Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([OH:21])=[O:20])[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:34]=[C:35]1[NH:40][N:39]=[C:38]([C:41]2[CH:48]=[CH:47][C:44]([CH2:45]O)=[CH:43][CH:42]=2)[CH2:37][CH2:36]1.C[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19]([O:21][CH2:45][C:44]2[CH:43]=[CH:42][C:41]([C:38]3[CH2:37][CH2:36][C:35](=[O:34])[NH:40][N:39]=3)=[CH:48][CH:47]=2)=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ccc(CO)cc2)=NN1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Agent: C[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1=C(C(=O)OCc2ccc(C3=NNC(=O)CC3)cc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
10 mmol of 4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxylic acid are suspended in 40 ml of absolute tetrahydrofuran and treated with 12.5 mmol of carbonyldiimidazole. The suspension is then stirred for 30 minutes at room temperature and for 30 minutes at reflux temperature. A solution of 11 mmol of 4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzyl alcohol and 10 mg of sodium methylate in 10 ml of tetrahydrofuran is then added, and the mixture is heated to reflux for 3.5 hours. It is then evaporated, and the residue is taken up in methylene chloride, washed successively with 1N hydrochloric acid, 1N sodium hydroxide solution and water, dried with magnesium sulphate and evaporated. The residue crystallizes from a little i-propanol.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:13]3[C:18]([N:19]=[C:20]4[C:25]=2[C:24](=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl-].[NH4+]>C1COCC1>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][CH2:10][NH:11][C:12]2[C:13]3[C:18]([N:19]=[C:20]4[C:25]=2[CH:24]([OH:26])[CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCCC(c3ccccc3)c3ccccc3)c21
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCCC(c3ccccc3)c3ccccc3)c21
Yield: 73.6 %

Procedure:
In 30 ml of dry THF was dissolved 3.00 g of 3,4dihydro-9-(4,4-diphenybutyl)aminoacridin-1-(2H)-one and the mechanically stirred solution was cooled in an ice bath under nitrogen atmosphere. To the solution under nitrogen was added 6.48 ml of 1M LiAlH4 in THF. Within 0.5 hour after addition the reaction was complete by TLC. The reaction was neutralized with 1 ml of saturated ammonium chloride solution and the inorganics were filtered off. The filtrate was evaporated to an oil and the oil was triturated with 30 ml of 10:1 ether/acetone to yield 2.22 g of solid, mp 147°-148° C. This sample was combined with a 1.0 g sample of an identical previous run and recrystallized from acetone to yield 2.87 g of powder, mp 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH:16]1[CH2:18][CH2:17]1)[CH2:13][CH2:14][OH:15])(=[O:11])=[O:10].[OH-].[Na+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([N:12]([CH2:13][CH2:14][O:15][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:16]1[CH2:18][CH2:17]1)(=[O:11])=[O:10]
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCO)C1CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
To a cold solution of 2-chloro-N-cyclopropyl-N-(2-hydroxyethyl)-6-methylbenzenesulfonamide (1 eq.) in dichloromethane (15 ml) was added tetrabutylammonium chloride (0.1 eq.) and 35% sodium hydroxide solution (15 ml) at 0° C. tert-Butyl 2-bromoacetate (1.2 eq.) was added dropwise to this cold reaction mixture maintaining the same temperature. After addition was complete, the reaction mixture was stirred at room temperature for 16 h (monitored by TLC). It was diluted with dichloromethane and the organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was purified by column chromatography (20% ethyl acetate in hexane). Yield: 70%
Reaction SMILES: [C:1]([O:4][C:5]1([OH:17])[CH:14]=[CH:13][C:8](/[CH:9]=[CH:10]/[CH:11]=[O:12])=[CH:7][CH:6]1[O:15][CH3:16])(=[O:3])[CH3:2]>C(Cl)Cl>[C:1]([O:4][C:5]1([OH:17])[CH:14]=[CH:13][C:8](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:6]1[O:15][CH3:16])(=[O:3])[CH3:2]
Reactant: COC1C=C(/C=C/C=O)C=CC1(O)OC(C)=O
Solvent: ClCCl
Product: COC1C=C(/C=C/CO)C=CC1(O)OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
