Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])([O-:8])=[O:7].[N:16]([O-])=O.[Na+]>O>[S:1](=[O:3])(=[O:2])([OH:5])[O-:4].[N+:6]([C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[N+:11]#[N:16])([O-:8])=[O:7]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: O=N[O-]
Reactant: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1[N+](=O)[O-]
Product: O=S(=O)([O-])O
Temperature: 75 °C

Procedure:
To a 500 mL three-necked flask fitted with a mechanical stirrer are added 65 g of concentrated sulfuric acid and 41.4 g of 2-nitroaniline. After heating to 75° C., 164 g of water is added at which time the temperature is reduced to 0° C. Sodium nitrite (54 g, 40 wt %) is added over two hours while maintaining the solution at 0-5° C. The diazonium salt solution (292 g) is then filtered and stored at −15° C. until use.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]3[N:40]=[CH:41][N:42]=[C:16]23)[CH2:11][CH2:10]1)(=O)=O.[NH:43]1[CH:47]=[CH:46][N:45]=[CH:44]1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[N:43]1([CH2:6][CH2:7][O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([C:29]5[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=5)=[CH:27][CH:28]=4)=[C:18]([CH2:37][CH2:38][CH3:39])[N:17]4[N:40]=[CH:41][N:42]=[C:16]34)[CH2:11][CH2:10]2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: c1c[nH]cn1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCOS(C)(=O)=O)CC2)c2ncnn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCn3ccnc3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]ethyl methanesulfonate (0.3 g), imidazole (0.042 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (0.024 g), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:28]#[N:29])=[N:4][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=2)=[CH:6][C:7]=1[NH:8][CH3:9].[N:30]([O-])=O.[Na+]>O.O1CCOCC1.Cl>[CH3:9][N:8]1[C:7]2[CH:6]=[C:5]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)=[C:12]([C:24]([F:27])([F:26])[F:25])[CH:11]=3)[N:4]=[C:3]([C:28]#[N:29])[C:2]=2[N:1]=[N:30]1
Reactant: CNc1cc(-c2ccc(OCc3cccnc3)c(C(F)(F)F)c2)nc(C#N)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCc4cccnc4)c(C(F)(F)F)c3)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
To a suspension of 3-amino-4-(methylamino)-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)picolinonitrile (1.33 g) in water (15 ml) and 1,4-dioxane (15 ml), 2N hydrochloric acid (2.5 ml) was added at 0° C. and sodium nitrite (0.332 g) in water (3 ml) was added then stirred at 0° C. for 10 min then at 20° C. for 70 h. The reaction mixture was filtered, washed with water, dried in vacuum oven to give 1.14 g brown solid. Purified by Biotage SNAP cartridge KP-Sil column (100 g, heptane:ethyl acetate=1:0, 2:1, 1:1, 1:2 to 0:1 then ethyl acetate:methanol=25:1, 20:1 to 15:1 then dichloromethane:methanol=15:1, 10:1), fractions were passed through Strata SCX column (5 g) to give 560.7 mg light brown solid as 1-methyl-6-(4-(pyridin-3-ylmethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (41%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:27]2
Reactant: Clc1cccc2c1CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3cccc(Cl)c3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 24 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 154 mg of 4-chloroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 93 mg of the target compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:7][CH:8]=2)[NH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH:16]1[CH2:15][CH2:14][CH:13]([O:12][C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][CH2:11][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)NC(=O)CC3)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCc2ccc(OC3CCNCC3)cc2N1
Temperature: 25 °C

Procedure:
tert-Butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yloxy)piperidine-1-carboxylate (0.2 g, 0.58 mmol) was dissolved in dichloromethane (20 mL) and treated with trifluoroacetic acid (1.3 mL). The resulting mixture was stirred at ambient temperature until all the starting material had been consumed, at which time the volatiles were removed by evaporation to dryness under reduced pressure. The residue was neutralized by addition of excess saturated NaHCO3 aq. and the mixture evaporated to dryness under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[F:11][C:12]1[CH:13]=[C:14]([NH2:20])[C:15]([NH2:19])=[CH:16][C:17]=1[F:18]>>[Cl:1][C:2]1[C:3]([C:4]2[NH:19][C:15]3[CH:16]=[C:17]([F:18])[C:12]([F:11])=[CH:13][C:14]=3[N:20]=2)=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Nc1cc(F)c(F)cc1N
Reactant: O=C(O)c1cccnc1Cl
Product: Fc1cc2nc(-c3cccnc3Cl)[nH]c2cc1F
Temperature: 180 °C
Yield: 48 %

