Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>>[OH:10][C:8]([C:11]1[N:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1)([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CC(=O)c1ccc(-c2ccc(C#N)nc2)cn1
Reactant: Ic1ccncc1
Product: CC(O)(c1ccncc1)c1ccc(-c2ccc(C#N)nc2)cn1
Yield: 18.4 %

Procedure:
Using 4-iodo pyridine (0.22 g, 1.076 mmol), and 6′-acetyl-[3,3′-bipyridine]-6-carbonitrile (0.12 g, 0.54 mmol) and procedure described for example 7 and step 4, crude product was obtained. The crude product was purified by preparative TLC (5% methanol in ethyl acetate) to obtain 6′-(1-hydroxy-1-(pyridin-4-yl)ethyl)-[3,3′-bipyridine]-6-carbonitrile as off-white solid (30 mg, 18% yield) in 98% HPLC purity. 1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 8.94 (s, 1H), 8.46 (d, 2H), 8.38 (dd, 1H), 8.23 (dd, 1H), 8.14 (d, 1H), 7.82 (d, 1H), 7.49 (d, 2H), 6.27 (s, 1H), 1.9 (s, 3H); LC-MS m/z calculated for [M+H]+303.12. found 303.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[C:6]=2[Cl:13].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>>[Cl:13][C:6]1[C:7]([OH:12])=[CH:8][CH:9]=[C:10]2[C:5]=1[C:4]([C:14]#[N:15])=[CH:3][C:2]([C:19]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([F:16])[CH:18]=1)=[CH:11]2
Reactant: N#Cc1cc(Br)cc2ccc(O)c(Cl)c12
Reactant: COc1ccc(B(O)O)cc1F
Product: COc1ccc(-c2cc(C#N)c3c(Cl)c(O)ccc3c2)cc1F

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-7-hydroxy-1-naphthonitrile (0.20 g, 0.71 mmol) with 3-fluoro-4-methoxyphenylboronic acid (0.17 g, 1.0 mmol) according to Method A to yield 0.14 (60%) of a yellow solid: mp 198-200° C.;1H NMR (DMSO-d6): δ 3.91 (3H, s), 7.27-7.33 (1H, m), 7.45 (1H, d, J=8.93 Hz), 7.71-7.74 (1H, m), 7.85 (1H, dd, J=2.23 Hz, J=13.09 Hz), 8.00 (1H, d, J=9.08 Hz), 8.48 (1H, d, J=1.97 Hz), 8.57 (1H, d, J=1.95 Hz), 11.18 (1H, s); MS (ESI) m/z 326/328 (M−H).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5]([O:12][CH3:13])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].O>C(Cl)Cl>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:8]1[CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:5]([O:12][CH3:13])=[C:6]([O:10][CH3:11])[CH:7]=1)=[O:25]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cccc(C(C)C)c1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)CCCCCBr)cc(C(C)C)c1OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
A solution of 5.0 g (0.028 mol) of 3-(1-methylethyl)-1,2-dimethoxybenzene in 5 mL of methylene chloride was added to an ice cooled mixture of 4.4 g (0.033 mol) of aluminum chloride and 7.0 g (0.033 mol) of 6-bromohexanoyl chloride in 50 mL of methylene chloride. The reaction mixture was kept at 0° for 18 hours. Water was added and the organic layer was separated and washed with sodium bicarbonate solution. The dried extract was concentrated under reduced pressure to an oil which was purified by HPLC using 5% ethyl acetate-hexane to give 8.1 g (82% yield) of 6-bromo-1-[3,4-dimethoxy-5-(1-methylethyl)phenyl]-1-hexanone as an oil. The nmr spectrum was consistent with the structure and the mass spectrum gave the molecular ion at m/z 356 (C17H25BrO3).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[NH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[C:4]([NH:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:5][C:6]2[C:11]([CH:2]=1)=[N:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: CCOC(=O)CCCN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNc1nc2cccnc2cc1[N+](=O)[O-]
Temperature: 5 °C

