Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=[O:15].[CH:16]1[C:21]([NH:22][NH2:23])=[CH:20][CH:19]=[C:18]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:17]=1.Cl>>[O:15]=[C:2]1[C:3](=[N:23][NH:22][C:21]2[CH:20]=[CH:19][C:18]([S:24](=[O:26])(=[O:25])[NH2:27])=[CH:17][CH:16]=2)[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:5]=2)[NH:1]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: NS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(S(N)(=O)=O)cc32)cc1

Procedure:
The title compound was prepared from 1H-indole-2,3-dione-5-sulfonic acid amide and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ7.04 (d, J=8.4 Hz, 1H), 7.25 (s, 2H), 7.26 (s, 2H), 7.60 (d, J=8.9 Hz, 2H), 7.70 (dd, J=8.2, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.98 (d, J=1.6 Hz, 1H), 11.43 (s, 1H), 12.75 (s, 1H); APCI−MS m/z 395 (M)−. Anal. Calcd for C14H13N5O5S2.0.5H2O: C, 41.58; H, 3.49; N, 17.32; S, 15.86. Found: C, 41.67; H, 3.46; N, 17.26; S, 15.78.
Reaction SMILES: [CH:1](/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:2].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[OH:2][CH2:1]/[CH:3]=[CH:4]/[C@:5]1([CH3:29])[S:11][C@H:10]2[N:7]([C:8](=[O:12])[CH2:9]2)[C@H:6]1[C:13]([O:15][CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:14]
Reactant: C[C@@]1(/C=C/C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@]1(/C=C/CO)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
5.80 g (14.2 mmol) of benzhydryl (E)-(2S,3S,5R)-3-(2-formyl-vinyl)-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2carboxylate were dissolved in 240 ml of toluene under argon and is cooled to 0° C. Then, 14.2 ml (21.3 mmol) of a 20% diisobutylaluminium hydride solution (in toluene) were added dropwise and the cooling bath is removed. The reaction mixture was stirred at room temperature for 6 hours, poured into 150 ml of saturated ammonium chloride solution and extracted three times with 200 ml of methylene chloride each time. The combined organic extracts were washed once with 300 ml of water as well as saturated sodium chloride solution, dried over magnesium sulfate, filtered and freed from solvent on a rotary evaporator. The residual yellow oil was chromatographed over silica gel (particle size 0.040-0.063 mm) with ethyl acetate:n-hexane (9:16) as the eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: c1c[nH]cn1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (311 mg) was reacted with imidazole to obtain the desired (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(1H-imidazol-1-yl)propanamide (86 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9].C1(P(=[CH:42][C:43](=[O:45])[CH3:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:42][C:43](=[O:45])[CH3:44])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1Oc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)C=Cc1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 38.7 %

Procedure:
A mixture of 2'-(2,4-difluorophenoxy)-4'-formylmethanesulfonanilide (2.3 g) and triphenylphosphoranylideneacetone (2.3 g) in dimethylsulfoxide (10 ml) was stirred for 13 hours at 80° C. After cooling of the mixture, ethyl acetate was added, and the resulting mixture was washed with water, then dried. The ethyl acetate layer was evaporated to dryness and the residue was purified by column chromatography on silica gel (80 g) eluting with a mixture of chloroform and methanol (200:1) and further recrystallized from ethanol to give pale yellow needles of 2'-(2,4-difluorophenoxy)-4'-(3-oxo-1-butenyl)methanesulfonanilide (1.0 g).
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[NH2:7][CH:8]([CH:14]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])O.[Na+]>O.C(Cl)Cl.C(O)(=O)C>[Si:23]([O:22][CH:14]([C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:8]([NH:7][CH3:3])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C(N)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C(NC)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
182 mg of 35% formalin, 0.1 ml of acetic acid and 121 mg of sodium cyanoborohydride were added to a solution of 0.7 g of ethyl 2-amino-3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 78) in 4 ml of a 3:2 by volume mixture of methylene chloride and water at 0° C., and the resulting mixture was stirred at 0° C. for 15 minutes. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, after Which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 8:1 to 1:1 by volume as the eluent, to give 200 mg of the title compound having Rf=0.38 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:25]/[CH:26]=[CH:27]/[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([CH2:7][N:8]([S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:22])[CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])[CH2:25][CH:26]=[CH:27][C:28]([O:30][CH3:31])=[O:29])=[O:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C/CBr
Reactant: CC(C)(C)OC(=O)CNS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C=CCN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 110.7 %

