Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:34])[CH:5]=[C:6]([Cl:33])[C:7]=1[CH2:8][C@@H:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:10][C:11]([C@H:13]1[NH:17][CH2:16][CH2:15][S:14]1)=[O:12].Cl[S:36]([C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=1)[C:42]([OH:44])=[O:43])(=[O:38])=[O:37]>N1C=CC=CC=1.Cl>[C:42]([C:41]1[CH:40]=[C:39]([S:36]([N:17]2[CH2:16][CH2:15][S:14][C@H:13]2[C:11]([O:10][C@H:9]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]3[CH2:32][CH2:31]3)[CH:19]=2)[CH2:8][C:7]2[C:6]([Cl:33])=[CH:5][N+:4]([O-:34])=[CH:3][C:2]=2[Cl:1])=[O:12])(=[O:38])=[O:37])[CH:47]=[CH:46][CH:45]=1)([OH:44])=[O:43]
Reactant: O=C(O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)[C@H]1NCCS1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)c1cccc(S(=O)(=O)N2CCS[C@H]2C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((S)-thiazolidine-2-carbonyloxy)ethyl)pyridine 1-oxide (209 mg, 0.390 mmol) was dissolved in pyridine (4 ml). 3-(chlorosulfonyl)benzoic acid (172 mg, 0.781 mmol) was added slowly at 0° C., and the reaction was stirred at RT for 8 hours. The reaction mixture was diluted with HCl 1N, filtered, and the precipitate was dissolved in DCM. The organic phase was washed with HCl 1N (2×) and brine, dried over Na2SO4 and concentrated under vacuum to give 4-((S)-2-((S)-3-(3-carboxyphenylsulfonyl)thiazolidine-2-carbonyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (100 mg, 0.139 mmol, 35.6% yield), that was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][Cl:34]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:31][CH2:32][CH2:33][Cl:34])[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]=1[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(Cl)c(Cc2ccccc2)c(=O)n1Cc1ccccc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(Cc2ccccc2)c(Cl)n(CCCCl)c(=O)n1Cc1ccccc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of 24.51 g (75 mmol) of 6-chloro-3,5-dibenzylpyrimidine-2,4(1H,3H)-dione and 16.58 g (120 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 14.8 ml (150 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 2 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 22.68 g (74.9%, yellow oily substance) of the desired product.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[CH2:19](Br)[CH:20]=[CH2:21]>O>[CH2:21]([S:11]([C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][CH:9]=1)(=[O:13])=[O:12])[CH:20]=[CH2:19]
Reactant: C=CCBr
Reactant: CC(=O)Nc1ccc(S(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: C=CCS(=O)(=O)c1ccc(NC(C)=O)cc1
Reaction time: 4 h

Procedure:
50 Parts of p-acetylaminophenylsulfinic acid and 25 parts of sodium hydrogen carbonate are suspended in 300 parts of water. While stirring intensely 36 parts of allyl bromide is dripped in within 3 hours at 50° to 60° C. Stirring is continued for another 4 hours at 60° C. 45 parts of p-allylsulfonylacetanilide is obtained with a melting point of 116° to 118° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][N:36]([CH3:40])[C:37](Cl)=[O:38].CCN(CC)CC.[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:35][N:36]([CH3:40])[C:37](=[O:38])[NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Reaction time: 48 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (75 mg, 0.17 mmol) and dimethylcarbamic chloride (30 μL, 0.33 mmol) in CH2Cl2 (2 mL) was added Et3N (46 μL, 0.33 mmol) and catalytic amount of DMAP. The reaction mixture was stirred at RT for 2 h after which 2 equivalents each of dimethylcarbamic chloride and Et3N were added. After 2 h of stirring another 2 equivalents of both the chloride and Et3N were added. Upon the addition of the third addition of the chloride and the Et3N the temperature was raised to 45° C. The reaction mixture was stirred for 48 h. Concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(3,3-dimethylureido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolated. (62 mg, 70%)
Reaction SMILES: Cl[C:2]1[O:3][CH:4]=[C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[CH2:22][O:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:8])[N:6]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:31]1([NH:30][C:2]2[O:3][CH:4]=[C:5]([C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]3[CH2:22][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:8])[N:6]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Cl)n2)C(COc2cccnc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2coc(Nc3ccccc3)n2)C(COc2cccnc2)C1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A solution of tert-butyl 4-(2-chlorooxazole-4-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (117 mg, 0.277 mmol), aniline (51 mg, 0.554 mmol) and potassium carbonate (76 mg, 0.554 mmol) in THF (2 mL) was heated to 70° C. overnight. Upon cooling to rt, the reaction mixture was filtered and concentrated under reduced pressure. The material was purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient), yielding 64.8 mg (40%) of the title compound as the TFA salt. LC-MS: RT=6.72 min, [M+H]+=480.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:15][CH:16]([CH3:25])[C:17]([C:19]1[CH:20]=[N:21][CH:22]=[N:23][CH:24]=1)=[O:18].[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:17]([OH:18])([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]([CH3:25])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)c1cncnc1
Reactant: C#Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)(C#Cc1ccc(Cl)cc1)c1cncnc1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
1(4'-Chlorophenyl)ethyne (1.43g:0.01 mole) was dissolved in tetrahydrofuran (10 ml) under nitrogen and cooled to -35° C. Butyllithium was added (6.5 ml of 1.6M solution:0.0104 mole) causing the colour to change. The mixture was stirred for 1/2 hour during which time it thickened and the colour changed to pink (from purple). Addition of a solution of chlorotanium triisopropoxide (10.6 ml or a 1 molar solution:0.0106 mole) caused the colour to change to yellow and the mixture was stirred for 20 minutes. The mixture was cooled to -60° C. and a solution of 2-methyl 1(pyrimidin-5-yl)propan-1-one in tetrahydrofuran (10 ml) was added and the reaction mixture allowed to warm up to room temperature within the cold bath. A solution of ammonium chloride in water (20%) was added and the mixture filtered. The aqueous was extracted with ethyl acetate (×3), washed (with water then brine), dried and the solvent removed in vacuo. The product was passed through silica (in ether) and then titurated with pentane and ether (0.467g: off white solid).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:27][C:22]1[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:21]=1
Reactant: Cc1cc(C)nc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(C)cc(C)n3)CC2)cc1
Yield: 45.3 %

