Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N:2]1[CH:3]=[CH:4][N:5]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=12.[CH3:13][OH:14]>CCOCC>[ClH:1].[CH3:13][O:14][C:11]([C:8]1[CH:9]=[CH:10][N:5]2[CH:4]=[CH:3][N:2]=[C:6]2[CH:7]=1)=[NH:12]
Reactant: N#Cc1ccn2ccnc2c1
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: COC(=N)c1ccn2ccnc2c1
Yield: 80 %

Procedure:
Hydrogen chloride gas was bubbled through a mixture of imidazo[1,2-a]pyridine-7-carbonitrile (1.0 g, 7.0 mmol), methanol (10 ml) and ether (25 ml) at room temperature for 3 minutes. The resultant mixture was stirred for 3 hours. The solid material was isolated by filtration and was washed with diethyl ether to furnish a 80% pure tan solid (1.7 g). MS:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:4]=[N:3]1.[H-].[Na+].Cl[C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:19]=1.O>C1COCC1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][C:18]([O:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][C:5]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cn1nnc(-c2ccccn2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
A solution of (3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-yl)-methanol (158 mg, 0.83 mmol) in THF (2.4 mL) was added dropwise at 0° C. to a suspension of NaH (60% in oil, 40 mg, 0.91 mmol) in THF (1.2 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (157 mg, 0.91 mmol) in THF (2.4 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 18 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (209 mg, 77%) as a white solid. MS: m/e=326.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl:28][CH2:29][C:30](OC)=[O:31]>CO.C[O-].[Na+]>[Cl:28][CH2:29][C:30]([NH:27][CH2:26][CH2:25][CH2:24][O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCN
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCNC(=O)CCl
Yield: 94 %

Procedure:
A four-necks-flask equipped with a stirrer, a temperature gage, a dehydrating pipe and a dropping funnel was charged with 383.69 g of 3-docosyloxypropylamine obtained in the same manner as in Example 24, 1000 g of methanol and 9.6 g of a methanol solution of 28% sodium methylate as a catalyst. 113.9 g of methyl chloroacetate was added to the mixture in one hour while the mixture was kept at 20 to 30° C. and the resulting mixture was reacted for 24 hours. After the reaction was completed, the precipitated crystal was filtered. The crystal was washed with 1000 g of methanol and then dried to obtain 432.6 g of 2-chloro-N-(3-docosyloxypropyl)-acetamide as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:27][C@H:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][C:12]=3[F:26])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 38 %

Procedure:
A solution of 3-((R)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (240 mg, 0.47 mmol, 1.00 equiv), cyclopropanecarbaldehyde (98.7 mg, 1.41 mmol, 3.00 equiv) and piperidine (42 mg, 0.47 mmol, 1.00 equiv) in ethanol (15 mL) was stirred for 3 h at 65° C. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm. This resulted in 100 mg (36%) of the title compound as a white solid. MS (ESI, pos. ion) m/z: 560 (M+1) H-NMR (400 MHz, CD3OD, ppm): 8.36 (s, 1H), 7.68-7.65 (t, J=7.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.14-7.11 (t, 1H), 7.03-7.00 (d, J=9.2 Hz, 2H), 6.58 (d, J=10.8 Hz, 1H), 4.92-4.87 (m, 1H) 3.65-3.60 (m, 1H), 3.50-3.46 (m, 1H), 2.14 (m, 1H), 1.99-1.81 (m, 4H), 1.24-1.23 (m, 2H), 0.93-0.77 (m, 2H).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([N:3]2[C:4]3=[N:5][CH:6]=[CH:7][CH:8]=[C:9]3[O:1][C:2]2=[O:10])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=c1[nH]c2ncccc2o1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1oc2cccnc2n1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19.3 %

