Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.Cl[Ni]Cl>[CH2:21]([C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2ccccc2n1
Reactant: Cl[Mg]Cc1ccccc1
Agent: Cl[Ni]Cl
Solvent: C1CCOC1
Product: c1ccc(Cc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
To a solution of the above-prepared (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added NiCl2 (dppp) (12 mg, 2.1.10−5 mol), followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). The solution is heated at 50° C. for 20 hours and the reaction mixture is then quenched with aqueous NH4Cl and the product extracted in ethyl acetate. The solvent is evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1.O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:23]([CH:20]3[CH2:22][CH2:21]3)=[O:24])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc(OC2CCC(N)CC2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OC2CCC(NC(=O)C3CC3)CC2)cc1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
To a solution of 4-(4-aminocyclohexyloxy)benzoic acid ethyl ester (4.15 g, 15.76 mmol) in DCM (40 mL) at 0° C. was added TEA (1.6 g, 15.7 mmol) followed by cyclopropane carbonyl chloride (1.98 g, 18.9 mmol) over a period of 1 hr. Stirring was continued at 0-5° C. for 2 h. Water (40 mL) was then added and extracted with EtOAc. The organic layer was washed with 2N HCl, satd.NaHCO3 and brine solution. It was dried and concentrated under vacuum affording 4.75 g (91%) of 4-[4-(cyclopropanecarbonyl-amino)-cyclohexyloxy]-benzoic acid ethyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18].Cl.[NH2:21][OH:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[C:8](=[N:21]/[OH:22])/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH3:17])[C:10]=1[OH:18]
Reactant: NO
Reactant: COc1ccc(C(=O)c2ccccc2F)c(O)c1C
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2ccccc2F)c(O)c1C
Temperature: 200 °C

Procedure:
2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone (30.0 g) is refluxed 18 hours in 350 ml of pyridine containing 32.0 g of hydroxylamine hydrochloride. The solvent is removed in vacuo and the residue is distributed between ether and 5% HCl. Drying and concentration of the ether gives a crude product that is heated as a melt at 200° C. for 30 minutes in a nitrogen atmosphere. The melt is allowed to cool and the solid mass is triturated well with hexane to give E-2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone oxime, mp 167°-169° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1)[S:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)[CH2:7][CH2:6]2.S(C1C=CC(C)=CC=1)(O[CH2:43][CH2:44][Cl:45])(=O)=O.[H-].[Na+]>CC(=O)CC>[Cl:45][CH2:44][CH2:43][O:36][C:34]1[CH:35]=[C:30]([CH:21]([S:22][C:23]2[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: COc1ccc(C(CCCCCCN2CCc3cc(OC)c(OC)cc3C2)Sc2ccc(C)cc2)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2c(cc1OC)CN(CCCCCCC(Sc1ccc(C)cc1)c1ccc(OC)c(OCCCl)c1)CC2
Temperature: 25 °C