Procedure:
A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (1.7 g) obtained in Example 88(2), 2-chloro-4,6-dimethylpyrimidine (1.0 g) and potassium carbonate (3.0 g) in acetonitrile (50 ml) was refluxed under heating for 7 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil. The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) and crystallized from diisopropyl ether and recrystallized from ethyl acetate-hexane to give the title compound (1.1 g) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][C:13]([CH2:17]O)([CH2:15]O)[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([B:9]2[O:10][CH2:14][C:13]([CH3:17])([CH3:15])[CH2:12][O:11]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC1(C)COB(c2ccc(F)c(Cl)c2)OC1
Yield: 80 %

Procedure:
The title compound (80%, crystalsl) was prepared from 3-chloro-4-fluorophenylboronic acid and neopentylglycol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[N:14]([CH3:18])[N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[N:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[C:20]=[O:21].FC1C=CC(C)=CC=1N=C=O>>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:20]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)=[O:21])=[CH:7][CH:6]=2)[N:14]([CH3:18])[N:15]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Cn1nc(N)c2c(-c3ccc(N)cc3)cncc21
Agent: Cc1ccc(F)c(N=C=O)c1
Product: Cn1nc(N)c2c(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)cncc21

Procedure:
The title compound was prepared using the procedure described in Example 1E using the product from Example 6A and 1-isocyanato-3-trifluoromethyl-benzene instead of the product from Example 1D and 1-fluoro-2-isocyanato-4-methyl-benzene. MS (ESI(+)) m/e 427 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 3.92 (s, 3H) 4.66 (s, 2H) 7.33 (d, J=7.49 Hz, 1H) 7.48 (d, J=8.73 Hz, 2H) 7.53 (t, J=7.95 Hz, 1H) 7.61 (d, J=9.05 Hz, 1H) 7.65 (d, J=8.73 Hz, 2H) 7.95 (s, 1H) 8.04 (s, 1H) 8.87 (s, 1H) 8.98 (s, 1H) 9.10 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 4-methyl-3-nitroanisole (16.53 mL; 119.64 mmol; 1 eq), in CCl4 (500 mL) is added N-bromosuccinimide (21.29 g; 119.64 mmol; 1 eq) and azoisobutyronitrile (392.9 mg; 2.39 mmol; 0.02 eq). The mixture is heated at 85° C. for 20 h. The solution is cooled down to room temperature and the precipitate of succinimide is removed by filtration. The filtrate is concentrated to afford a yellow oil. The oil crystallizes after one night at −25° C. It is redissolved in EtOAc (15 mL) and petroleum ether is added. After 2 h at −25° C., the compound recrystallizes. After filtration and washing with petroleum ether, the solid is dried under vacuum to afford 17.4 g (59%) of the title compound as a liquid. 1H NMR (DMSO-d6) δ 7.68 (d, J=8 Hz, 1H), 7.56 (d, J=3 Hz, 1H), 7.33 (dd, J=8.0, 3.0 Hz, 1H), 4.89 (s, 2H), 3.87 (s, 3H). HPLC (max plot) 99%; Rt 4.09 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[CH3:19][C:20]1[C:21]([CH2:26][OH:27])=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:27][CH2:26][C:21]2[C:20]([CH3:19])=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Reactant: Cc1cccnc1CO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2nc(N)nc(OCc3ncccc3C)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 3-methyl-2-pyridinemethanol and DBU in DME. ES-MS m/e (%): 322 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:13][OH:14])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(F)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: ON=C1CCc2cc(F)ccc21