Procedure:
A solution of oxazolo[4,5-b]pyridin-2(3H)-one (200 mg) in DMF (3.5 mL) was treated with a 60% dispersion of sodium hydride in mineral oil (62 mg) and the resulting mixture stirred at ambient temperature for 5 min. The mixture was treated with 1-fluoro-4-nitrobenzene (248 mg) then stirred at 100° C. for 17 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (100 ml), washed with water (2×50 ml), 5% aqueous lithium chloride (50 mL) then brine (50 mL), dried over sodium sulfate, and filtered and the filtrate was concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, heptane to 1:1 ethyl acetate/heptane) to afford 3-(4-nitrophenyl) [1,3]oxazolo[4,5-b]pyridin-2(3H)-one (73 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:17])=C([CH:9]=[C:10]([Br:16])[C:11]=1[S:12][CH2:13][CH:14]=[CH2:15])C#N)[CH:2]=[CH2:3].[OH-].[Na+].Cl.C[CH2:22][O:23][C:24]([CH3:26])=[O:25]>CCO.O>[Br:16][C:10]1[C:11]([S:12][CH:13]=[CH:14][CH3:15])=[C:4]([CH:1]=[CH:2][CH3:3])[C:5]([Cl:17])=[C:26]([CH:9]=1)[C:24]([O:23][CH3:22])=[O:25]
Reactant: CCOC(C)=O
Reactant: C=CCSc1c(Br)cc(C#N)c(Cl)c1CC=C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=CSc1c(Br)cc(C(=O)OC)c(Cl)c1C=CC
Temperature: 100 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-allyl-4-(allylthio)-5-bromo-2-chlorobenzonitrile 94 (1.1 g, 3.35 mmol) in a mixture of EtOH (90 mL) and H2O (10 mL) was added NaOH (545 mg, 13.4 mmol). The reaction mixture was warmed up to 100° C., and stirred overnight. After reaction complete, the resulting solution was cooled down to room temperature. 1N HCl solution was used for acidify reaction solution, and normal work-up with EtOAc was proceeded. Removal of volatile solvent was preceded by drying with MgSO4. Without further purification, crude acid was used for next step. The crude acid was dissolved in MeOH (50 mL), treated with SOCl2 (1 mL) provisionally. The reaction mixture was refluxed overnight and resulting solution was cooled down to room temperature and evaporated in vacuo. The residue was purified by silica gel chromatography to afford the desired product (710 mg, 63% overall yield) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[C:10]([CH3:18])=[C:11]([CH2:15][CH2:16]O)[C:12](=[O:14])[O:13][C:8]=2[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=1)[CH3:2].C(Cl)(Cl)[Cl:23].C(O)C>>[Cl:23][CH2:16][CH2:15][C:11]1[C:12](=[O:14])[O:13][C:8]2[CH:7]=[C:6]([O:19][CH2:20][CH3:21])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:9]=2[C:10]=1[CH3:18]
Reactant: ClC(Cl)Cl
Reactant: CCOc1cc(OCC)c2c(C)c(CCO)c(=O)oc2c1
Solvent: CCO
Product: CCOc1cc(OCC)c2c(C)c(CCCl)c(=O)oc2c1
Yield: 83 %

Procedure:
Process E; starting material: 5,7-diethoxy-3-(2-hydroxyethyl)-4-methyl-2H-1-benzopyran-2-one (Example 50); yield 83%; m.p. 123°-126° C. (from chloroform/ethanol).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[CH3:18][N:19](C=O)C.N.C1(C)C=CC=CC=1>O>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COCCc1ccc(-c2ccc(I)cc2)cc1
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: COCCc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 149 °C
Reaction time: 6 h

Procedure:
Into a 200 ml three-neck flask were added 4'-(β-methyloxyethyl)-4-iodobiphenyl obtained in Step C (20 g, 0.59 mol), cuprous cyanide (6.2 g, 0.688 mol) and DMF (67 ml), and the mixture was reacted together under reflux with stirring at 149° C. for 6 hours. After completion of the reaction, the reaction liquid was cooled down to room temperature and 29% aqueous ammonia (20 ml) was added, followed by agitation. Toluene (50 ml) and water (100 ml) were then added and the reaction liquid was subjected to suction-filtration. The toluene layer of the filtrate was washed with 6 N-hydrochloric acid and then with sodium hydroxide aqueous solution and further with water till the layer became neutral. The resulting toluene layer was dried with anhydrous sodium sulfate (10 g), and passed through an active alumina layer, followed by distilling off toluene, recrystallizing the residual crystals from methanol (30 ml), filtering and drying to obtain objective 4'-(β-methyloxyethyl)-4-cyanobiphenyl (3 g) having a melting point (C-I point) of 50.7° C. When this product was mixed with 4'-octyloxy-4-cyanobiphenyl and the mixture was subjected to measurement for N→I point, its N→I point through extrapolation was -5° C. (With the above product alone, measurement of N→I point was impossible.) The values of the elemental analysis of the product accorded well with the calculated values thereof as follows:
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:7][CH:5]1[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=[C:2]([NH:1][C:14](=[O:16])[CH3:15])[CH2:6]1
Reactant: CC1CC(N)=NN1c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC1=NN(c2ccccc2)C(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.0 g. of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 5), 5.0 ml. of acetic anhydride and 100 mg. of 4-dimethylaminopyridine is allowed to stand at room temperature for 3 hours. The mixture is filtered to give a white solid. The solid is dissolved in dichloromethane and is columnized and recrystallized as for Example 14 (B) to give 0.90 g. of the desired product as colorless plates, m.p. 144.5-146.5° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]#[C:13][Si](C)(C)C)[CH:9]=[CH:8][C:7]=1[CH3:18])=[O:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:18])=[C:6]([NH:5][C:3](=[O:4])[C:2]([F:19])([F:1])[F:20])[CH:11]=1)#[CH:13]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C)c(NC(=O)C(F)(F)F)c1
Yield: 78.3 %

