Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCN1CCCC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (230 mg, 1.06 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (234 mg, 1.37 mmol) and potassium carbonate (440 mg, 3.18 mmol) in 5 mL DMF was stirred at room temperature for 4 days. After this time, the mixture was poured into 20 mL H2O then extracted with 2×30 mL CH2Cl2. The organic layers were combined together, washed with brine (20 mL) and concentrated. Product was subjected to flash chromatography on the biotage using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow solid. Yield: 218 mg of yellow solid (71%). 1H NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.20 (d, J=9.0 Hz, 1H), 4.13 (t, J=7.5 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.73-2.68 (m, 4H), 2.63-2.60 (m, 4H), 1.82-1.78 (m, 4H). MS (ESI): 290.2 (M+1, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:13].C1COCC1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH2:7])=[S:13]
Reactant: COc1ccccc1C(N)=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1CCOC1
Product: COc1ccccc1C(N)=S
Yield: 185.7 %

Procedure:
Combine 2-methoxy benzamide (10.0 g, 66.2 mmol) with phosphorus pentasulfide (10.1 g, 22.7 mmol) and THF (200 mmol) in a sealed vessel and stir for 30 minutes at room temperature. Sonicate the mixture for 1 hour and then allow the mixture to stand at room temperature. Decant the THF solution from the solids and concentrate. Chromatograph the resulting residue over silica gel (MeOH/CH2Cl2) to give 2-methoxy-thiobenzamide (7.05 g, 64%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>C(#N)C>[CH3:21][CH:22]([CH3:46])[CH2:23][N:24]([C:18]([C:10]1[N:11]=[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]2[C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:20])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:43])([CH3:45])[CH3:44])=[O:40])[CH2:26]1
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1nc2ccccn2c1CCc1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)CN(C(=O)c1nc2ccccn2c1CCc1ccccc1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.4 %

Procedure:
Ethyl 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylate (883 mg) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (3 ml) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, neutralized with 1N hydrochloric acid, subjected to DIAION HP-(manufactured by Mitsubishi Chemical), and washed with water. The fraction eluted with acetone was concentrated under reduced pressure to give 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (1.03 g). The obtained 3-(2-phenylethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (341 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (370 mg) and N,N-diisopropylethylamine (862 μl) were dissolved in acetonitrile (20 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (561 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, and the residue was diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (9:1) was concentrated under reduced pressure to give the object product (522 mg).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH2:15])=[CH:11][CH:10]=1>CO>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][NH:15][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])=[CH:11][CH:10]=1
Reactant: COc1ccc(CCN)cc1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCCc1ccc(OC)cc1
Yield: 97.9 %

Procedure:
A mixture of methyl acrylate (6.0 g, 69.7 mmol) and p-methoxyphenethyl amine (10.5 g, 69.7 mmol) in anhydrous methanol (88 mL) was refluxed for 3 days and then was concentrated to give methyl 3-[(4-methoxyphenethyl)amino]-propionate (16.2 g). To a solution of methyl 3-[(4-methoxyphenethyl)amino]-propionate (3.0 g, 12.6 mmol) in anhydrous methylene chloride (35 mL) was added 3-nitrobenzenesulfonyl chloride (2.8 g, 12.6 mmol), followed by triethylamine (2.6 g, 25.3 mmol). After stirring for 18 h at room temperature, the mixture was quenched with 1 N HCl solution (150 mL) and extracted with methylene chloride (100 mL). Combined organic layers was washed successively with 1 N HCl solution (100 mL) and brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel flash chromatography (2.5/1 to 2/1: hexanes/EtOAc) to provide methyl 3-[(4-methoxyphenethyl)-(4-cyanobenzenesulfonyl)-amino]-propionate (3.28 g, 7.8 mmol).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[N:27]1>CN(C)C=O>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[C:28]([N:35]2[CH2:36][CH2:37][N:38]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:39][CH2:40]2)=[N:27]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2noc3ccccc23)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.6 g), triethylamine (1.8 cc) and 4(1,2-benzisoxazol-3-yl)piperazine (2.69) in dimethylformamide (200 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on silica gel, under a current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-{3-[4-(1,2-benzisoxazol-3-yl) -1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained, m.p. 263° C.
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH2:3]1.[ClH:15].[NH2:16]O.CCOCC>C(#N)CC>[ClH:15].[NH2:16][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:11]([O:13][CH3:14])=[O:12])[S:4][CH:3]=1
Reactant: COC(=O)C1SCC(=O)C1C(=O)OC
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: CCC#N
Product: COC(=O)c1scc(N)c1C(=O)OC