Procedure:
To a stirred solution of 5.57 g of 5-[7-(3,4-dihydro-6,7-dimethoxy-2(1H) -isoquinolinyl)-1-[(4-methylphenyl) thio]heptyl ]-2-methoxyphenol and 2.0 mL of 2-chloroethyl tosylate in 50 mL of 2-butanone is added 0.44 g of 60% sodium hydride in oil. The solution is heated to reflux for 48 hours and then cooled to room temperature. The solution is partitioned between chloroform and brine and the organic layer dried. The solvent is removed at reduced pressure and the residue chromatographed on silica gel with a gradient elution going from hexane to chloroform to methyl alcohol. The desired fractions are concentrated, dissolved in diethyl ether and passed through a short hydrous magnesium silicate pad. The solvent is removed at reduced pressure to afford 1.6 g of the desired product as a light tan gum. MS(CI): m/z 598(M+H+) and 474(M-(TolSH)+H+). Calcd for C34H44ClNSO4 : C=68.26, H=7.41, N=2.34, Cl=5.93, S=5.36 Found C=68.41, H=7.01, N=2.12, Cl=5.71, S=5.15
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22](Cl)=[O:23])([O-:18])=[O:17]>C1(C)C=CC=CC=1>[N+:16]([C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([N+:28]([O-:30])=[O:29])[CH:27]=1)[C:22]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])=[O:23])([O-:18])=[O:17]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1CCCCCN1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
All glassware is dried thoroughly, and the reaction is kept under an inert atmosphere (argon) at all times. With stirring, 2.33 g (20.6 mmol) of caprolactam (Aldrich) and 2.30 g (22.7 mmol) of triethylamine (Aldrich, d=0.726 g/mol) are added to 100 mL toluene (Aldrich) in a 3-neck round bottom flask equipped with a reflux condenser, addition funnel, and mechanical stirrer, to give a clear, pale yellow solution. Addition of a solution of 4.75 g (20.6 mmol) of 3,5-dinitrobenzoyl chloride (Aldrich) in 100 mL toluene proceeds dropwise over a period of 30 min. The resulting reaction mixture is heated to reflux and stirred for 16 h. Upon cooling to room temperature, the reaction is filtered to remove the triethylamine hydrochloride, and poured into a separatory funnel. After dilution with 300 mL of chloroform, the organic solution is extracted with 5% aq HCl, 5% aq NaOH, and finally D.I. water. The organic layer is dried over Na2 SO4, filtered, and the solvent removed by evaporation under reduced pressure. Recrystallization of the crude product from toluene followed by drying under vacuum yields N-(3,5-dinitrobenzoyl)caprolactam as a light yellow, crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1.Cl.[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][N:25](C3CCCCO3)[C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CCCCO>[Cl:19][C:20]1[C:28]2[N:27]=[CH:26][NH:25][C:24]=2[CH:23]=[CH:22][C:21]=1[CH2:35][N:36]([CH3:37])[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([F:17])=[CH:4][N:3]=1
Reactant: CNCc1ccc2c(ncn2C2CCCCO2)c1Cl
Reactant: Fc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc2[nH]cnc2c1Cl)c1ncc(F)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoropyrimidin-4-amine (55, 95 mg, 0.37 mmol, CASRN 854434-98-5), the bis-HCl salt of 220 (185 mg, 0.52 mmol), DIPEA (0.33 mL) and n-BuOH (0.8 mL), sealed and heated at 120° C. for 96 h. The reaction mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC to afford 93.2 mg (60%) of I-86: MS (ESI) m/z=413.1 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1F>CN(C=O)C>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Fc1cccc(Br)c1F
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(Oc2c(F)cccc2Br)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
Add slowly a solution of 1-methyl-piperidin-4-ol (2.98 g) in DMF (20 mL) into a suspension of sodium hydride (95%) (0.72 g) in DMF (25 mL) at room temperature. Heat the mixture in an oil bath at 65° C. After 30 min., add 1-bromo-2,3-difluoro-benzene (5.0 g) and stir at 65° C. After 2 hr., partition the reaction mixture between water and ether, dry over anhydrous sodium sulfate, and evaporate to give a yellow oil. Separate on a silica gel column (110 g, solvent: ether, ether-2M NH3 in methanol 19:1, 9:1) to obtain 4-(2-bromo-6-fluoro-phenoxy)-1-methyl-piperidine (4.06 g, 54% yield) and the title compound (1.60 g, 21% yield). Mass spectrum (electric spray) m/z=288 (M+1), 290 (M+2+1); 1H NMR (CDCl3): 7.12 (m, 1H), 6.92 (m, 2H), 4.30 (m, 1H), 2.69 (m, 2H), 2.30 (s, 3H), 2.28 (m, 2H), 1.97 (m, 2H), 1.89 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:7](I)=[CH:6][N:5]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[N:4]=1)[CH3:2].C1COCC1.C([Mg]Cl)(C)C.CO[B:28]1[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]1.[NH4+].[Cl-]>>[CH2:1]([C:3]1[C:7]([B:28]2[O:32][C:31]([CH3:34])([CH3:33])[C:30]([CH3:36])([CH3:35])[O:29]2)=[CH:6][N:5]([C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[N:4]=1)[CH3:2]
Reactant: CCc1nn([C@H]2CC[C@H](O)CC2)cc1I
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1nn([C@H]2CC[C@H](O)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reaction time: 1 h

Procedure:
To a solution of trans-4-(3-ethyl-4-iodo-1H-pyrazol-1-yl)cyclohexanol (150.0 mg, 0.4685 mmol) in THF (10 mL, 100 mmol) at rt was added 2 M isopropylmagnesium chloride in THF (0.70 mL, 1.4 mmol), and the mixture was stirred for 1 h. The reaction was quenched with 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.31 mL, 1.9 mmol), and allowed to stir at rt for 1 h. Sat. NH4Cl was added, and the organic solvent was removed in vacuo. The material was extracted with DCM and water. The organic layer was concentrated in vacuo to afford the title compound as a white solid. The material was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[C:8]([CH2:15][C:16]([OH:18])=O)([CH3:14])[CH2:7][CH2:6]2)#[N:2].O.[NH2:20][NH2:21].C(O)(=O)C>O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[C:8]([CH3:14])([CH2:15][C:16](=[O:18])[NH:20][N:21]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:2]
Reactant: NN
Reactant: CC1(CC(=O)O)CCc2cc(C#N)ccc2C1=O
Solvent: CC(=O)O
Solvent: O
Product: CC12CCc3cc(C#N)ccc3C1=NNC(=O)C2