Procedure:
The preparation of 4-chloro-3-nitro[1,5]naphthyridine is described in Part A of Example 1. Ethyl 4-aminobutyrate hydrochloride (9.6 g, 57.3 mmol, 1.2 eq) was added to a suspension of 4-chloro-3-nitro[1,5]naphthyridine (10.0 g, 47.7 mmol, 1.0 eq) in dichloromethane (200 mL) and stirred at 5° C. Triethylamine (16.6 mL, 119.3 mmol, 2.5 eq) was added and the reaction mixture was stirred for 2 hours and allowed to warm to ambient temperature. The mixture was diluted with dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2×150 mL). The phases were separated and the combined aqueous layers were extracted with chloroform (100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.5 g of ethyl 4-[(3-nitro[1,5]naphthyridinyl)amino]butyrate as a yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[C:37]2=[O:52].CCOC(C)=O>CN(C)C=O>[O:51]=[C:45]1[CH:44]([N:38]2[C:37](=[O:52])[C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12]([C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:11][N:10]=4)=[O:14])[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)nc1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
A stirred mixture of 5-ethanesulfonyl-pyridine-2-carboxylic acid (0.34 g, 1.60 mmol) and CDI (0.27 g, 1.70 mmol) in N,N-dimethylformamide (15 mL) was heated to 40° C. under nitrogen. After 2 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (0.61 g, 1.60 mmol) was added and the mixture was heated at 40° C. for 2 h. The mixture was cooled to rt and EtOAc (75 mL) was added. The organic layer was washed with sat. aq. NaHCO3 (3×75 mL) then concentrated in vacuo. The crude residue was purified by column chromatography (EtOAc/hexanes, gradient, product eluted at 80-90% EtOAc). The product fractions were combined and concentrated to give 5-ethanesulfonyl-pyridine-2-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.25 g, 32% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.15 min (96.20%); mp: 265-267° C.; 1H NMR (DMSO-d6) δ 1.15 (t, J=7.4 Hz, 3H), 2.00-2.20 (m, 1H), 2.52-2.67 (m, 2H), 2.77-3.01 (m, 1H), 3.48 (q, J=7.4 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 5.14 (dd, J=5.4, 12.7 Hz, 1H), 7.73-8.04 (m, 3H), 8.29 (d, J=8.3 Hz, 1H), 8.49 (dd, J=2.3, 8.1 Hz, 1H), 9.10 (d, J=1.7 Hz, 1H), 9.86 (t, J=6.3 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 6.83, 21.99, 30.93, 42.58, 49.01, 49.34, 122.17, 122.68, 123.54, 129.87, 131.59, 133.63, 137.04, 138.13, 147.09, 147.60, 153.38, 163.02, 166.97, 167.12, 169.80, 172.72; LCMS: MH=485; Anal Calcd for C22H20N4O7S: C, 54.54; H, 4.16; N, 11.56. Found: C, 54.82; H, 3.92; N, 11.57.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][CH2:19][OH:20].[H-].[Na+].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CS(C)=O.C1C=CC=CC=1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][CH2:19][O:20][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1c2ccccc2N(c2ccccc2)CN1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: O=Cc1ccc(OCCN2CN(c3ccccc3)c3ccccc3C2=O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
1.2 g of 2-(4-oxo-1-phenyl-1,2,3,4-tetrahydroquinazolin-3-yl)ethanol was dissolved in 8 ml of dimethyl sulfoxide. 0.27 g of 60% sodium hydride (oil) was added under ice cooling and the mixture was stirred for one hour at 40° C. Then, 0.84 g of p-fluorobenzaldehyde in 8 ml of benzene was gradually added dropwise and the mixture was allowed to stand room temperature while stirring for one hour. The reaction mixture was processed in the same manner as in the Preparation Example 1 to obtain 0.84 g (yield 50.4%) of the title compound as colorless crystals.
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11](Cl)([F:13])[F:12]>O>[F:12][CH:11]([S:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[F:13]
Reactant: SCc1ccccc1
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)SCc1ccccc1
Yield: 75 %