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 5-fluoroindanone (10 g), hydroxylamine hydrochloride (9 g), potassium carbonate (23 g) and water (3.5 ml) in 96% ethanol (40 ml) was heated to reflux, cooled to ca 45 and additional hydroxylamine hydrochloride (4.5 g) and potassium carbonate (11.5 g) were added and refluxed for an additional 30 min. At this time the mixture was poured into cold water (300 ml) and stirred in an ice bath for one hour; 5-fluoroindanone oxime (9.8 g) was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:12]1[C:13]([S:18][CH3:19])=[N:14][CH:15]=[N:16][CH:17]=1.[F:21][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]1[C:12]1[C:13]([S:18][CH2:19][F:21])=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: CSc1ncncc1C1c2ccccc2CCC1(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC1(C)CCc2ccccc2C1c1cncnc1SCF
Yield: 33.1 %

Procedure:
To a solution of 2.0 g (7.0 mmol) of 5-(2,2-dimethyltetralin-1-yl)-4-methylthiopyrimidine in 100 mL of dry acetonitrile was added with stirring 3.0 g (9.1 mmol) of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate). The mixture was allowed to react for 16 hours and then most of the acetonitrile was removed by evaporation under reduced pressure. The residue was partitioned between ether and water and the organic phase was recovered, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual oil was purified by column chromatography on silica gel to obtain 700 mg of the title compound as a tan solid melting at 126°-128° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Product: c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of phenylmagnesium bromide, and 200 ml. of diethyl ester is stirred for four hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1 N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated; unchanged 2-tetralone is removed by distillation. The residue, containing 2-phenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5 percent palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for six hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-phenylnaphthalene.
Reaction SMILES: [N:1]1[NH:2][C:3](=O)[CH:4]=[C:5]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6]2.O(Cl)[Cl:17].[P+3]>>[Cl:17][C:3]1[N:2]=[N:1][C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: ClOCl
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CC2
Agent: [P+3]
Product: Clc1cc2c(nn1)-c1ccccc1CC2

Procedure:
5,6-Dihydrobenzo[h]cinnolin-3(2H)-one (4.5 g) was heated at 100° C. with phosphorus (III) Oxychloride (80 mL) for 6.5 h. The solvent was removed under vacuum and the residue was treated with ice water. The resulting solid was filtered off, washed well with water and air dried to give 3-chloro-5,6-dihydrobenzo[h]cinnoline; 1H NMR (DMSO-d6, 300 MHz) 8.32 (m, 1H), 7.36 (s, 1H), 7.32 (m, 2H), 7.19 (d, 1H), 2.91 (s, 4H) ppm; MS (ES) 217/219 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([NH2:12])[CH:6]=1.C([O:16][C:17](=O)[CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:19](=O)[CH3:20])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:13])=[C:6]2[C:7]=1[NH:12][C:19]([CH3:20])=[C:18]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1)[C:17]2=[O:16]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1)C(C)=O
Reactant: COC(=O)Cc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1[nH]c2c(Cl)ccc(CC(=O)O)c2c(=O)c1Cc1ccc(Cl)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenyl)acetic acid methyl ester (1.0 g), 2-(4-chlorobenzyl)-3-oxobutyric acid ethyl ester (1.3 g), polyphosphoric acid (5 mL) and dioxane (10 mL) was heated at 130° C. for 1.5 hours. The mixture was diluted with water and the pH of this solution adjusted to 3 by the addition of sodium acetate. The resulting precipitate was collected by filtration and purified by column chromatography on silica gel, eluting with a mixture of dichloromethane, ethyl acetate and methanol (1:0:0 to 10:1:0 to 1:1:0 to 20:0:1 and 0:0:1 by volume) to afford title compound, 0.60 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CC([O-])(C)C.[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[N:7]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1NCCc2nc(Cl)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCc3nc(Cl)ccc3C2=O)cc1
Temperature: 60 °C