Procedure:
3-Oxo-4,5-bismethoxycarbonyltetrahydrothiophene (2.65 g) was dissolved in propionitrile (5 ml) and hydroxylamine hydrochloride (1 g) was added. The mixture was heated under reflux on the steam bath for 11/2 hours by which time it was almost solid. Ether was added to the cooled mixture and the title compound was filtered off. Yield 2.37 g (77.5%) M.P.166°-169° dec. 3-Amino-4,5-bismethoxycarbonylthiophene was liberated from the title compound by treatment with aqueous ammonia followed by bulk distillation (220° C., 0.1 mm Hg) and exhibited 'H n.m.r. δ (CDCl3) 6.40 (1H,s), 4.40 (2H, brs), 3.90, 3.94 (2×3H,s).
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)[N:3]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CCCCO2)nc1I
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (10.8 g, 40.60 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (10 g, 118.88 mmol, 2.93 equiv) and TsOH (780 mg, 4.53 mmol, 0.11 equiv) in THF (100 mL) was stirred for 2 h at 60° C. The reaction mixture was cooled to room temperature and quenched by the addition of 100 mL of saturated sodium bicarbonate solution. The resulting solution was extracted with 2×80 mL of dichloromethane. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with ethyl acetate/petroleum ether (1:20) to give 13 g (91%) of ethyl 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carboxylate as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H), 5.40-5.38 (m, 1H), 4.34-4.29 (m, 2H), 4.08-4.05 (m, 1H), 3.73-3.70 (m, 1H), 2.07-1.98 (m, 3H), 1.69-1.62 (m, 3H), 1.39-1.32 (m, 3H) ppm. LCMS (method C, ESI): RT=1.53 min, m/z=351.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35](=[O:43])([O:39][CH:40]([CH3:42])[CH3:41])[O:36][CH2:37]I>CC(C)=O>[C:35](=[O:43])([O:39][CH:40]([CH3:42])[CH3:41])[O:36][CH2:37][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C@H:7]3[N:18]([C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:17][CH2:16][C@@:13]4([C:14]=2[CH:15]=1)[C@H:8]3[CH2:9][CH2:10][CH2:11][CH2:12]4
Reactant: CC(C)OC(=O)OCI
Reactant: O=C(OCc1ccccc1)N1CC[C@]23CCCC[C@H]2[C@H]1Cc1ccc(O)cc13
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)OCOc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)OCc1ccccc1)CC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To (+)-3-hydroxy-N-(benzyloxycarbonyl)morphinan (33.0 g, 87.4 mmol) and cesium carbonate (28.5 g, 87.4 mmol) in acetone (450 mL) was added iodomethyl isopropyl carbonate (21.3 g, 87.4 mmol) (see Rigel Pharmaceuticals, Inc. US2006/247287 A1, Appl.; US2006-381215 (2006 May 2)) at room temperature. The reaction mixture was stirred vigorously at room temperature overnight. The acetone was then removed by rotary evaporation under vacuum. To the residue was added saturated NaHCO3 solution. The mixture was extracted with EtOAc (300 mL×2). The combined organics were washed with 1N HCl solution (300 mL), dried over MgSO4, filtered, and evaporated under vacuum to provide the title compound (42.0 g, 97%) as a yellow gum.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH2:5][OH:6].[Cl:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:12][NH:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[C:17](Cl)=[N:16][N:15]=1>O>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:6][CH2:5][CH2:4][CH2:3][OH:7])=[N:16][N:15]=[C:14]2[NH:13][CH2:12][C:11]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:9]([Cl:8])[CH:10]=1
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(Cl)cc23)cc1Cl
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(CNc2nnc(OCCCO)c3ccc(Cl)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60% Sodium hydride (0.12 g, 3.0 mmol) was added to 8 ml of 1,3-propanediol. The obtained mixture was stirred at room temperature for one hour, followed by the addition of 1.0 g (2.7 mmol) of the compound prepared in Example 27. The obtained mixture was stirred at 150° C. for one hour, followed by the addition of water. The resulting mixture was extracted with ethyl acetate. The organic phase was washed with water and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and freed from the solvent by distillation. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol (30:1)] and recrystallized from aqueous ethanol to give 0.58 g of the title compound as white needles.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:36][C:35]1[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 125 °C
Yield: 90.4 %

