Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].O.O.Cl[Sn]Cl.[OH-].[NH4+]>C(O)(=O)C.Cl>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:2]([CH3:1])[CH:3]=1)#[N:6]
Reactant: Cc1cc(C#N)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C#N)ccc1N
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a stirred, 25° C. solution of 3-methyl-4-nitrobenzonitrile (24 g, 0.148 mol) in acetic acid (250 mL) under nitrogen was added dropwise a solution of SnCl2.2H2O (133.57 g., 0.592 mol) in concentrated HCl (250 mL). After stirring for 3 hours, the reaction mixture was added carefully to excess cold ammonium hydroxide. The reaction mixture was extracted several times with ethyl ether. The organic extracts were then combined, dried (Na2SO4) and evaporated under reduced pressure to afford 12 g (61%) of the title compound, 4-cyano-2-methylaniline, as a white solid; m.p. 64°-66° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[N+:39]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([O-:41])=[O:40]>CN(C=O)C.O>[N+:39]([C:42]1[CH:47]=[CH:46][C:45]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[CH:44][CH:43]=1)([O-:41])=[O:40]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCOCCOCCOCCOCCOC2CCCCO2)cc1
Temperature: 80 °C

Procedure:
To a stirred solution of 27 (2.90 g, 6.09 mmol) in anhydrous DMF (11 mL) were added K2CO3 (2.53 g, 18.3 mmol) and 4-nitrophenol (0.847 g, 6.09 mmol), and the reaction mixture was heated to 80° C. for 16 h. After cooling, the reaction mixture was diluted in water, extracted three times with CH2Cl2, and then dried over MgSO4. The filtrate was concentrated under reduced pressure to give 28 as an oily residue (2.65 g, 98%): 1H NMR (300 MHz, CDCl3) δ 8.18 (d, J=9.2 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 4.69-4.56 (m, 1H), 4.28-4.17 (m, 2H), 3.97-3.42 (m, 18H), 1.95-1.41 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 163.82, 141.40, 125.75, 114.52, 98.83, 70.81, 70.51, 70.43, 69.27, 68.15, 66.54, 62.12, 30.48, 25.34, 19.41.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN1CCCC1=O>[OH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:16])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: O=C1CCCCCO1
Solvent: CN1CCCC1=O
Product: O=C(CCCCCO)CC(=O)c1ccccc1

Procedure:
In accordance with the procedure of Example 8, 61.3 g of acetophenone and 57.7 g of ε-caprolactone are condensed in 117.0 g of N-methylpyrrolidone as solvent with 52.9 g of sodium tert-butylate (97%) as base. Working up is as described in Example 8.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])[CH3:22])[CH2:12][C@@H:11]([O:37][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:8][C@@H:9]1[C@@:34]2([CH3:35])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][CH2:25][C:26]([OH:29])([CH3:27])[CH3:28])[CH3:22])[CH2:12][C@@H:11]([OH:37])[CH2:10]1
Reactant: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](OCCC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene (27 mg, 0.0419 mmol) in tetrahydrofuran (1 ml) was combined with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml, 0.25 mmol), and stirred at room temperature for 20 hours, then with heating under reflux for 2 hours. The reaction solution was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and brine successively, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by preparative thin layer chromatography (0.5 mm×1 and 0.25 mm×1, dichloromethane:ethanol 20:1, developed twice) to give the title compound as a colorless oil (17.3 mg, 99%).
Reaction SMILES: C(OC(=O)COCCOCCOCC[O:20][C@H:21]1[C@H:26]([NH:27][C:28](=[O:30])[CH3:29])[C@@H:25]([O:31]C(=O)C)[C@@H:24]([O:35]C(=O)C)[C@@H:23]([CH2:39][O:40]C(=O)C)[O:22]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:20][CH:21]1[O:22][C@H:23]([CH2:39][OH:40])[C@H:24]([OH:35])[C@H:25]([OH:31])[C@H:26]1[NH:27][C:28]([CH3:29])=[O:30]
Reactant: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 3 h
Yield: 109.8 %