Procedure:
A mixture of 6-cyano-2-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthyl acetic acid (3.5 g), hydrazine hydrate (20 ml), acetic acid (20 ml) and water (40 ml) was stirred under reflux for 4 hours. The reaction mixture was cooled and the precipitated solid filtered off. Recrystallisation from DMF/ethanol gave 8-cyano-4a-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (2.5 g; m.p.>300°); ν(Nujol mull) 3315, 3210, 2214, 1675, 1635, 1615, 1590 and 844 cm-1 ; δ(DMSO-d6) 1.06, (3H,s,CH3), 1.80 (2H,m,5-H) 2.40 (2H,m,4-H), 2.92 (2H,m,6-H), 7.61 (1H,m,9-H), 7.70 (1H, s, 7-H), 8.13 (1H,d,10-H), 11.05 (1H,s,NH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:20]([C:19]1[CH:22]=[CH:23][C:16]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[CH3:14])=[N:17][CH:18]=1)#[N:21]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(C#N)cn1
Temperature: 150 °C
Yield: 39.7 %

Procedure:
3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 1.0 mmol) was dissolved in dry DMF (10 mL) taken in a shield tube. To the reaction mixture was added 6-chloronicotinonitrile (70 mg, 1.0 mmol) followed by potassium carbonate (140 mg, 1.0 mmol) and the mixture was heated to 150° C. for 3 h. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The product was extracted with EtOAc and the organic layer was washed with H2O and brine and dried over anhydrous sodium sulfate. Solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 30% EtOAc in petroleum ether) to afford compound tert-butyl 4-(5-cyanopyridin-2-yl)-3-methylpiperazine-1-carboxylate (120 mg, yield 40%) as yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.63 (dd, J=9.0 Hz, J=2.4 Hz, 1H), 6.56 (d, J=9.0 Hz, 1H), 4.53 (m, 1H), 4.13-3.91 (m, 3H), 3.29-3.16 (m, 2H), 3.02 (m, 1H), 1.49 (s, 9H), 1.20 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C.[Pd]>[CH3:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[NH2:16]
Reactant: Cc1ccc(COC2CCCCO2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(COC2CCCCO2)cc1N

Procedure:
The solution of 12.3 g of 2-(4-methyl-3-nitrobenzyloxy)tetrahydropyran in 150 ml of ethanol is hydrogenated in the presence of 1.25 g of 10% Pd/C over 24 hours. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (1:2 EtOAc-heptane); Rt=2.72.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:17]=2[N:18]=[C:19]([C:21]2[O:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[O:25]1[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[S:26][C:17]=3[N:18]=2)=[CH:22][CH:23]=[N:24]1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]1[C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[C:7]([NH:9][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2Cc2ccc(F)cc2)cc1
Yield: 29.1 %

Procedure:
The title compound (D117) (20 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-piperidine-2-carboxamido)ethyl)benzoate (D86) (50 mg) and 4-fluorobenzyl bromide (0.043 ml, 0.34 mmol). (Na2CO3: 2.5 eq; reaction time: 4 hrs; 60° C.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1.ClCCl>CO.[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Cc1cccc(C(CCOCCN2CCC[C@@H](C(=O)O)C2)c2ccccc2)c1
Yield: 27.9 %

Procedure:
The acid prepared in Example 47 (8.2 g, 21.6 mmol) was dissolved in methanol (150 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was disolved into dichloromethane and dried (Na2SO4). The solvent was evaporated in vacuo to give 2.3 g (28 %) of the title compound as a foam.
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:12]2[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][C@H:13]2[CH2:26]OS(C)(=O)=O)[CH:8]=[CH:9][C:10]=1[Cl:11].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([CH2:26][C@H:13]1[C@H:12]([C:7]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:5]([Cl:4])[CH:6]=2)[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])[CH2:14]1)#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COS(C)(=O)=O)C1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CC#N)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Potassium cyanide (1.720 g) was added to a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(methylsulfonyl)oxy]methyl}-1,4-oxazepane-4-carboxylate (3 g) in DMF (30 ml), and the mixture was stirred at 80° C. overnight. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (2.00 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[N:12]([C:23](=[O:37])[N:24]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=4)[N:25]=3)[CH:13]=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:39][OH:40]>C1COCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]2[CH:14]=[CH:13][N:12]3[C:23](=[O:37])[N:24]([CH2:26][C:27]4[CH:28]=[N:29][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:31][CH:32]=4)[N:25]=[C:11]3[C:10]=2[C:7]2[CH:8]=[CH:9][C:4]([C:1](=[N:39][OH:40])[CH3:2])=[CH:5][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NO
Reactant: CC(=O)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=NO)c1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Reaction time: 108 h