Procedure:
To a mixture of 1-(3-(7-chloroimidazo[1,2-a]pyridin-3-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (20 mg, 0.052 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 mg, 0.066 mmol) and cesium carbonate (51 mg, 0.156 mmol) in THF/H2O mixture (2/1, 0.75 ml) was added Pd(PtBu3)2 (3 mg, 0.005 mmol). The vial was degassed for 5 minutes then capped and heated to 125° C. for 20 minutes in a microwave. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad and purified via flash chromatography (0-10% MeOH/DCM gradient containing 10% NH4OH) to yield the title compound (20 mg, 90% yield). MS (ES+) C22H18F3N5O requires: 425. found: 426 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[S:27](Cl)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:11]([S:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[NH:1][S:27]([C:19]1[O:18][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:20]=1)(=[O:28])=[O:29])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(N)c(SCc2ccccc2)c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: N#Cc1ccc(NS(=O)(=O)c2cc3ccccc3o2)c(SCc2ccccc2)c1
Yield: 99.4 %

Procedure:
Following General Procedure B, the title compound (752 mg, 47%) was prepared from 4-amino-3-(benzylthio)benzonitrile (430 mg, 1.80 mmol), benzofuran-2-sulfonyl chloride (391 mg, 1.80 mmol), and DMAP (cat.) in pyridine (3 ml).
Reaction SMILES: [C:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].NNC(N)=S>C(O)C>[CH3:21][C:19]1[NH:10][N:9]=[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NNC(=S)Nc1ccccc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: NNC(N)=S
Solvent: CCO
Product: CCOC(=O)c1c(Nc2ccccc2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 16.7 g (0.1 mole) of 4-phenyl3-thiosemicarbazide in 60 mL of absolute ethanol was treated with 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate and the mixture stirred for 1 hr at room temperature. As the thiosemicarbazide began to dissolve the reaction mixture became exothermic and a reddish-brown solid precipitated. Alcoholic hydrogen chloride (2N, 50 mL) was added, and the reaction mixture heated at reflux for 1.0 hr. The solution was filtered while hot and the filtrate was evaporated under reduced pressure. The solid residue was triturated in cold absolute ethanol and a red solid collected by filtration. The solid was warmed in 2N hydrochloric acid (100 mL) and the suspended sulfur removed by filtration. An orange-red solid precipitated from the filtrate, was collected by filtration and air dried for ~16 hr (14.6 g, mp 160°-4° C.). Recrystallization from benzene left 10.5 g of product, mp 165°-6° C. The material was air dried and submitted for elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12](=O)[NH:11][N:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:12]1[C:13]2[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:10][N:11]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccc(C)cc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nnc(Cl)c3ccc(C)cc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-(4-methoxyphenyl)-6-methyl-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:27])([CH3:26])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.CO>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][C@H:22]3[CH2:24][C:25]([CH3:26])([CH3:27])[C@@H:19]2[C:20](=[O:28])[O:21]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(OCc4ccccc4)cc3)[C@H]1C(=O)O2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)C[C@@H]2CN(S(=O)(=O)c3ccc(O)cc3)[C@H]1C(=O)O2
Yield: 82.9 %