Procedure:
One equivalent of 40% by weight of sodium hydroxide in water was mixed with one equivalent of benzyl mercaptan with R-22 (1.1 molar equivalents) at 60° C. for 1 h. The tests are carried out in a 500 ml Hastelloy reactor at an autogenous pressure at 60° C. The pressure is 3.5 bar. A chemical yield of 75%, by quantitative determination by 19F NMR, is obtained over two tests carried out under the same conditions.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:11]=1)[C:8](Cl)=[O:9]>O1CCCC1.[Cl-].[Na+].O>[Br:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:1])=[O:9])[CH:6]=[N:5][CH:4]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In an amount of 555 mg of 5-bromonicotinoyl chloride was dissolved in 5.5 ml of tetrahydrofuran, added with 768 μl of 28% aqueous ammonia under ice cooling, stirred for 40 minutes, then warmed to room temperature, and further stirred at room temperature for 20 minutes. The reaction system was added with 15% brine, and extracted with tetrahydrofuran, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure until about half amount of crystals were deposited, and added with ethyl acetate until the deposition of crystals was terminated, and the crystals were taken by filtration to obtain 374 mg of the title compound.
Reaction SMILES: CO.[NH3:3].[C:4]([NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16](Cl)(=[O:18])=[O:17])(=[O:6])[CH3:5]>CO.O1CCCC1>[F:15][C:13]1[CH:12]=[CH:11][C:10]([S:16](=[O:18])(=[O:17])[NH2:3])=[C:9]([CH:14]=1)[CH2:8][NH:7][C:4](=[O:6])[CH3:5]
Reactant: N
Reactant: CC(=O)NCc1cc(F)ccc1S(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)NCc1cc(F)ccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(Step 2) To a solution of 8N ammonia methanol solution (2 ml) in methanol (15 ml) was added dropwise a suspension of 2-[(acetylamino)methyl]-4-fluorobenzenesulfonyl chloride obtained in Step 1 (1.34 g) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture was allowed to warm to room temperature, and stirred for 1 hr. The reaction mixture was quenched with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give N-(5-fluoro-2-sulfamoylbenzyl)acetamide (1.34 g) as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([OH:22])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([O:22][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(O)c2CC1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(OCc3ccccn3)c2CC1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
Prepare a slurry of sodium hydride (60% in mineral oil, 168 mg, 4.2 mmol) in DMF (4 mL) and heat to 65° C. Add dropwise a solution of 3-tert-butoxycarbonyl-7-chloro-6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.84 mmol) in DMF (5 mL) and stir for 1 h. Add a solution of 2-(bromomethyl)-pyridine hydrobromide (256 mg, 1 mmol) in DMF (1 mL), stir at 65° C. for 0.5 h and cool to ambient temperature. Add water (1 mL) and concentrate the reaction mixture to an oily residue. Partition the residue between EtOAc/hexane (1:1) and water. Dry the organic layer over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1, 5:1 and 3:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(pyridin-2-ylmethoxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:25][CH2:24][CH2:23][C:10]2([CH:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:12]([CH3:21])[C:11]2=[O:22])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH:13]2[C:10]3([CH2:23][CH2:24][CH2:25][NH:8][CH2:9]3)[C:11](=[O:22])[N:12]2[CH3:21])=[CH:19][CH:18]=1
Reactant: CN1C(=O)C2(CCCN(C(=O)OC(C)(C)C)C2)C1c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)C2(CCCNC2)C1c1ccc(F)cc1