4-Acetoxyconiferaldaldehyde was prepared in 94-96% yield by acetylation of coniferaldehyde with acetic anhydride/pyridine and then reduced with borane/tert-butylamine complex to give the corresponding alcohol, as follows. The 4-acetoxyconiferaldehyde was dissolved in methylene chloride to which borane/tert-butylamine complex (1.5 equiv) was added. The mixture was stirred at room temperature for 2 h, when TLC showed that the starting material had disappeared completely. The solvent was evaporated at 40° C. under reduced pressure. The residue was hydrolyzed with 0.5 M H2SO4 in ethanol/water (1:1) for 1.5 h. Most of the ethanol was removed by evaporation, and the product was extracted with ethyl acetate. The ethyl acetate solution was washed with saturated NH4Cl and dried over MgSO4. Evaporation of the ethyl acetate gave the product, 4-acetoxyconiferyl alcohol as a pale yellow oil (96% yield); 1H NMR (acetone-d6) δ 2.31 (3H, s, OAc), 3.83 (3H, s, OAc), 3.90 (1H, t, J) 5.5 Hz, γ-OH), 4.22 (2H, dt, J) 5.5, 1.7 Hz, γ), 6.38 (1H, dt, J) 15.9, 5.2 Hz, β), 6.58 (1H, dt, J=15.9, 1.7 Hz, α), 6.97 (2H, m, A5/6), 7.15 (s, 1H, A2); 13C NMR δ 20.5 (OAc), 56.2 (OMe), 63.1 (γ), 110.9 (A2), 119.5 (A6), 123.6 (A5), 129.3 (α), 131.4 (β), 137.2 (A1), 140.2 (A4), 152.3 (A3), 169.0 (OAc).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH2:24][OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.O=[Mn]=O>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[N:13]=[C:12]2[CH:24]=[O:25])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(CO)nn2C1CCCCO1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)c(C=O)nn2C1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 80.4 %

Procedure:
A mixture of (R/S) (5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)methanol (1 g, 2.76 mmol, 1.00 equiv) and MnO2 (2.4 g, 27.61 mmol, 10.01 equiv) in dichloromethane (10 mL) was stirred at room temperature for 5 h. The solid material was removed by filtration. The filtrate was concentrated under vacuum to give 0.8 g (80%) of 5-(tert-butyldimethylsilyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 10.0 (s, 1H), 7.44 (s, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.81 (d, J=1.2 Hz, 1H), 5.57-5.54 (m, 1H), 3.85-3.70 (m, 2H), 3.42-3.20 (m, 2H), 1.70-1.35 (m, 4H), 0.80 (s, 9H), 0.10 (s, 6H) ppm. LCMS (method A, ESI): RT=1.88 min, m/z=360.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C@@H:17]3[CH2:19][C@H:18]3[NH:20]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[ClH:28].C(OCC)(=O)C>>[ClH:28].[NH2:20][C@@H:18]1[CH2:19][C@H:17]1[C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3NC(=O)OC(C)(C)C)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl [trans-2-(4-{[(3-methylphenyl)carbonyl]amino}phenyl)cyclopropyl]carbamate (141 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL). The mixture was stirred at room temperature for 2 hr and the solvent was evaporated under reduced pressure to give the title compound (51.6 mg).
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=[O:15])[CH2:9][CH2:8]2.OP(O)(O)=O.BrC1CCC2C(=CC=CC=2)C1=O.[C:33](C1CCC2C(=CC=CC=2)C1=O)#[N:34]>C1(C)C=CC=CC=1.O.CC#N>[C:33]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10](=[O:15])[CH2:9][CH2:8]2)#[N:34]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: N#CC1CCc2ccccc2C1=O
Agent: O=C1c2ccccc2CCC1Br
Agent: O=P(O)(O)O
Agent: [C-]#N
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1ccc2c(c1)CCC(=O)C2
Temperature: 80 °C
Reaction time: 64 h

Procedure:
A flame dried 1 liter round bottom flask with argon inlet, digital thermometer, and magnetic stir bar, was charged with a 68% NaCN/alumina mixture (21.22 g, 433 mmol)(NaCN and alumina were ground together in a morter and pestle according to the procedure of Dalton et al. J. Org. Chem., 44, (24) 4443(1979)), and tetrakis(triphenylphospine) palladium(0) (10.0 g, 8.65 mmol). The flask was purged three times via vacuum with argon and a solution of 6-bromo-2-tetralone (19.46 g, 86.5 mmol) in degassed toluene (400 mL) was added. The mixture was heated to 80° C. and stirred for 64 hrs at that temperature. Analysis by HPLC indicated 89% conversion (HPLC conditions, column: Waters C18 Bondapak, eluent: 80:20 (0.1% H3PO4 in H2O: CH3CN), flow: 2 mL/min, wavelength: 220 nm, Rt: bromotetralone=9.65 min, cyanotetralone=3.46 min). The reaction was cooled and the mixture filtered through silfca gel (elution with 60% ethyl acetate in hexane.) Concentration of the appropriate fractions gave 9.4 g (68%) of 6-cyano-2-tetralone (98.7% by HPLC).