Procedure:
To a suspension of 2-chloro-nicotinic acid (4.10 g, 0.026 mol; CAS Reg. No. 2942-59-8) in polyphosphoric acid (50 g) was added 4,5-difluoro-benzene-1,2-diamine (3.86 g, 0.026 mol; CAS Reg. No. 76179-40-3) and the resulting mixture was heated to 180° C. for 1 h. The reaction mixture was then cooled and neutralized with ice cold 10% aqueous sodium carbonate solution, and then extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude residue thus obtained was purified by column chromatography over silica gel (25% ethyl acetate/n-hexane) to give the title compound as a brown solid (48%). MS (Turbo Spray): m/z=266.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([CH:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:13][CH:12]=3)=[O:15])[CH2:21][CH2:20]2)=[O:30])=[CH:28][CH:27]=1
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(Br)nc2)CC1
Reactant: O=C1CCCN1
Product: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCC3=O)nc2)CC1
Yield: 50.7 %

Procedure:
Using pyrrolidin-2-one (102 mg) and (6-bromopyridin-3-yl)[4-(4-chlorobenzoyl)piperidin-1-yl]methanone (408 mg) described in Preparation Example 190 and by the reaction and treatment in the same manner as in Example 1, the title compound (209 mg) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].CS[C:17](=[NH:19])[NH2:18]>C(O)C>[S:10]([OH:14])([OH:13])(=[O:12])=[O:11].[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([CH2:7][CH2:8][NH:9][C:17]([NH2:19])=[NH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: CCO
Product: N=C(N)NCCc1ccccc1
Yield: 127 %

Procedure:
2-Phenylethylamine (8.49 g, 70.1 mmol) and S-methylisothiourea sulfate (9.43 g, 33.9 mmol) was dissolved in 100 ml distilled water. Air was passed over the reaction mixture and through 50% NaOH (500 ml) and then through 5% cuprous sulfate (250 ml). The reaction mixture was heated at reflux for 5 hours. Evaporation of the solvent yielded a white powder. The product was isolated by crystallisation from 96% ethanol, washed with cold acetone and diethyl ether and dried in a desecrator. After three crystallizations, the product contained only minor amounts of starting material. The reaction yielded 61.5% (9.14 g) 2-phenylethylguanidine hemisulfate.
Reaction SMILES: [C:1]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Na].[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12]>C1(C)C=CC=CC=1.C1C=CC=CC=1>[C:10]([N:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1=[O:8])(=[O:14])[C:11]([CH3:13])=[CH2:12]
Reactant: O=C1CCCCCN1
Reactant: C=C(C)C(=O)Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: C=C(C)C(=O)N1CCCCCC1=O

Procedure:
74 g of ε-caprolactam in 700 ml dry toluene is heated with 9.5 g of sodium at 90°-95° C. When all of the sodium metal has reacted, 43 ml of methacryloyl chloride in 50 ml dry benzene is added dropwise into the voluminous caprolactam salts at 4°-6° C. The mixture is then poured into a separatory funnel, washed with 200 ml water, 200 ml of sodium dicarbonate solution, and again with 20 ml water. The organic compounds are extracted with ether from the water phase, and the ether solution and benzene solution are dried over CaCl2 and the solvent evaporated under reduced pressure. The product, N-methacryloylcaprolactam, comes off at 90° C./2 mm hg. The yield is 32.3 g (42.8% based on sodium).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH2:36]([NH:38][CH2:39][CH2:40][CH3:41])[CH3:37].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[N:38]([CH2:36][CH3:37])[CH2:39][CH2:40][CH3:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CCCNCC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(CC)C(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (80 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (72 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 15 min. Next, N-ethylpropylamine (44 μl) was added to the reaction solution, and the mixture was stirred at room temperature for additional 30 min. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol. The solvent was removed by distillation. The resultant crystal was washed with hexane to give 40 mg (yield 37%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:10][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:15]=1[C:16]#[N:17]
Reactant: CC(O)c1cccc(F)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 1-(3-fluorophenyl)ethanol (0.7 ml; 5.6 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (224 mg; 5.6 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, and stirred for 45 minutes. In another vessel, a solution of 2,6-difluorobenzonitrile (780 mg, 5.6 mmol) in dimethylformamide was chilled to 0° C., and activiated anion was added over 20 minutes. Mixture was then stirred 2 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford g of solid (yield) of 2-fluoro-6-[1-(3-fluorophenyl)-ethoxy]-benzonitrile.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].CSC.[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[C:23](OS(C(F)(F)F)(=O)=O)=[C:22]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[C:21]1=[O:45])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:13]([N:20]1[C:29]2[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=2)[C:23]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:22]([C:39]2[O:43][N:42]=[C:41]([CH3:44])[CH:40]=2)[C:21]1=[O:45])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cl[Mg]C1CCCCC1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cc(-c2c(C3CCCCC3)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A solution of cyclohexylmagnesium chloride (250 ul, 0.50 mmol, 2M in THF) was added to a suspension of cupper (I) bromide-dimethylsulfide (51 mg, 0.25 mmol) in 2 ml of THF at −78° C. under N2. The mixture was warmed to rt until a dark color homogenous solution was observed (ca. 15 min), then re-cooled to −78° C. A solution of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (80 mg, 0.16 mmol) in 2 ml of THF was added to the mixture. The resulting mixture was stirred at −78° C. for 2 h and warmed to rt. Treated with 2 ml of sat. NH4Cl followed by 20 ml H2O, the mixture was extracted with EtOAc (2×20 ml). The combined organic layers were washed with H2O (10 ml), brine (10 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (20-30% EtOAc/hexanes) gave 61 mg (88%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ8.08 (br s, 1H), 7.40 (dd, 1H, J=9.2, 2.2 Hz), 7.20-7.34 (m, 6H), 6.42 (s, 1H), 5.53 (s, 2H), 2.98 (br s, 1H), 2.41 (s, 3H), 1.67-1.93 (m, 7H), 1.22-1.40 (m, 3H). Mass spectrum (ESI, m/z): Calcd. for C26H25ClN2O2, 433.2 (M+H), found 433.1.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:10]4[C:15]([C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1)=[CH:14][CH:13]=[CH:12][N:11]=4.[H][H]>[Pd].C(O)C>[OH:1][C:2]1[CH:26]=[CH:25][C:24]2[C:8]3[N:9]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:10]4[NH:11][CH2:12][CH2:13][CH2:14][C:15]=4[C:16](=[O:17])[C:7]=3[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: [H][H]
Reactant: O=c1c2c(n(-c3ccccc3)c3ncccc13)-c1ccc(O)cc1CC2
Agent: [Pd]
Solvent: CCO
Product: O=c1c2c(n(-c3ccccc3)c3c1CCc1cc(O)ccc1-3)NCCC2