Procedure:
A mixture of (6-chloro-naphthalene-2-sulfonyl)glycine tert-butyl ester (17.79 g), methyl 4-bromocrotonate (13.426 g) and potassium carbonate (8.28 g) in DMF (150 ml) was stirred at 50° C. for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed with water and brine, dried and concentrated to obtain a residue, which was crystallized from ether to obtain methyl 4-[(tert-butoxycarbonylmethyl)(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (25.13 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH3:21])=[C:11]([C:17](I)=[CH:18][CH:19]=1)[CH2:12][O:13][C:14](=[O:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[CH2:27])=[O:25].C(=O)(O)[O-].[Na+]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][O:23][C:24](=[O:25])[C:26]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])=[CH:27][C:17]1[CH:18]=[CH:19][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([CH3:21])[C:11]=1[CH2:12][O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OCc1c(I)ccc(NC(=O)OC(C)(C)C)c1C
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)c(C)c1COC(C)=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 69 %

Procedure:
Palladium (II) acetate (105 mg, 0.43 mmol) was added to a mixture of acetic acid 3-tert-butoxycarbonylamino-6-iodo-2-methyl-benzyl ester (2.89 g, 7.1 mmol), Z-dehydroalanine methyl ester (2.20 g, 9.4 mmol), tetrabutylammonium chloride hydrate (2.70 g, 9.7 mmol), and sodium bicarbonate (1.80 g, 21.4 mmol) in THF (100 mL). Reaction was heated at reflux for 3.75 hours. Mixture was cooled to room temperature then filtered through a plug of silica gel eluting 70% ethyl acetate-hexanes (500 mL). Filtrate was concentrated in vacuo. Silica gel chromatography afforded the title compound as a yellow solid in 69% yield. 1H NMR (300 MHz, CDCl3): δ=7.79 (d, J=8.4, 1H), 7.42 (s, 1H), 7.27 (m, 6H), 6.30 (s, 1H), 5.11 (s, 2H), 5.02 (s, 2H), 3.81 (s, 3H), 2.21 (s, 3H), 2.02 (s, 3H), 1.51 (s, 9H). MS m/e (M−H)−=511.0.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[CH:8][N:9]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C)C=O>[C:17]1([S:14]([N:9]2[C:10]3[C:6](=[C:5]([O:4][CH2:3][CH2:2][N:23]=[N+:24]=[N-:25])[CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(OCCCl)cccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1cccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A suspension of 4-(2-chloroethoxy)-1-(phenylsulfonyl)-1H-indole (3.35 g, 10 mmol) and sodium azide (1.95 g, 30 mmol) in anhydrous dimethylformamide is stirred under nitrogen for 20 hr at 60° C., poured into water and extracted with diethyl ether. The extracts are combined, washed sequentially with 1N HCl, H2O and saturated NaCl, dried over MgSO4 and concentrated in vacuo to afford the title product as an off-white solid, 3.3 g (96%), identified by NMR and mass spectral analyses.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH3:22][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:18][CH:17]=1
Reactant: CI
Reactant: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1
Reaction time: 2 h

Procedure:
4-(1-phenylcyclohexyl)phenol (20 mg, 0.08 mmol) was dissolved in DMF (2 mL). A suspension of NaH in oil (60%, 5 mg, 0.125 mmol) was added. After stirring for 5 minutes methyl iodide (0.05 mL; 0.8 mmol) was added. The reaction mixture was stirred for 2 h. (tic indicated full conversion of the starting material) then quenched with water (10 mL). Dichloromethane (10 mL) was added. The mixture was shaken and the organic phase separated off, dried (Na2SO4) and concentrated to syrup. The title product was afforded after work-up by flash-chromatography (eluent dichloromethane). Yield: 20 mg, quantitatively. LC-MS purity (UV/MS): 100/-, Rt 6.48 min. 1H NMR data were in accordance with the data written above.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9](COCC[Si](C)(C)C)[N:8]=[CH:7]3)[CH2:3][CH2:2]1.C(N)CN>ClCCl.FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[CH:7]3)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C3CC3)ccc21
Solvent: NCCN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]ncc2cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.3 %