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[N:10][C:9]([C:15]([OH:17])=O)=[CH:8]2)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:51]1[CH:55]=[CH:54][N:53]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[NH:66][C:65]([NH2:68])=[N:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]>O.CN(C=O)C>[NH:53]1[CH:54]=[CH:55][N:51]=[C:52]1[NH:56][C:57]([C:59]1[C:67]2[N:66]=[C:65]([NH:68][C:15]([C:9]3[N:10]=[CH:11][C:12]4[C:7]([CH:8]=3)=[CH:6][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:14][CH:13]=4)=[O:17])[NH:64][C:63]=2[CH:62]=[CH:61][CH:60]=1)=[O:58]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: CC(C)Oc1ccc2cnc(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc2cnc(C(=O)Nc3nc4c(C(=O)Nc5ncc[nH]5)cccc4[nH]3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
0.05 g (0.23 mmol) of 6-isopropoxy-isoquinoline-3-carboxylic acid and 0.19 g (0.50 mmol) of HBTU were combined in a flask charged with DMF (3 mL) and DIEA (1 mL). This reaction mixture was then treated with 0.1 g (0.4 mmol) 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (Intermediate B,) and stirred at 80° C. for 1 h. The reaction mixture was diluted with water, and the resultant solid precipitate was filtered and washed with saturated NaHCO3. The solid was dissolved with MeOH, evaporated onto silica gel and isolated by flash column chromatography (500 mL DCM/20 mL NH3/MeOH) to yield 10 mg (9%) of 6-isopropoxy-isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide. LCMS: 456 (M+1)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH:11]=[CH2:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:12][CH:11]=[CH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: O=C(O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
To a 250 mL round bottom flask equipped with a reflux condensor was added 25 g of benzoic acid, 51 g of allyl alcohol, and 2.5 g of sulfuric acid. The mixture was heated at reflux for 17 hr, allowed to cool to room temperature, and 50 g of toluene was added. Using a 1 L separatory funnel, the mixture was washed once with 100 mL of water, once with 50 mL of 5 wt % Na2CO3 in water, and once more with 100 mL of water. The organic phase was dried over Na2SO4, filtered and distilled to yield allyl benzoate. The allyl benzoate distilled at a boiling point of 135° C. at about 60 mm Hg.
Reaction SMILES: BrCCO.OCC[O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[O:13]>>[OH:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH:18]([CH3:20])[CH3:19])[CH:12]=[O:13]
Reactant: CC(C)Oc1ccc(C=O)cc1OCCO
Agent: OCCBr
Product: CC(C)Oc1ccc(C=O)cc1O
Yield: 75 %

Procedure:
from 3-hydroxy-4-isopropoxybenzaldehyde (prepared in 75% yield by monoalkylation of 3,4-dihydroxybenzaldehyde with isopropyl bromide and K2CO3 in DMF) and 2-bromoethanol there was obtained 3-(2-hydroxy-ethoxy)-4-isopropoxy-benzaldehyde, which was subsequently converted by reaction with 4-aminobenzonitrile and toluene-4-sulphonyl methylisocyanide into methyl (RS)-(4-cyano-phenylamino)-[3-(2-hydroxy-ethoxy)-4-isopropoxy-phenyl]-acetate and then into methyl (RS)-(4-carbamimidoyl-phenylamino)-[3-(2-hydroxy-ethoxy)-4-isopropoxy-phenyl]-acetate hydrochloride (1:1);
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6]Cl)[CH3:4].[S:8]([O-])([O-])(=O)=[S:9].[Na+].[Na+].Cl.[OH-].[Na+]>O>[CH3:2][N:3]([CH3:4])[CH2:5][CH2:6][S:9][S:8][CH2:6][CH2:5][N:3]([CH3:4])[CH3:2]
Reactant: O=S([O-])([O-])=S
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)CCSSCCN(C)C
Yield: 113.8 %

Procedure:
In a 100 ml round-bottom flask, 8.5 g of N,N-dimethyl-2-chloroethylamine hydrochloride, 8.7 g of sodium thiosulfate and 50 ml of distilled water were charged and heated under reflux for 2 hours. 36% hydrochloric acid (5.1 g) was added, and the mixture was further heated under reflux for 1 hour. With cooling the mixture on an ice bath, 5.5 g of sodium hydroxide was slowly added to make the mixture alkaline, which was then subjected to extraction twice with 50 ml of ethyl acetate. After desiccating with anhydrous potassium carbonate, the solvent was removed by distillation and distilled under reduced pressure to give 7.0 g of bis(N,N-dimethyl-2-aminoethyl)disulfide, the precursor.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][C:3]([C:9]1[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15](=[O:27])[N:16]3[C:19]3[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:26])=[C:11]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[Cl:35])[N:10]=1)=[CH:2]2>C(OCC)(=O)C.O=[Pt]=O>[CH:5]12[NH:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][CH:3]([C:9]1[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15](=[O:27])[N:16]3[C:19]3[C:20]([Cl:26])=[CH:21][CH:22]=[CH:23][C:24]=3[Cl:25])=[C:11]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[Cl:35])[N:10]=1)[CH2:4]2
Reactant: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(C3=CC4CCC(C3)N4)cc2n1-c1c(Cl)cccc1Cl
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: O=c1ccc2c(-c3ccc(F)cc3Cl)nc(C3CC4CCC(C3)N4)cc2n1-c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
39 mg of PtO2 (Adam's catalyst) was added to the mixture of 7-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-5-(2chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (77 mg) in 2 mL ethyl acetate. The resulting reaction mixture was evacuated and purged with argon. Then hydrogen was bubbled through and the reaction mixture was stirred under hydrogen for 8 h. The reaction mixture was filtered, concentrated under reduced pressure, and purified by preparative thin-layer chromatography, eluting with 95:5 CH2Cl2-2M NH3 in methanol to yield 7-(8-azabicyclo[3.2.1]oct-3-yl)-5-(2-chloro-4-fluorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one. Mass spectrum (ESI) 528.6 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:9]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C@H:3]1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])[N:9]=1
Reactant: CC1CCCNC1c1nc(-c2cccc(C#N)c2)no1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H]1CCCN(Cc2ccccn2)[C@H]1c1nc(-c2cccc(C#N)c2)no1
Yield: 51.5 %

Procedure:
The reaction was carried out as described in Example 43 from 3-[5-(3-methyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (29 mg, 0.108 mmol) with pyridine-2-carbaldehyde (13.9 mg, 0.13 mmol) and sodium triacetoxyborohydride (34.3 mg, 0.162 mmol) in dichloroethane (2 mL) to give cis-3-[5-(3-Methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (20 mg, 51.5%); 1H NMR (CDCl3), δ(ppm): 8.55 (d,1H), 8.45 (s, 1H), 8.38 (d, 1H), 7.80 (d,1H), 7.65 (m, 2H), 7.41 (d, 1H), 7.18(m, 1H), 4.40 (d, 1H), 3.76 (d, 1H), 3.53 (d, 1H), 3.03 (m,1H), 2.68 (m,1H), 2.30 (m, 1H), 1.74(m, 4H), 0.82 (d, 3H); and trans-3-[5-(3-methyl-1-pyridin-2-ylmethyl-piperidin-2-yl)-[1,2,4]oxadiazol-3-yl]-benzonitrile (5 mg, 12.9%); 1H NMR (CDCl3), δ(ppm): 8.49+ (d,1H), 8.43 (s, 1H), 8.35 (d, 1H), 7.80 (d,1H), 7.65 (m, 2H), 7.55 (d, 1H), 7.14(m, 1H), 3.59 (m, 3H), 3.03 (m, 1H), 2.25 (m, 2H), 1.92 (m,1H), 1.73 (m, 2H), 1.27(m, 1H), 0.87 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[C:7]([CH:8]2[CH2:11][C:10](=[O:12])[C:9]2(Cl)Cl)=[CH:6][N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:7]([CH:8]2[CH2:9][C:10](=[O:12])[CH2:11]2)=[CH:6][N:5]([C:15]2[C:16]([Cl:26])=[CH:17][C:18]([C:22]([F:23])([F:24])[F:25])=[CH:19][C:20]=2[Cl:21])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC(=O)C1
Temperature: 2 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
3-Cyano-4-(2,2-dichloro-3-oxocyclobutyl)-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (3.00 g, 6.77 mmol, Example 1) was dissolved in dry toluene (60 ml) in a dry, nitrogen-flushed flask and cooled to 2° C. 2,2'-Azobisisobutyronitrile (134 mg, 0.81 mmol) was added in one portion followed by dropwise addition of tributyltin hydride (4.73 ml, 17.60 mmol) in dry toluene (10 ml). The mixture was allowed to slowly warm to room temperature and was stirred for 18 hr. The toluene was removed in vacuo and the residue dissolved in acetonitrile (50 ml). This solution was washed with hexane (4×50 ml) to remove organotin residues. The combined hexane fractions were extracted with acetonitrile (50 ml). The acetonitrile phases were combined and the solvent removed in vacuo to give a yellow oil. This was purified by silica chromatography (eluting with 10% diethyl ether/hexane) to yield 2.07 g of the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[CH:3][CH:2]=1.[N:15]1[CH:16]=[C:17](B(O)O)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[N:15]1[CH:16]=[C:17]([C:10]2[CH:9]=[C:8]([NH:7][C:4]3[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=3)[CH:13]=[CH:12][CH:11]=2)[N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=12