Procedure:
Charge a Paar bottle with 5,6-dihydro-3-hydroxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, an equal weight of 5% Pd on carbon, and ethanol. Pressurize the bottle with hydrogen to about 50 psi, and shake the contents in a Paar apparatus at 25° C. Monitor the progress of hydrogenation by pressure changes or by thin-layer chromatography. When hydrogen uptake ceases, remove catalyst by filtration and ethanol by evaporation. Crystallize the residue to obtain 5,6,8,9,10,11-hexahydro-3-hydroxy-12-phenyl-naphtho[1,2-b][1,8]naphthyridin-7(12H)-one, m.p. >330° C. after crystallization from C2H5OH.
Reaction SMILES: O[CH2:2][CH:3]1[C:9]2=[N:10][C:11]([CH3:19])=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[Br:40][CH2:2][CH:3]1[C:9]2=[N:10][C:11]([CH3:19])=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:13]=[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1cc2c(nc1C)C(CO)CCCC2
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(nc1C)C(CBr)CCCC2
Yield: 107 %

Procedure:
In an atmosphere of argon, ethyl 9-hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (263.0 mg, 1.00 mmol) was dissolved in methylene chloride (5.0 ml), the solution was mixed with triphenylphosphine (393.0 mg, 1.50 mmol) at 0° C. and then with carbon tetrabromide (663.3 mg, 2.00 mmol) and the mixture was stirred at room temperature for 3 hours. The reaction solution was mixed with saturated sodium bicarbonate aqueous solution and water and extracted with ethyl acetate, and the resulting organic layer was washed with water and saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ether:hexane=1:5) to obtain the title compound (349.1 mg, quantitative) as white powder.
Reaction SMILES: [Br:1]Br.[CH:3]([O:5][CH2:6][CH3:7])=[CH2:4].C(NC(C)C)(C)C.[OH:15][C:16]1[C:17]([O:41][CH3:42])=[CH:18][CH:19]=[C:20]([CH:39]=[O:40])[C:21]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][Si:29]([CH:36]([CH3:38])[CH3:37])([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][CH2:4][CH:3]([O:5][CH2:6][CH3:7])[O:15][C:16]1[C:17]([O:41][CH3:42])=[CH:18][CH:19]=[C:20]([CH:39]=[O:40])[C:21]=1[C:22]1[CH:23]=[CH:24][C:25]([O:28][Si:29]([CH:30]([CH3:31])[CH3:32])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:34])[CH3:35])=[CH:26][CH:27]=1
Reactant: BrBr
Reactant: C=COCC
Reactant: COc1ccc(C=O)c(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c1O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(CBr)Oc1c(OC)ccc(C=O)c1-c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 98.6 %