Procedure:
In a 1 L round-bottomed flask, 5-cyclopropyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (1.7 g, 5.89 mmol) was dissolved in a solution of dichloromethane (292 mL) and trifluoroacetic acid (194 mL). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane and ethylenediamine (24.2 mL, 5.89 mmol) was added. After stirring at room temperature overnight, the reaction mixture was poured onto water (50 mL) and extracted with EtOAc (2×100 mL). The organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 1 g of 5-cyclopropyl-1H-indazole that was used without further purification.
Reaction SMILES: [F:1][C:2]([F:44])([C:31]1[O:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])=[N:34][N:35]=1)[C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[C:14]([NH:15]C(=O)OC(C)(C)C)=[CH:13][N:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][C:14]1[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:44])[C:31]3[O:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[O:42][CH3:43])=[N:34][N:35]=3)=[CH:30][CH:29]=2)=[N:11][N:12]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1
Reactant: COc1ccccc1-c1nnc(C(F)(F)c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3NC(=O)OC(C)(C)C)cc2)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1nnc(C(F)(F)c2ccc(C(=O)Nc3nn(-c4ccccc4)cc3N)cc2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl {3-[(4-{difluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzoyl)amino]-1-phenyl-1H-pyrazol-4-yl}carbamate (10 mg) in methylene chloride (2 mL) was added trifluoroacetic acid (1 mL) and the solution was stirred at ambient temperature for 16 hours. The reaction was evaporated to dryness to give N-(4-amino-1-phenyl-1H-pyrazol-3-yl)-4-{difluoro[5-(2-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}benzamide as a yellowish solid. 1H NMR (CD3OD) δ 8.45 (s, 1H), 8.23 (d, J=8.21 Hz, 2H), 7.93 (m, 3H), 7.79 (d, J=7.62 Hz, 2H), 7.64 (m, 1H), 7.52 (t, J=7.62 Hz, 2H), 7.37 (t, J=7.62 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 7.14 (t, J=7.62 Hz, 1H), 3.96 (s, 3H); ESIMS calcd 503.2 (M++H), found 503.1 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:3]=[C:4]([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][N:29]([CH2:32][CH2:33][OH:34])[CH2:30][CH2:31]4)=[C:22]([C:23]#[N:24])[CH:25]=3)=[O:16])[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(N)ccc1N1CCN(CCO)CC1
Reactant: Cc1c(C(=O)O)cnn1-c1cccc(Cl)c1
Product: Cc1c(C(=O)Nc2ccc(N3CCN(CCO)CC3)c(C#N)c2)cnn1-c1cccc(Cl)c1
Yield: 12.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (2 g) and 5-amino-2-[4-(2-hydroxyethyl) piperazin-1-yl]benzonitrile (2.5 g), the title compound (0.5 g) was obtained, melting point: 176–177° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.CCCCCC.[CH3:19][CH:20]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([C:33]#[N:34])[CH2:23][CH2:22][CH2:21]1.[O:35]=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[C:33]([C:24]1([C:36]2([OH:35])[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[CH2:39]2)[CH2:23][CH2:22][CH2:21][CH:20]([CH3:19])[N:25]1[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)#[N:34]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC1CCCC(C#N)N1Cc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1CCCC(C#N)(C2(O)CN(C(=O)OC(C)(C)C)C2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 6.8 %

Procedure:
To a solution of N,N-diisopropylamine (1.6 mL, 11.2 mmol) cooled to −78° C. in THF (15 mL) was added a 2.5 M solution of n-BuLi in hexane (4.5 mL, 11.2 mmol) dropwise over 5 minutes and the mixture was stirred at this temperature for an addition 15 minutes. 6-methyl-1-(phenylmethyl)piperidine-2-carbonitrile (2.4 g, 11.2 mmol) (prepared using procedures similar to those in Bonin et. al. Tet. Lett. 1982, 23(33), 3369-72) in THF (10 mL) was then added dropwise over 20 minutes and the reaction mixture was stirred for a further minutes. Next a solution of 1,1-dimethylethyl 3-oxoazetidine-1-carboxylate (1.3 g, 7.5 mmoL), prepared using procedures similar to those in Example 3, in THF (10 mL) was added dropwise over 30 minutes. The reaction mixture was gradually warmed to room temperature and allowed to stir overnight. The reaction mixture was quenched with 10% citric acid and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate then filtered and concentrated in vacuo to give crude product as yellow oil. Further purification by flash chromatography (30% ethyl acetate in hexanes) afforded 1,1-dimethylethyl 3-[2-cyano-6-methyl-1-(phenylmethyl)piperidin-2-yl]-3-hydroxyazetidine-1-carboxylate as a pale yellow oil (0.2 g, 7% yield). 1H NMR (400 MHz, CDCl3): 7.17-7.40 (m, 5H), 4.42 (d, 1H), 4.04-4.18 (m, 1H), 3.83-4.00 (m, 1H), 3.70-3.75 (m, 2H), 1.70-1.87 (m, 4H), 1.45 (s, 3H), 1.41 (s, 9H), 1.22-1.26 (m, 1H), 1.13-1.18 (m, 2H); MS (EI) for C22H31N3O3: 386 (MH+).
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[C:3]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].ClC[Si](C)(C)C.Cl>CN(C)C=O>[C:10](#[N:11])[C:3]1[C:4](=[CH:7][CH:8]=[CH:9][CH:2]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(O)c1C#N
Agent: C[Si](C)(C)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 30 h
Yield: 131 %