Procedure:
A solution comprising of rac-1-(4-Fluoro-phenyl)-2-methyl-3-oxo-2,6-diaza-spiro[3.5]nonane-6-carboxylic acid tert-butyl ester (830 mg, 2.38 mmol) and TFA (1 ml, 12.98 mmol) in DCM (15 ml) was stirred at RT overnight. The reaction mixture was concentrated in vacuo and the resulting crude product was dissolved with ethyl acetate and washed with a saturated solution of sodium bicarbonate. The organic layer was separated, dried (MgSO4) and concentrated in vacuo to yield a the title compound as a yellow oil;
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[ClH:15].Cl.[CH2:17]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:15].[ClH:15].[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[C:3]([CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH2:27][CH2:28]1)=[O:4]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: O=C(CN1CCNCC1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCN(CC(=O)c2ccc3ccccc3c2)CC1)c1ccccc1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
A mixture of 2-bromo-1-(naphthalen-2-yl)ethanone (0.95 g, 3.8 mmol), N-phenacyl piperazine dihydrochloride (0.89 g, 3.2 mmol) and K2CO3 (1.56 g, 11.2 mmol) in 30 ml of DMF was stirred at 50° C. for 10 h, and treated according to the general preparation 2 to give compound (IV-7), 0.88 g (60.69%), mp 236-237° C., M+ 373.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]1[CH:13]=O.O.NN.[OH-].[K+]>C(O)COCCOCCO>[CH3:1][N:2]1[C:3]([CH3:13])=[CH:4][CH:5]=[C:6]1[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cn1c(C=O)ccc1-c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCOCCO
Solvent: O
Product: Cc1ccc(-c2cccnc2)n1C
Temperature: 175 °C
Reaction time: 1.25 h

Procedure:
A mixture of 1-methyl-5-(3-pyridyl) pyrrole-2-carboxaldehyde (8.0 g, 43 mmoles), hydrazine hydrate (8.0 g, 160 mmoles) and potassium hydroxide (10.6 g of 85% pellets) in 80 ml triethyleneglycol is stirred at 125° L C for 75 min. during which time vigorous evolution of gas is observed. The temperature is then increased to 175° C and stirring continued until evolution of gas ceases. After cooling, the reaction mixture is extracted with 3 × 50 ml portions of diethyl ether. The combined ether layers are dried (anhydrous magnesium sulfate) and removed under vacuum. Fractional vacuum distillation of the residue provides the pure product.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14]>CO>[C:1]([NH:9][N:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: NNC(=O)c1cccnc1
Reactant: C/C=C/C=O
Solvent: CO
Product: C/C=C/C=NNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 50 ml of methanol was suspended 22 g of nicotinic acid hydrazide. To the suspension was added dropwise 13.2 ml of crotonaldehyde, followed by stirring for 30 minutes at room temperature. Methanol was distilled away under reduced pressure, and the residue washed with ether, filtered off, and dried. Thus there was obtained 27.5 g of crotonaldehyde nicotinoyl hydrazone (mp. 144°-145° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:14])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: O=C(Cl)Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 3-chlorophenylacetic acid (51 g) was added thionyl chloride (100 ml) and N,N-dimethylforraamide (50 μl). After stirring at room temperature for 18 hours, the thionyl chloride was evaporated at reduced pressure. The residue was dissolved in toluene (60 ml) and again evaporated at reduced pressure to give 3-chlorophenylacetylchloride.
Reaction SMILES: [C:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N12CCN(CC1)CC2.CN(C)C=O.[N:30]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1>O>[C:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]([C:35]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:36])[C:12](=[O:16])[NH:13]3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c2cnc(-c3ccccc3)nc2[nH]1
Reactant: O=C(Cl)N1CCCC1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CCCC1)n1c(=O)[nH]c2nc(-c3ccccc3)ncc21
Reaction time: 10 h

Procedure:
To a mixture of 2-phenyl-7,9-dihydro-8H-purine-8-one <prepared according to the similar method to those of Reference Example 19> (4.0 g), 1,4-diazabicyclo[2.2.2]octane (2.2 g) and N,N-dimethylformamide (50 ml) was added dropwise 1-pyrrolidinecarbonyl chloride (2.6 g) at room temperature and the mixture was stirred for 10 hours. To the reaction mixture was added water (100 ml), and the crystals precipitated were collected by filtration and was dried to give the title compound 4.8 g.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1)C.Cl>CN(C)C=O.O>[NH:15]1[C:16]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:13]([CH2:12][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14]1
Reactant: O=Cc1ccccc1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1c[nH]c2ccccc12)c1ccccc1
Reaction time: 0.5 h
Yield: 131.9 %