Procedure:
To a solution of 2,2,2-trifluoro-N-{2-methyl-5-[(trimethylsilyl)ethynyl]phenyl}-acetamide (10.9 g, 36 mmol) in THF (350 mL) cooled to 0° C. was added a 1M solution of tetrabutylammonium fluoride in THF (40 mmol, 40 mL). The reaction was diluted with water and extracted two times with EtOAc. The combined organic extractions were washed with water, dried over MgSO4 and concentrated onto silica gel. The crude material was purified by column chromatography to give the desired product (6.4 g, 78%). 1H NMR (400 MHz, d6-DMSO) δ 11.00 (s, 1H), 7.36-7.30 (m, 3H), 4.19 (s, 1H), 2.17 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)#[N:2].[OH-:24].[Na+]>S(=O)(=O)(O)O>[C:1]([C:3]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)(=[O:24])[NH2:2]
Reactant: [OH-]
Reactant: N#CC(CCc1ccccn1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: NC(=O)C(CCc1ccccn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 2-(3-cyano-3,3-diphenylpropyl)pyridine (5.0 g, 16.8 mmol) (prepared as described in U.S. Pat. No. 2,649,455) in 90% sulphuric acid (10 ml) was heated at 95° C. for 3.5 hours, allowed to cool to room temperature, poured onto ice and basified with 5M aqueous sodium hydroxide solution. The resulting precipitate was collected, washed with water, dried and recrystallised from 2-propanol to give the title compound (4.5 g, 85%) as colourless crystals, m.p. 145°-146° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])(O)[CH:17]=[CH2:18])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4].C(O)=[O:24].O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([O:5][C@H:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]([CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][CH2:18][OH:24])=[C:8]([CH3:21])[C:7]1=[O:22])=[O:4]
Reactant: C=CC(C)(O)C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C
Reactant: O=CO
Solvent: O
Solvent: ClCCl
Product: CC(C=CC1=C(C)C(=O)[C@@H](OC(=O)CCl)CC1(C)C)=CCO
Reaction time: 0.75 h

Procedure:
47.8 g of 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-1-yl]-3-methyl-penta-1,4-dien-3-ol are dissolved in 720 ml of methylene chloride. After the addition of 200 ml of formic acid, the solution is stirred at room temperture for 45 minutes, then introduced into water and extracted with diethyl ether. The ether extract is evaporated. The residue is taken up in 500 ml of methanol, treated with 100 g of potassium carbonate 250 ml of water, stirred for 1 hour, then introduced into water and extracted with ethyl acetate. The 5-[4(S)-(chloroacetoxy)-3-oxo-2,6,6-trimethyl-cyclohex-1-en-yl]-3-methyl-penta-2,4-dien-1-ol isolated from the extract is processed further as follows:
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH3:16])([S:7]([CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13])(=[O:9])=[O:8])[CH3:6])C.[Li+].[OH-]>C1COCC1.O>[CH3:16][C:5]([S:7]([CH2:10][CH2:11][C:12]([F:14])([F:15])[F:13])(=[O:9])=[O:8])([CH3:6])[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)S(=O)(=O)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.4 %