Procedure:
A mixture of (1R,4R)-5-(4-benzyloxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVII, 3.7 g, 9.3 mmol), 10% palladium on charcoal (0.8 g) and 470 ml of 1:1 ethyl acetate-methanol was stirred for about 1.5 hours under about 50 psi of hydrogen gas. The mixture was filtered through a pad of Celite®. Concentration of the filtrate afforded 2.4 g (1R,4R)-5-(4-hydroxy-benzenesulfonyl)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVIII) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C>[CH2:14]([O:13][C:11]1[CH:10]=[C:5]([CH:4]=[C:3]([C:1]2[NH:18][N:17]=[N:16][N:2]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:15]
Reactant: CCOc1cc(C#N)cc(C(=O)OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(=O)OC)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-cyano-5-ethoxybenzoate (182 mg, 0.89 mmol), sodium azide (173 mg, 2.66 mmol), triethylamine hydrochloride (366 mg, 2.66 mmol) and DMF (4.4 mL) was stirred in a nitrogen atmosphere at 100° C. for 12 hours. After left cooled, aqueous 5 N sodium hydroxide solution (0.53 mL, 2.66 mmol) was added to the reaction mixture, and washed with chloroform. The aqueous layer was made to have a pH of 2 with 5 N hydrochloric acid, and extracted with chloroform. The organic layer was dried with sodium sulfate, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to obtain the title compound as a colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=1.[Br:17]N1C(=O)CCC1=O>FC(F)(F)C(O)=O.C(OCC)(=O)C>[Br:17][C:8]1[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][O:11][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cc(-c2ccccn2)on1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1noc(-c2ccccn2)c1Br
Yield: 69.1 %

Procedure:
A solution of ethyl 5-(pyridin-2-yl)isoxazole-3-carboxylate (212 mg, 0.972 mmol) and N-bromosuccinimide (432 mg, 2.43 mmol) in trifluoroacetic acid (6 mL) was heated to 150° C. for 30 minutes via microwave. Concentration under reduced pressure afforded a yellow oil which was diluted with ethyl acetate (80 mL), washed with a saturated aqueous solution of sodium bicarbonate (20 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1:3 mixture ethyl acetate and hexane afforded ethyl 4-bromo-5-(pyridin-2-yl)isoxazole-3-carboxylate (0.217 g, 0.672 mmol, 69% yield). The product had an HPLC retention. time=2.65 min.—Column: YMC S5 COMBISCREEN® 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=299.02. 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (t, J=7.15 Hz, 3H), 4.52 (q, J=7.28 Hz, 2H), 7.43-7.48 (m, 1H), 7.90 (td, J=7.78, 1.76 Hz, 1H), 8.11 (d, J=8.03 Hz, 1H), and 8.84 (d, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][NH2:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1([CH:22]([C:28]([CH3:30])=O)[C:23](OCC)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:23](=[O:24])[C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:28]([CH3:30])[NH:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)C(C(C)=O)c1ccccc1
Product: Cc1[nH]n(C2CCN(Cc3ccccc3)CC2)c(=O)c1-c1ccccc1
Yield: 77.7 %

Procedure:
When 1.4 g of 1-benzyl-4-hydrazinopiperidine and 2.0 g of ethyl 2-phenylacetoacetate were used in the procedure of Example 124, Step A, there was obtained 1.84 g of 1-benzyl-4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine. ESI-MS 348.2 (M+H); HPLC A: 1.95 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[C:11]1(=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:6][CH2:5]2
Reactant: O=C1CCCCC1
Reactant: Brc1ccc2c(c1)CCN2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc2c(c1)CCN2C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 5-bromo-2,3-dihydro-1H-indole (94.0 g, 20.2 mmol), cyclohexanone (4.6 mL, 44.4 mmol) and sodium cyanoborohydride (1.6 g, 25.5 mmol) in methanol (100 mL) was heated at reflux for 16 hours. More cyclohexanone (2.3 mL, 22.2 mmol) and sodium cyanoborohydride (1.6 g, 25.5 mmol) were added. Heating was continued for 1 day. The solvent was evaporated in vacuo, and the residue was treated with ammonium hydroxide in water. The product was extracted into dichloromethane, and dried over sodium sulfate. The solvent was evaporated in vacuo, and the product was purified by flash silica gel chromatography, eluted with ethyl acetate (1% to 2%) in hexane to give an oil, 7.49 g (37%). MS: m/z 280 (MH+). 1H NMR (CDCl3): 1.08-1.20 (m, 1 H), 1.25-1.42 (m, 4 H), 1.64-1.74 (m, 1 H), 1.76-1.88 (m, 4 H), 2.91 (t, 2 H), 3.24-3.32 (m, 1 H), 3.36 (t, 2 H), 6.23 (d, 1 H) and 7.08-7.11 (m, 2 H).