Procedure:
In 180 ml of N,N-dimethylformamide were dissolved with heating 20 g of 3-hydroxyphthalonitrile and 10.55 g of potassium carbonate, to which 18 g of chloromethyltrimethyl-silane were added dropwise at 40° C. in the atmosphere of argon. After the addition, the mixture was stirred for 30 hours while maintaining the reaction temperature at 80°-90° C. The reaction vessel was then cooled to room temperature and 250 ml of dilute hydrochloric acid was added. The mixture was extracted with 1.2 liters of toluene. The organic layer was washed well with water and water was removed with magnesium sulfate. Thereafter, toluene was removed by distillation and the residue was purified with a toluene/silica gel column to obtain 23.3 g (yield: 73.0%) of a compound having the formula (XII) below. The compound is in the form of white crystals and has a melting point of 112.5° C. The IR spectrum of the compound is shown in FIG. 3. ##STR37##
Reaction SMILES: C(O)C.[C:4]1([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N1C=CC=CC=1.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl.CCCCCC.C(OCC)(=O)C>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:16][CH:13]2[CH2:12][CH2:11][CH:10]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:15][CH2:14]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC(c2ccccc2)CC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Commercial chloroform (Aldrich) is freed from stabilizing ethanol by passing the chloroform through a column of alumina. 4-Phenylcyclohexanol (28.3 g; 160 mmol.) is dissolved in the chloroform (150 mL) and the resulting solution is cooled in an ice bath (0° C.). Pyridine (25.3 g; 25.9 mL; 320 mmol.) is added to the solution, followed by the addition of p-toluenesulfonyl chloride (45.8 g; 240 mmol.) in small portions with constant stiffing. The reaction mixture is left overnight. TLC (hexane-ethyl acetate 15:1) shows that the starting 4-phenylcyclohexanol is consumed completely. Ether (500 mL) and water (150 mL) are added, and the organic layer is washed successively with 300 mL of 2N HCl, 5% NaHCO3, and water and then dried with Na2SO4. TLC exhibits three spots, the major one having the lowest Rf. The solvent is removed in a rotary evaporator, and the crude tosylate (70.4 g) is dissolved in 125 mL of hexane-ethylacetate (4:1) mixture upon heating and then left to crystallize in the freezer at −20° C. White product is collected and dried in vacuum, yield 40.6 g (76%), identified as 4-phenylcyclohexyl 4-methylbenzenesulfonate. TLC (hexane-ethyl acetate 15:1)—one spot, Rf=0.16. 1H NMR CDCl3, ppm): 1.2-2.2 (m, 8H, cyclohexyl), 2.46 (s, 3H, CH3), 2.48 (m, 1H, PhCH), 4.50 (m, 1H, TsOCH), 7.1-7.3 (m, 5H, Ph), 7.35 and 7.83 (two d, J=8.1 Hz, 4H, C6H4).
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3][CH:2]1[CH2:10][NH:11][C:12]([C:14]1[C:15]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=2)=[N:16][C:17]([N:20]2[CH2:25][CH:24]3[CH:22]([CH2:23]3)[CH2:21]2)=[N:18][CH:19]=1)=[O:13].[CH2:37]=O.[BH4-].[Na+]>CO>[CH:22]12[CH2:23][CH:24]1[CH2:25][N:20]([C:17]1[N:16]=[C:15]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=3)[C:14]([C:12]([NH:11][CH2:10][CH:2]3[CH2:3][C:4]4([CH2:5][CH2:6][N:7]([CH3:37])[CH2:8][CH2:9]4)[CH2:1]3)=[O:13])=[CH:19][N:18]=1)[CH2:21]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCNCC3)C2)cc1Cl
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCC2CC3(CCN(C)CC3)C2)cc1Cl
Reaction time: 10 h
Yield: 27.2 %

Procedure:
In methanol (50 mL) was dissolved the above N-(7-azaspiro[3.5]nonan-2-ylmethyl)-2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-formamide (357 mg, 0.7 mmol). Formalin (284 mg, 3.5 mmol) was added. Sodium borohydride (133 mg, 3.5 mmol) was added slowly. The reaction was continued for 10 h then quenched with water. The reaction mixture was extracted with ethyl acetate. The organic phase was dried and concentrated. The obtained solid was purified by silica gel column chromatography (DCM/methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((7-methyl-7-azaspiro[3.5]nonan-2-yl)methyl)pyrimidine-5-form amide (100 mg, 27.4% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].Cl[CH2:30][C:31]1[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[CH:23]=[CH:22][N:21]([CH2:30][C:31]4[CH:32]=[N:33][N:34]([CH3:36])[CH:35]=4)[C:20](=[O:24])[CH:19]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:25]([F:28])([F:26])[F:27]
Reactant: Cn1cc(CCl)cn1
Reactant: O=c1cc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Product: Cn1cc(Cn2ccc(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)cc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-2 (1H)-pyridinone and 4-(Chloromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z 504 [M+H]+; 3.68 min (ret time).