1ccc(C2(CBr)OCC(c3ccccc3)O2)cc1

Procedure:
A mixture of 11.6 parts of 2-bromo-4'-chloroacetophenone, 8.4 parts of α-(hydroxymethyl)benzylalcohol, 0.1 parts of p-toluene sulfonic acid, 210 parts of benzene and 40 parts of ethanol is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is triturated in methanol. The product is filtered off and crystallized from methanol, yielding 2-(bromomethyl)-2-(p-chlorophenyl)-4-phenyl-1,3-dioxolane; mp. 60° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][N:6]=[CH:5][CH:4]=1.[C:15](OCC)(OCC)(OCC)[CH3:16]>>[CH3:15][C:16]1[O:10][C:9]([C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([F:1])([F:13])[F:14])=[N:11][N:12]=1
Reactant: NNC(=O)c1cnccc1C(F)(F)F
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2cnccc2C(F)(F)F)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg of 4-trifluoromethylnicotinic hydrazide were heated under reflux in 3.5 ml of triethyl orthoacetate for 2 hours. The reaction mixture was subsequently concentrated and the residue was carefully admixed with 2 ml of phosphorus oxychloride. The mixture was stirred at room temperature for 1 hour and then poured on ice and extracted with ethyl acetate. Chromatographic purification of the crude product obtained after drying and concentrating gave the desired compound as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Reactant: N#Cc1ccc(Br)nc1
Product: N#Cc1ccc(N2CCC[C@H](N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)C2)nc1

Procedure:
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following a procedure analogous to that described in Example 16. LC-MS Method 2 tR=1.218 min, m/z=439.1; 1H NMR (CDCl3) 1.21-1.36 (m, 1H), 1.62 (m, 1H), 1.78 (m, 3H), 1.56 (m, 2H), 1.86-2.00 (m, 2H), 2.19 (m, 1H), 2.29 (m, 1H), 2.67-2.86 (m, 3), 3.20 (m, 1H), 3.50 (t, 2H), 3.79 (m, 1H), 4.12 (m, 1H), 4.30 (d, 1H), 6.53 (m, 1H), 7.01 (t, 2H), 7.24 (m, 2H), 7.51 (d, 1H), 8.30 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.N1C=CC(CN[C:29]([C:31]2[S:32][C:33]([C:36]([NH:38][NH2:39])=[O:37])=[CH:34][CH:35]=2)=[O:30])=CC=1.CS(C)=[O:42]>>[OH:1][C:2]1[C:3]([C:18](=[N:39][NH:38][C:36]([C:33]2[S:32][C:31]([C:29]([OH:30])=[O:42])=[CH:35][CH:34]=2)=[O:37])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: CS(C)=O
Reactant: NNC(=O)c1ccc(C(=O)NCc2ccncc2)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 56 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol) in dimethyl sulfoxide (0.88 mL) was heated with 5-hydrazinocarbonylthiophene-2-carboxylic acid 4-picolylamide prepared in Reference Synthetic Example 4 at 100° C. for 24 hours. The solvent was evaporated, and the residue was washed with water and chloroform to give 54 mg of the desired product (yield 56%).
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]=1[O:11][CH2:12][CH2:13][OH:14].C(N(CC)CC)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.Cl>ClCCl.O>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:14][CH2:13][CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: OCCOc1ccc2ccccc2c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(OCCOc1ccc2ccccc2c1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of 2-(2-naphthyloxy)-1-ethanol (1.5 g, 7.97 mmol) and triethylamine (1.21 g, 11.95 mmol) in dichloromethane (20 mL) at 0° C. was added 4-bromobenzenesulfonyl chloride (2.12 g, 8.36 mmol) in dichloromethane (10 mL) dropwise over 30 minutes. The reaction was then warmed to room temperature and stirred for 16 hours before more 4-bromobenzenesulfonyl chloride (0.20 g, 0.80 mmol) was added and stirring was continued for 2 hours. The mixture was then poured into water (50 mL) and acidified with 2N aqueous hydrochloric acid (15 mL). The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by column chromatography on silica gel (50 g), eluting with hexane:ethyl acetate (9:2), to give the title compound (0.56 g, 17%) as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CN(C)C=O
Product: Clc1ncnc2[nH]cc(I)c12
Yield: 74.6 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine 10.75 g (70 mmol) and N-iodosuccinimide (16.8 g, 75 mmol) were dissolved in 400 ml of dry DMF and left at ambient temperature in the darkness over night. The solvent was evaporated. The yellow residue was suspended in hot 10% solution of Na2SO3, filtered, washed twice with hot water and crystallized from ethanol to yield 14.6 g (74.6%) of the title compound as off-white crystals. The mother liquid was evaporated up to ⅓ volume and crystallized again from ethanol to give 2.47 g (12.3%) of the title product. The total yield is close to 100%.