Procedure:
To a stirred solution of 8-(4-acetylphenyl)-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (43.3 mg, 0.083 mmol) in THF (2 mL) and water (2 mL) at room temperature was added hydroxylamine hydrochloride (11.5 mg, 0.17 mmol). After 108 h, the reaction mixture was diluted with water and extracted twice with EtOAc. The organic extracts are combined, dried (MgSO4), filtered and evaporated. Purification by preparative reverse phase HPLC (methanol-water-trifluoroacetic acid), pooling the fractions, evaporating, redissolving the residuum in dichloromethane, washing with saturated aq. NaHCO3 solution, drying (MgSO4), filtering and evaporating provided the title compound as a yellow solid, 38 mg, 85%. HPLC/MS: retention time=3.38 min, [M+H]+=538. 1H NMR (CDCl3): δ 8.79 (d, J=1.8 Hz, 1H), 8.62 (br s, 1H), 7.92 (dd, J=1.8, 8.0 Hz, 1H), 7.84 (d, J=7.0 Hz, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.57 (dd, J=2.2, 6.6 Hz, 2H), 7.23 (m, 5H), 7.06 (d, J=6.6 Hz, 2H), 6.65 (d, J=7.1 Hz, 1H), 5.27 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]>C(OCC)(=O)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][C:28]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:18][CH3:19])=[N:7][N:8]3[C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)([OH:31])[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(O)(c2ccc3c(CC)nn(-c4ccc(F)cc4)c3c2)CC1
Yield: 56.2 %

Procedure:
This compound was prepared according to the method described in Example 6 of U.S. Ser. No. 08/046,858, filed May 8, 1997 as Attorney Docket No. PC9798, starting with 3.0 grams (9.4 mmol) of 6-bromo-3-ethyl-1-(4-fluoro-phenyl)-1H-indazole and 2.0 grams (11.7 mmol) of 4-oxo-cyclohexanecarboxylic acid ethyl ester to give after silica gel flash column chromatography (using 20% ethyl acetate 80% hexane as elutant) 2.17 grams of light yellow semi-solid which was a mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) δ1.25-1.3 (t, 3H); 1.4-1.5 (t, 3H); 1.6-1.78 (m, 2H); 1.8-2.5 (m, 7H); 2.70 (m, 1H); 3.04 (m, 2H); 4.16 (m, 2H); 7.17-7.28 (m, 3H); 7.61-7.79 (m, 4H); MS, m/z 324.4 (M+H+, base).
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][OH:16])[C:4]([CH3:17])=[N:3]1.[OH-].[K+].Cl[CH2:21][C:22]1[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=1.O>CS(C)=O>[CH3:1][N:2]1[C:6]([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([CH:14]=[N:15][O:16][CH2:21][C:22]2[CH:32]=[CH:31][C:25]([C:26](=[O:30])[S:27][CH2:28][CH3:29])=[CH:24][CH:23]=2)[C:4]([CH3:17])=[N:3]1
Reactant: Cc1nn(C)c(Oc2ccccc2)c1C=NO
Reactant: CCSC(=O)c1ccc(CCl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCSC(=O)c1ccc(CON=Cc2c(C)nn(C)c2Oc2ccccc2)cc1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
1.0 Gram (0.0043 mole) of 1,3-dimethyl-5-phenoxypyrazole-4-carbaldehyde oxime was dissolved in 20 ml of dimethyl sulfoxide, and after adding 0.3 g (0.0053 mole) of powdery potassium hydroxide, the resulting solution was stirred. To this solution was added 0.92 g (0.0043 mole) of S-ethyl 4-cloromethylbenzothiate, and reaction was carried out at room temperature for 3 hours. After completion of the reaction, 200 ml of water was added to the reaction solution which was then extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and ethyl acetate was removed by evaporation to obtain an oily product. This oily product was column-chromatographed on silica gel to obtain 1.4 g of the desired compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:11]=1[F:25]>O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([F:25])[CH:12]=1
Reactant: [C-]#N
Reactant: Fc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1F

Procedure:
To a solution of 0.6 gm. of sodium cyanide in 25 ml. of dimethyl sulfoxide preheated to 65°-70° C. is slowly added 2.5 gm. of 2-(4-bromomethyl-3-fluorophenyl)benzoxazole. The reaction mixture is heated at 60°-70° C. for 1 hour, then cooled and poured into water. The resulting precipitate is filtered off and chromatographed on 300 gm. of silica gel. Elution with methylene chloride gives 4-(benzoxazol-2-yl)-2-fluorophenylacetonitrile.