Procedure:
NaCN (1.4 g, 29 mmol) was provided in absolute dimethylformamide (10 ml) in argon. At a bath temperature of 35° C. benzaldehyde (3 ml, 29 mmol) dissolved in absolute dimethylformamide (10 ml) was added in drops within 1.5 h and stirred for a further 0.5 h at this temperature. Gramine (10.1 g, 58 mmol) dissolved in absolute dimethylformamide (30 ml) was added in drops to this reaction solution within 2 h at an inside temperature of 70° C. The mixture was stirred a further 1 h at this temperature. For work up the vessel contents were placed in water (150 ml). The aqueous phase was acidified with 2N HCl to separate non-converted gramine as, a water-soluble hydrochloride. The aqueous phase was then extracted with chloroform (3×50 ml). The combined extracts were washed with NaHCO3 solution (50 ml) and dried over Na2SO4. The volatile constituents were then completely removed in a vacuum. The residue (9 g) obtained after distilling off the solvent was purified by column chromatography [silica gel 60 (300 g); cyclohexane/ethyl acetate 6:1 (1500 ml)].
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19](O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25].C(N1C2=NC=C(C(N[C@H](C3C=CC=CC=3)CO)=O)C(NC3CCOCC3)=C2C=N1)C>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)O)cnc21
Reactant: CC(C)(N)CO
Agent: CCn1ncc2c(NC3CCOCC3)c(C(=O)N[C@@H](CO)c3ccccc3)cnc21
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NC(C)(C)CO)cnc21

Procedure:
Intermediate 49 was prepared from Intermediate 17 and 2-amino-2-methyl-1-propanol (commercially available from Aldrich) using an analogous method to that for Intermediate 42. LCMS showed MH+=362; TRET=2.28 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[NH:38]1[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:38]3[CH2:43][CH2:42][CH2:41][CH:40]([OH:44])[CH2:39]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: OC1CCCNC1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCCC(O)C3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and piperidin-3-ol according to conditions described in general procedure C. Mp: 93-95° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.24-1.26 (m, 2 H), 1.58-1.60 (m, 7 H), 1.75-1.85 (m, 1 H), 2.68-2.80 (m, 2 H), 3.27-3.36 (m, 6 H), 4.80 (d, J=4.0 Hz, 1 H), 6.14 (d, J=5.5 Hz, 1 H), 6.95 (d, J=12.8 Hz, 1 H), 7.14 (d, J=9.1 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.61 (m, 3 H), 7.82-7.84 (m, 1H), 7.97 (d, J=7.3 Hz, 1H), 8.22 (d, J=5.4 Hz, 1H), 10.44 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:12]N1C(=O)CCC1=O>CN(C)C=O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[N:5][OH:6])[Cl:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1ccc(F)cc1F
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccc(F)cc1F
Yield: 68.4 %

Procedure:
In a fashion similar to that for preparation 14, 2,4-difluorobenzaldehyde oxime (2.52 g, 16.1 mmol), N-chlorosuccinimide (2.21 g, 16.5 mmol), and dimethyl formamide (25 ml) gave 2,4-difluorobenzoyl chloride oxime (2.11 g, 68%) after chromatography (silica gel, hexanes/ether).
Reaction SMILES: [Na].[C:2](OCC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.Cl>O.C(O)C>[C:21]([CH:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)[CH2:2][C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)#[N:22]
Reactant: CCOC(=O)c1ccncc1
Reactant: N#CCc1ccc(F)cc1
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(Cc1ccncc1)c1ccc(F)cc1

Procedure:
250 ml of dry ethanol were added dropwise to metallic sodium (17.3 g/0.7 mol). Ethyl isonicotinate (75.8 g/0.5 mol) and 4-fluorophenylacetonitrile (67.6 g/0.5 mol) were then added dropwise, and the mixture was subsequently heated under reflux for 15 min. After cooling, 600 ml of distilled water were added to the mixture. When the mixture was acidified to pH 1 using concentrated hydrochloric acid (HCl), the desired compound 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethane precipitated as a yellow precipitate. The precipitate was filtered off, washed with distilled water and dried under reduced pressure over phosphorus pentoxide (P2O5). The yield was 85.0 g (62%).