Procedure:
The above prepared (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester (15.7 g, 25 mmol) was dissolved in 525 mL of ethyl acetate and hydrogenated over 1.6 g of Pd/C: (10%) under 1 atm. Of H2 at ambient temperature for 3 h. Filtration over Celite, evaporation of the solvent, followed by flash chromatography (SiO2, CH2Cl2/MeOH 80/20) gave 6.07 g of the title compound as a brownish gum MS (ISP): 536.5 [M−H]−.
Reaction SMILES: [CH:1]1[C:10]2[O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][N:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>ClCCl>[CH:1]1[C:10]2[O:9][C:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][N+:2]=1[O-:23]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)Oc1ccncc1O2
Solvent: ClCCl
Product: [O-][n+]1ccc2c(c1)Oc1ccccc1O2
Reaction time: 96 h

Procedure:
A solution of 3.5 g of pyrido[3,4-B][1,4]benzodioxin in 40 ml of dichloromethane is treated with 4.04 g of 85% m-chloroperbenzoic acid. The mixture is refluxed with stirring for 4 days. The mixture is diluted with 250 ml of dichloromethane and washed with excess 25% sodium hydroxide solution. The organic layer is dried and evaporated to yield pyrido[3,4-B][1,4]-benzodioxin-2 oxide, mp 232°-233° C. dec.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]([C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)#[N:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:39]3[CH:40]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:33]#[N:34])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 39 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (39%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:25]([OH:27])=O.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[NH:36][NH2:37].Cl>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][CH2:23][CH:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:25]([NH:37][NH:36][C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C(CCCCl)c1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)C(CCCCl)c1ccc(F)cc1
Yield: 70.6 %

Procedure:
IPEA (2.22 mL), HOBT (573 mg) and EDC (813 mg) were added to a solution of 5-chloro-2-(4-fluorophenyl)pentanoic acid (490 mg) synthesized according to the method described in Tetrahedron Letters, 2003, vol. 44, p. 365 and tert-butyl carbazate (420 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. Ethyl acetate and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer washed with saturated sodium bicarbonate water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 517 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@@H:40]2[C:44]([CH3:46])([CH3:45])[CH2:43][O:42][C:41]2=[O:47])[CH2:29]1)(C(C)(C)C)(C)C.CCCCCC.C(OCC)(=O)C>C1COCC1.C(OCC)C>[OH:26][CH2:27][C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@@H:40]2[C:44]([CH3:45])([CH3:46])[CH2:43][O:42][C:41]2=[O:47])[CH2:29]1
Reactant: CC1(C)COC(=O)[C@@H]1N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC1(C)COC(=O)[C@@H]1N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Reaction time: 2 h
Yield: 55 %

Procedure:
Tetrabutylammonium fluoride (3.6 mL, 1N in THF, 3.6 mmol) was added to a solution of dihydro-3-(R)-(3-(R)-((t-butyldimethylsilyloxy)methyl)-4-(S)-(3-fluorophenyl)-pyrrolidin-1-yl)-4,4-dimethyl-2(3H)furanone (500 mg, 1.2 mmol, from Step A) in 1 mL of THF. After 2 h. at room temperature, the solution was diluted with diethyl ether and washed with 1N NaOH and brine. The solution was dried over Na2SO4, filtered and concentrated. Flash chromatography (1:1 hexane:ethyl acetate) provided 203 mg (55% yield) of the title compound. 1H NMR (300 MHz, CDCl3). δ1.17 (s, 3H), 1.22 (s, 3H), 1.80-1.90 (m, 1H), 2.39-2.52 (m, 1H), 3.03-3.20 (m, 5H), 3.25-3.32 (m, 1H), 3.58-3.67 (m, 1H), 3.69-3.78 (m, 1H), 3.88-3.98 (m, 2H), 6.85-6.95 (m, 1H), 7.00-7.10 (m, 2H), 7.21-7.32 (m, 1H). ESI-MS. M/z; (M+H)=308.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[C@H:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42](Cl)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>ClCCl.C(=O)(O)[O-].[Na+]>[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([N:17]3[CH2:18][CH2:19][N:14]([C@H:11]4[CH2:12][CH2:13][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:9][C@H:10]4[C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=4)[CH2:15][CH2:16]3)=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Clc1ccc([C@@H]2CN(Cc3ccccc3)CC[C@@H]2N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCC1c2ccccc2-c2ccccc21)N1CCN([C@H]2CCN(Cc3ccccc3)C[C@H]2c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
Rac-cis-1-[1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine (2.00 g, 5.41 mmol) was dissolved in dichloromethane (130 mL) and 9-fluorenylmethyl-chloroformate (1.71 g, 6.49 mmol) in dichloromethane (50 mL) was added at 0° C. The reaction mixture was stirred at room temperature overnight and diluted with sat sodium bicarbonate solution (100 mL). The organic phase was separated and the aqueous layer was extracted twice with 150 mL dichloromethane. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with cyclohexane/ethyl acetate 6:1 gave rac-cis-4-[1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-piperazine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (1.75 g, 55%) as a light yellow solid, MS: m/e=592.3 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:3]=1[C:4]([NH:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:23]=[C:22]([C:31]#[N:32])[CH:21]=1)=[O:6]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: COc1cc(Cl)c(C(=O)O)cc1-c1ccccn1
Product: COc1cc(Cl)c(C(=O)Nc2cc(C#N)nn2-c2ccccc2)cc1-c1ccccn1