Procedure:
2-Methyl-2-(3,3,3-trifluoro-propane-1-sulfonyl)-propionic acid ethyl ester (1.3 g, 4.63 mmol) is dissolved in THF/water (14 mL, 4:1 ratio) and LiOH (0.2 g, 9.27 mmol, 2 eq.) is added. The mixture is stirred for 18 h at room temperature, then concentrated under reduced pressure to remove the organic solvent. The aqueous residue is further diluted with water, washed with DCM and then acidified to pH ˜2 and extracted with DCM. The combined acidic organic extracts are concentrated to afford 0.97 g of title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.72 (3H, s), 2.64-2.81 (2H, m), 3.46-3.6 (2H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O>[Br:12][C:9]1[CH:10]=[CH:11][C:2]([NH:1][C:21](=[O:22])[CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C(O)Cc1ccccn1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1ccccn1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Into a 250-mL round-bottom flask was placed a solution of methyl 2-amino-5-bromobenzoate (5 g, 21.73 mmol, 1.00 equivalent), 2-(pyridin-2-yl)acetic acid hydrochloride (4.5 g, 25.92 mmol, 1.20 equivalent), HATU (10 g, 26.30 mmol, 1.20 equivalents), and DIEA (8.5 g, 65.77 mmol, 3.00 equivalents) in N,N-dimethylformamide (100 mL). After stirring overnight at 20° C., the reaction was quenched with 100 mL of water and extracted with 3×100 mL of dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with dichloromethane/methanol (1:50) to give the title compound as a red solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)CCBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Product: CC(C)CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2
Yield: 47.2 %

Procedure:
The title compound (0.030 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 1-bromo-3-methyl-butane (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C18H24ClN3, 317.17; found, m/z 318.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56-7.54 (m, 4H), 4.34 (s, 2H), 3.57-3.55 (br m, 2H), 3.44-3.42 (br m, 2H), 3.40-3.38 (br m, 2H), 3.29-3.27 (br m, 2H), 1.79-1.77 (br m, 1H), 1.02 (d, J=4.5 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:14](OCC)=[O:15].[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:14]=[O:15])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC=O
Reactant: COc1ccc(CC#N)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(C#N)C=O)cc1OC
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a mixture of [3,4-bis(methyloxy)phenyl]acetonitrile (2.0 g, 11 mmol) and ethyl formate (1.1 mL, 14 mmol) in ethanol (4 mL) was added a sodium ethoxide solution (21%, 8.4 mL, 23 mmol), and the resulting mixture was heated at reflux for 18 hours. After cooling to room temperature, it was poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 1. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with aqueous sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-[3,4-bis(methyloxy)phenyl]-3-oxopropanenitrile as a brown oil (2.0 g, 9.8 mmol, 89% yield). MS (EI) for C11H11NO3: 206 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]3[O:21][CH2:20]3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([OH:21])[CH2:20][NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(C(CCCN2CCN(CC3CO3)CC2)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CNCc1ccccc1)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 10.1 %

Procedure:
3.86 g (0.01 mol) of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(2,3-epoxypropyl)piperazine and 1 g (0.01 mol) of benzylamine were refluxed with heating together with 200 ml of DMF for 24 hours in the presence of a catalytic amount of an alkali such as potassium carbonate. DMF was distilled off under reduced pressure, and a residue was extracted with ethyl acetate. After washing with water and drying, the ethyl acetate was distilled off under reduced pressure to obtain 5 g of a crude subject compound of a viscous liquid. The obtained compound was refined by flush chromatography and fractional thin-layer chromatography with solvent mixtures of ethyl acetate--methanol and methylene chloride--methanol respectively to obtain 0.5 g of the subject compound in a viscous liquid state.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cnccn1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cnccn1

Procedure:
The title compound, MS: m/e=296.1 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloropyrazine.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:24])[N:11]([CH2:16][O:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=[N:13]3)=[CH:8][C:7]=2[O:25][CH3:26])[CH2:30][CH2:29]1
Reactant: CN1CCNCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCBr
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCN(C)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
A suspension of 7-(3-bromopropoxy)-6-methoxy-3-((pivaloyloxy)methyl) -3,4-dihydroquinazolin-4-one (36.7 g, 86 mmol) in 1-methylpiperazine (370 ml) was stirred at 100° C. for 90 minutes. After removal of the volatiles under vacuum, the residue was partitioned between methylene chloride and aqueous ammonium chloride. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 7-(3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (31.9 gr, 83%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[NH:5][C:6]2=[O:11].[CH2:13]([O:15][C:16](=[O:22])[CH:17](Cl)[O:18][CH2:19][CH3:20])[CH3:14]>>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH3:20])[N:5]1[C:4](=[O:12])[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[C:6]1=[O:11])[CH3:14]
Reactant: CCOC(=O)C(Cl)OCC
Reactant: O=C1NC(=O)c2c(F)cccc21
Product: CCOC(=O)C(OCC)N1C(=O)c2cccc(F)c2C1=O

Procedure:
According to general procedure H, 4-fluoro-1H-isoindole-1,3(2H)-dione (CAS51108-29-3) was reacted with 2-chloro-2-ethoxyacetic acid ethyl ester to give (RS)-ethoxy-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetic acid ethyl ester, MS 296.3 ([M+H]+).