Reactant: Brc1cccc(Nc2ccccc2)c1
Reactant: OB(O)c1cnc2ccccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: c1ccc(Nc2cccc(-c3cnc4ccccn34)c2)cc1
Temperature: 80 °C
Yield: 2.3 %

Procedure:
To 3-Bromodiphenylamine (0.16 g, 0.6 mmol) was added imidazo[1,2-a]pyridine-3-ylboronic acid (0.1 g, 0.6 mmol), tetrakis(triphenylphosphine)palladium (0) (35 mg, 5 mol %), EtOH (0.5 ml), toluene (0.5 ml) and 2M Na2CO3 (0.9 ml). The reaction mixture was heated at 80° C. for 6 h, before being allowed to cool and then partitioned between EtOAc and H2O. The organic fraction was separated, washed with brine, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by silica column chromatography (20%-100% EtOAc/hexane) to afford the product (4 mg). MS: [M+H]+ 286.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]=1[CH2:25][N:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](=[O:29])[CH3:28])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:24])[N:11]([CH3:23])[CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]=1[CH2:25][N:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(Cc1cc(C(=O)N(C)Cc2cc3ccccc3n2C)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(Cc1cc(C(=O)N(C)Cc2cc3ccccc3n2C)ccc1N)c1ccccc1
Reaction time: 4 h
Yield: 68.1 %

Procedure:
To a solution of N-[(2-nitro-5-{N-methyl-N-[(1-methylindol-2-yl)methyl]carbamoyl}phenyl)methyl]-N-phenylacetamide (0.82 g, 1.7 mmole) in CH3OH (50 mL) in a Parr hydrogenation flask was added 10% Pd/C (0.50 g). The contents were shaken on a Parr shaker under H2 (50 psi) for 4 hours. The reaction suspension was filtered through celite and concentrated under vacuum. Purification on silica (CHCl3/CH3OH, 95:5) afforded the title compound (0.51 g, 68%) as an off-white solid: MS (ES) m/e 441 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10].C(N(CC)CC)C.[Br:18][CH2:19][C:20](Br)=[O:21]>ClCCl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[CH3:10])[C:20](=[O:21])[CH2:19][Br:18]
Reactant: O=C(Br)CBr
Reactant: CNc1cccc(C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(N(C)C(=O)CBr)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Methyl-2,3-dimethylaniline S14 (4.6 g) and triethylamine (5.0 ml) were dissolved in dichloromethane (50 ml). 2-Bromoacetyl bromide (3.0 ml) in dichloromethane (30 ml) was added to the resulting solution under ice cooling and the solution was stirred for 2 hours at room temperature. The reaction mixture was washed successively with 1N HCl, water and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 8.4 g of the title compound as an oily substance.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=1N)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]>CN(C)C=O.C(OCC)C>[CH2:8]([O:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[C:19]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)[CH:18]=[CH:17][CH:16]=2)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(C)cc3N)cccc2[nH]1
Agent: CC(C)(C)ON=O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3ccc(C)cc3)cccc2[nH]1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
Tert-butyl nitrite (0.176 ml, 1.48 mmol) is dissolved in 5 ml of dimethylformamide and heated to 65° C. A solution of 139 (460 mg, 1.48 mmol) in 5 ml of dimethylformamide is added dropwise and the mixture is stirred of additional 10 minutes. The brown solution is cooled to room temperature, diluted with diethyl ether and washed with 2N HCl and brine. The organic layers are dried over sodium sulphate and evaporated. The crude product (420 mg of a brown oil) is further purified by flash-chromatography (hexane/ethyl acetate 9:1).