Procedure:
The title compound was prepared according to the method described for Example 99 using 2-chloro-4-methoxy-5-(pyridin-2-yl)benzoic acid (Preparation 26) and 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53). The residue was purified using reverse phase chromatography eluting with 5-60% MeCN (with 0.1% formic acid) in water (with 0.1% formic acid).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH2:26])=[C:24]([O:30][CH3:31])[CH:23]=1.CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[Br:21][C:22]1[CH:28]=[C:27]([CH3:29])[C:25]([NH:26][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([N:12]4[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]4)=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Reactant: COc1cc(Br)cc(C)c1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCc1cc(CC)n(-c2cccc3nc(Nc4c(C)cc(Br)cc4OC)n(C)c23)n1
Temperature: 110 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of 83 mg (0.287 mmol) of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole, 186 mg (0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 20 hours. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to give 112 mg (83%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]Cl)=[CH:10][CH:9]=1>C(#N)C>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(CCl)cc1
Solvent: CC#N
Product: COc1ccc(Cn2ccnc2)cc1
Yield: 69.3 %

Procedure:
To a stirred solution of imidazole (25.53 g, 375 mmole) in acetonitrile (625 ml) was added p-methoxybenzyl chloride (16.95 ml, 125 mmole). The reaction was refluxed for 16 hours, evaporated to dryness, and redissolved in methylene chloride and saturated sodium bicarbonate. The organic layer was extracted with water twice. Standard acid/base workup gave N-p-methoxybenzylimidazole (16.3 g, 69%) which was used without further purification:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1.Br.Br.[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(=O)(O)[O-].[Na+].[I-].[K+]>C(O)CCC>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][CH2:5][CH:6]2[O:10][C:9](=[O:11])[N:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7]2)[CH2:29][CH2:28]1
Reactant: O=C1OC(CCCCCl)CN1c1ccccc1
Reactant: Oc1ccccc1N1CCNCC1
Agent: Br
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCCCO
Product: O=C1OC(CCCCN2CCN(c3ccccc3O)CC2)CN1c1ccccc1
Yield: 112 %