Procedure:
To a solution of bromine (0.91 mL, 17.8 mmol) in CH2Cl2 (50 mL) at 0° C. was added drop-wise ethyl vinyl ether (2.13 mL, 22.2 mmol). The resulting colorless solution was stirred for 20 min at 0° C. and N,N-diisopropylamine (DIEA) (6.23 mL, 35.6 mmol) added drop-wise, followed by a CH2Cl2 (20 mL) solution of 10 (3.55 g, 8.9 mmol). The resulting solution was stirred for 16 h at 23° C., until all starting material was consumed, as determined by TLC. The mixture was poured onto saturated aqueous NaHCO3 (100 mL), and extracted with CH2Cl2 (3×70 mL). The combined extracts were washed with brine (80 mL), dried (Na2SO4), and concentrated in vacuo to yield orange oil. The crude oil was purified via flash column chromatography (SiO2, 10% EtOAc/hexanes) to give 12 (4.84 g, 99% yield) as a thick orange oil. Rf 0.52 (3:1 hexanes/EtOAc). IR (thin film) 2966, 2944, 2892, 2867, 1684 cm−1. 1H NMR (300 MHz, CDCl3) δ 9.64 (1H, s), 7.85 (1H, d, J=8 Hz), 7.25-7.18 (2H, m), 7.03 (1H, d, J=8 Hz), 6.96 (2H, d, J=8 Hz), 5.06-5.02 (1H, m), 3.98 (3H, s), 3.65-3.55 (1H, m), 3.42-3.34 (1H, m), 3.12-3.01 (2H, m), 1.35-1.20 (3H, m), 1.13 (18H, d, J=7 Hz), 1.05 (3H, t, J=7 Hz). 13C NMR (75 MHz, CDCl3) δ 191.1, 156.9, 156.1, 141.5, 140.5, 132.4, 128.4, 125.1, 119.4, 113.6, 111.0, 103.5, 64.5, 55.9, 31.7, 17.8, 14.9, 12.5. HRMS calcd. for C27H40O5SiBr (MH+) 551.1828. Found 551.1821.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]([N:7]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]=1)[CH3:3]>C1(C)C=CC=CC=1>[C:25]1([CH2:24][N:7]2[CH:6]=[CH:5][C:4]([CH2:2][CH3:3])=[CH:9][CH:8]2[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:12]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:10]
Reactant: CCOC(=O)C1CC2C(CC)=CC1N(Cc1ccccc1)C2Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC
Product: CCC1=CC(Cc2ccccc2)N(Cc2ccccc2)C=C1
Yield: 451.8 %

Procedure:
Following a procedure similar to that described in Example 1(c), 132 g (44%) of ethyl 8-ethyl-2,3-di(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate hydrochloride, m.p. 197°-200° C., was obtained from 1,2-dihydro-N,2-di(phenylmethyl)-4-ethylpyridine of Example 3(b), toluene (1400 mL) and ethyl acrylate (154 mL, 1.4 mol).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](=[O:20])([O:15][C:16]([CH3:19])(C)C)OC(C)(C)C.[CH2:21]1COC[CH2:22]1>>[CH2:16]([O:15][C:9]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])=[O:20])[CH2:19][CH2:21][CH3:22]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccccc1F
Product: CCCCOC(=O)Nc1ccccc1F

Procedure:
A solution of 2-fluoroaniline (30.0 g, 0.27 mol) and di-t-butyl carbonate (66.5 g, 0.30 mol) in 100 ml of THF was heated at reflux for 4 hours. The solvent was removed by evaporation at reduced pressure, and the residue was partitioned between 1M aqueous citric acid and ethyl acetate. The organic phase was washed with saturated aqueous NaCl. The solvent was removed to afford the desired product, which was used without further purification. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[C:24]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:32][CH2:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)c1

Procedure:
A mixture comprising {1-[(1S,4R)-4-(2,6-dichloro purin-9-yl)-cyclopent-2-enyl]-1H-pyrazol-4-yl}-methanol (0.675 g, 1.92 mmol), diphenylethylamine (0.398 g, 2.02 mmol) and DIPEA (0.298 g, 2.31 mmol) in dry THF (20 mL) is stirred at 35 C for 3 days. The solvent is removed in vacuo and the resulting crude residue is partitioned between DCM and 0.1 M HCl. The organic portion is separated, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]([CH2:23][CH3:24])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>COCCOC.O.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>[C:1]1([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)[CH:6]=[CH:5][C:4]([C:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]([CH2:23][CH3:24])[N:15]=2)=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(B(O)O)cc1
Reactant: CCn1nc(Br)c2ncccc21
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCn1nc(-c2ccc(-c3nn(CC)c4cccnc34)cc2)c2ncccc21
Yield: 7.3 %

Procedure:
A mixture of 1,4-phenylenediboronic acid (37.0 mg), 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (101 mg), Pd(PPh3)4 (25.8 mg) and Cs2CO3 (0.280 g) in DME/water (3/1, 4 mL) was exposed to microwave irradiation (120° C., 40 min), treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). Crystallization from AcOEt/hexane gave the title compound (6.00 mg).