Procedure:
2-chloro-7,8-dihydro-6H-[1,6]naphthyridin-5-one, (1.6 g, 8.77 mmol) was dissolved in DMF (20 mL) and treated with KOtBu (1.3 g, 10.7 mmol), followed by p-methoxybenzyl chloride (1.6 mL, 11.8 mmol). The mixture was heated to 60° C. for 2 h, concentrated and purified by silica chromatography (0 to 100% EtOAc in Hexanes) to give the compound. LC-MS (M+H)=303.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:26][CH:27]([CH3:29])[CH3:28]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Reactant: CC(C)CI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine and 1-iodo-2-methylpropane.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>C1COCC1>[F:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C:7]2[S:8][C:9]([CH:21]=[O:22])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Oc2cccs2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Oc2ccc(F)cc2)s1
Reaction time: 0.33 h
Yield: 85.5 %

Procedure:
To a solution of 2-(4-fluorophenoxy)thiophene (3.66 g, 18.9 mmol) in THF (90 mL) at -78° C., was added butyllithium (7.5 ml of a 2.5M solution in hexanes, 18.9 mmol) dropwise. Upon completion of addition, the mixture was stirred for 20 min. N,N-Dimethylformamide (1.52 g, 20.8 mmol) was then added and the reaction was stirred for 40 min at -78° C. It was then quenched with saturated aqueous NH4Cl (100 mL) and extracted with ethyl acetate (3×100 mL). The organics were combined, dried over MgSO4 and concentrated. The resulting residue was chromatographed (silica gel; 3:1 hexanes, ether) to afford 3.59 g (86%) of 5-(4-fluorophenoxy)-2-thiophenecarboxaldehyde as a slightly orange solid.
Reaction SMILES: [CH:1]1([C:4](=[O:7])[CH:5]=[CH2:6])[CH2:3][CH2:2]1.C(O[CH2:13][N:14]([CH2:23][Si](C)(C)C)[C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])CCC.FC(F)(F)C(O)=O>ClC(Cl)C>[CH:1]1([C:4]([CH:5]2[CH2:6][CH2:13][N:14]([C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:23]2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCCCOCN(C[Si](C)(C)C)[C@H](C)c1ccccc1
Reactant: C=CC(=O)C1CC1
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccccc1)N1CCC(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.6 %

Procedure:
The product (8.01 g) containing 1-cyclopropyl-2-propen-1-one described in Reference Example 1 and N-(n-butoxymethyl)-N-[1-(R)-phenylethyl]trimethylsilylmethylamine (23.2 g, 79.9 mmol) were dissolved in dry dichloroethane (350 ml), and trifluoroacetic acid (500 μl) was added dropwise thereto. After 12 hours of stirring at room temperature, the reaction solution was washed with saturated sodium bicarbonate aqueous solution (100 ml) and then with saturated brine (100 ml). After drying over anhydrous magnesium sulfate and subsequent filtration, the filtrate was concentrated under a reduced pressure. The thus obtained residue was subjected to a flash silica gel chromatography, and 9.08 g (49.6%) of the title compound was obtained from an eluate of n-hexane:ethyl acetate=2:1 as a colorless oil component. In this case, this product was obtained as a diastereomer mixture of 1:1.
Reaction SMILES: [CH:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C=O.[CH2:12](NCCCC)CCC.C(O)(=O)CCCCCCCCC>>[CH2:12]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:1]=[O:9]
Reactant: CCCCNCCCC
Reactant: CCCCCCCC=O
Agent: C=O
Agent: CCCCCCCCCC(=O)O
Product: C=C(C=O)CCCCCC
Temperature: 95 °C
Yield: 1636.4 %

Procedure:
A 2 L four-necked flask equipped with a stirrer, a thermometer and a reflux condenser was charged with 762 g (6.0 mol) of n-octanal, 520 g (6.4 mol) of a 37% by mass formaldehyde aqueous solution, 15 g (0.33 mol) of dibutyl amine and 10 g (0.06 mol) of decanoic acid, and the contents in the flask were stirred while heating at 95° C. After the elapse of 45 min, it was confirmed that no n-octanal was present in the raw mixture, and then the mixture was cooled and separated into two layers. The thus separated organic layer was subjected to distillation treatment, thereby obtaining 790 g (5.4 mol) of a-methylene octanal (purity as measured by gas chromatography: 95%) (yield based on theoretical amount: 90%).