Procedure:
Following the procedure of Example 5, a mixture of 5-(4-chlorobutyl)-3-phenyl-2-oxazolidinone (6.0 g, 0.0237 mol), 1-(2-hydroxyphenyl)piperazine dihydrobromide (8.06 g, 0.0237 mol), sodium bicarbonate (7.98 g, 0.095 mol), and potassium iodide (1.0 g) in n-butanol (200 mL) gave an oil (10.5 g) which crystallized on standing and was recrystallized from isopropanol/isopropyl ether. Drying under high vacuum gave 6.15 g (66% yield), mp 123°-129° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[NH:29]1[CH2:32][CH:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:29]2[CH2:32][CH:31]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:30]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CN(C2CNC2)CCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (80 mg, 0.21 mmol), 4-azetidin-3-ylmorpholine (36 mg, 0.25 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (5 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (90 mg, 0.42 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 328 as a cream solid (71 mg, 67%). LCMS (Method G): RT 5.18 min [M+H]+ 504.2. 1H NMR (CDCl3, 400 MHz): δ 8.10-8.05 (m, 1 H); 7.73-7.69 (m, 1 H); 7.28-7.23 (m, 2 H); 4.35 (m, 4 H); 3.91-3.82 (m, 9 H); 3.73 (m, 4 H); 3.58 (m, 2 H); 3.18-3.04 (m, 3 H); 2.94 (s, 3 H) and 2.35 (m, 4 H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12](OS(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:36]1([Mg]Cl)[CH2:40][CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3cccc(Cl)c3)c2=O)cc1
Reactant: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Cl)c3)c(=O)c2C2CCCC2)cc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a −78° C. solution of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone, prepared in Example 333, (0.175 g, 0.33 mmol) in THF (3.3 mL) was added cyclopentyl magnesium chloride (0.17 mL, 1.0 M in diethyl ether). The resulting solution was stirred under nitrogen less than 1 hour with warming to room temperature. The reaction was poured into water and extracted with ethyl acetate. The combined organics were dried over MgSO4 and concentrated in vacuo. The resulting crude product was purified using flash chromatography (SiO2, 2:1 ethyl acetate:hexanes) to provide the desired product (yield: 0.1328 g, 94%). mp 155-157° C. 1H NMR (300 MHz, DMSO d6) δ 1.50 (m, 2H), 1.66 (m, 2H), 1.79 (m, 2H), 2.09 (m, 2H), 2.90 (m, J=8 Hz, 1H), 3.26-3.37 (3H, obstructed by H2O), 7.49-7.63 (m, 3H), 7.71 (m, 3H), 7.97 (s, 1H), 8.10 (m, 2H). MS (DCI/NH3) m/z 429 (M+H)+, 446 (M+NH4)+. Anal. calc. for C22H21ClN2O3S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.48; H, 4.81; N, 6.22.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].C([O-])(=O)C.[Na+].[Br:16]Br.O>C(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2
Reactant: O=C1Cc2ccccc2N1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(Br)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1 g, 25.5 mmol) in CHCl3 (20 cm3) was treated with bromine (2.4 g, 15.0 mmol) in CHCl3 (10 cm3). After 30 min. the mixture was allowed to warm to RT and stirred for 1 h. The reaction mixture was diluted with EtOAc (500 cm3) and poured into water. The aqueous layer was extracted with EtOAc (×2), the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, brine, dried (MgSO4), and evaporated to give the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solid which was used without further purification: m.p. 221-223° C.; 1H NMR (DMSO-d6) δ 3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33 (dd, 1H, J=8.1, 1.7 Hz), 7.37 (s, 1H), 10.49 (brs, 1H); 13C NMR (DMSO-d6) δ 36.10 (t), 111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s), 176.24 (s); MS (EI) m/z 211, 213 (M)+.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5](=[O:18])[CH:6]([S:15][CH2:16][CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:29][CH:28]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CS(C)=O>[CH3:3][O:4][C:5](=[O:18])[CH:6]([S:15][CH2:16][CH3:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[CH:32][CH:31]=2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Reactant: CCSC(Cc1ccc(O)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCSC(Cc1ccc(OCCc2ccc(NC(=O)OC(C)(C)C)cc2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Sodium hydroxide (0.045 g; 1.25 mmole) was pulverized and added to DMSO (10 ml). 2-Ethylsulfanyl-3-(4-hydroxyphenyl)propanoic acid methyl ester (0.21 g; 0.87 mmole) was added followed by addition of 2-[4-(tert-butoxycarbonylamino)phenyl]ethyl-4-methylbenzenesulfonate (described in Example 40a) (0.342; 0.87 mmole). The reaction mixture was stirred at room temperature for 3 hours then all the starting material were consumed according to LC-MS. Water (10 ml) and tetrahydrofuran (5 ml) were added and the stirring was continued over night. Then the reaction mixture was treated with diethyl ether and water and in order to avoid foam formation diluted hydrochloric acid was added. The phases were separated and the organic phase was washed three times with water. The water phases were combined and washed once again with diethyl ether. All the organic phases were combined, dried with sodium sulfate and evaporated. Chromatography in ether:petroleum ether (1:9 and 1:3) gave 0.18 g (41.4% yield) of 3-[4-{2-(4-[tert-butoxycarbonylamino]phenyl)ethoxy}phenyl]-2-ethylsulfanylpropanoic acid methyl ester.