Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:25][C:26]([CH2:29][CH3:30])=[N:27][N:28]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Reactant: CCc1nnc(CCl)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1nnc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a 50 mL round-bottom flask was added (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x3, 200 mg, 0.882 mmol) in DMSO (8 mL) followed by sodium tert-butoxide (102 mg, 1.059 mmol). The reaction mixture was stirred at room temperature for 10 minutes. 2-(Chloromethyl)-5-ethyl-1,3,4-oxadiazole (155 mg, 1.059 mmol) was then added to give an orange solution. After 1 hour, LC/MS indicated the reaction was complete. The reaction mixture was subsequently diluted with EtOAc and washed with aqueous saturated NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (12 g SiO2 column, EtOAc (20-80%)/hexane gradient) to give the title compound as a pale yellow solid (165 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 1.24 (t, J=7.58 Hz, 3H), 2.83 (d, J=7.33 Hz, 2H), 2.93-3.03 (m, 1H), 3.04-3.21 (m, 2H), 3.36-3.51 (m, 2H), 3.59-3.71 (m, 1H), 3.85-3.98 (m, 2H), 4.20-4.29 (m, 1H), 4.57-4.67 (m, 1H), 4.84-4.94 (m, 1H), 7.57 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C14H17ClN6O2, 337.78. found 337.2.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[Br:27][CH2:28][C:29](Br)=[O:30]>C1COCC1>[Br:27][CH2:28][C:29]([N:17]1[CH2:18][CH2:19][CH:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH2:16]1)=[O:30]
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Reactant: O=C(Br)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (prepared using general procedures E, F, 0.051 g, 0.17 mmol) and Et3N (0.05 mL, 0.34 mmol) in THF (1.7 mL) was added bromoacetylbromide (0.015 mL, 0.17 mmol). The reaction mixture was stirred at ambient temperature for about 12 h then concentrated in vacuo to give 2-bromo-1-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethanone that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH:40]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[NH2:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36]([NH:41][NH:40][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)NNC(=O)OC(C)(C)C)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of [(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]acetic acid (0.77 g), tert-butyl hydrazinecarboxylate (0.23 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.34 g), 1-hydroxybenzotriazole (0.24 g) and N,N-dimethylformaldehyde (8 mL) was stirred at room temperature for 12 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.69 g, 72%).
Reaction SMILES: [OH:1][CH:2]([CH2:28]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17].[BrH:30].O.C([O-])(O)=O.[Na+].[C:37]([OH:40])(=O)[CH3:38]>>[C:37]([O:1][CH:2]([CH2:28][Br:30])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])(=[O:40])[CH3:38]
Reactant: CC(=O)O
Reactant: Br
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCCCC(O)CO)c(=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(13,14-Dihydroxytetradecyl)-3,7-dimethylxanthine (0.80 g, 1.96 mmol) was stirred with HBr (1.94 mL of a 30% solution in acetic acid, 5.88 mmol) for 2 hours. The mixture was then added over 10 minutes to water (20 mL), ice (15 g) and NaHCO3 (3.5 g) and stirred for 30 minutes. The reaction mixture was extracted with dichloromethane (2×50 mL), the combined organic phases were dried using magnesium sulfate and the solvent was evaporated to obtain a residue of 1-(13-acetoxy-14-bromotetradecyl)-3,7-dimethylxanthine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([N:6]2[CH2:7][CH2:8][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: OCC1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
Into a 1-Neck round-bottom flask 4-(Hydroxymethyl)piperidine (6.53 g, 56.7 mmol), Potassium carbonate (7.84 g, 56.7 mmol), Acetonitrile (50 mL, 1000 mmol), and [A] 4-Fluoronitrobenzene (4.00 g, 28.3 mmol)were added. The reaction was heated at 60° C. overnight. The reaction content was poured into ice water and stirred for 30 minutes. The solid was filtered, washed with water and dried under vacuum to give [1-(4-Nitro-phenyl)-piperidin-4-yl]-methanol as an off-white solid (5.20 g, 78%). NMR 1H (DSMO-d6)-8.02 (d, 2H, J=9.40 Hz), 7.00 (d, 2H J=9.49 Hz), 4.50 (bs, 1H), 4.07 (bd, 1H, J=13.33 Hz), 3.27 (d, 1H, J=5.84 Hz), 2.94 (t, 2H), 1.80-1.95 (m, 3H), 1.02-1.13 (m, 2H)
Reaction SMILES: C(N[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)CCC>[Pd].CO>[CH:15]1([O:14][N:9]2[C:8]([CH3:22])([CH3:21])[CH:7]=[CH:6][CH2:11][C:10]2([CH3:13])[CH3:12])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Agent: [Pd]
Solvent: CO
Product: CC1(C)C=CCC(C)(C)N1OC1CCCCC1

Procedure:
Hydrogenation at this stage (MeOH, 5% Pd/C, 5 bar H2, 40° C.) leads to butyl-(1-cyclohexyloxy-2,2,6,6-tetramethyl-piperidin-4-yl)-amine, compound D.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[NH:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1.I[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:27][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[N:4][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH3:9])=[N:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(=O)[nH]3)CC2)cc1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3ncc(Br)c(OC4CCCC4)n3)CC2)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-Bromo-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-pyrimidin-4-one(100 mg, 0.22 mmol) in 2 ml DMF was added iodo-cyclopentane (85.7 mg, 0.22 mmol) and potassium carbonate (152.0 mg, 1.1 mmol). This reaction was heated to 90° C. for 18 hours. After cooling down to room temperature, the K2CO3 was filtrated. Purification was accomplished by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 5-bromo-4-cyclopentyloxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-pyrimidine. (Yield 11.5 mg, 9.9%). 1H NMR (400 MHz, CDCl3): δ 1.30 (d, J=6.82 Hz, 3H), 1.64-1.51 (m, 2H), 1.82-1.67 (m, 4H), 1.96-1.82 (m, 2H), 2.65-2.52 (m, 4H), 3.00-2.85 (m, 4H), 3.67 (q, J=6.82 Hz, 1H), 3.78 (s, 3H), 5.41 (m, 1H), 6.90 (d, J=9.09, 2H), 7.59 (d, J=9.09, 2H), 8.39 (s, 1H). MS m/z calc. 525.2 found (ESI); 526.2 (M+1)+. Retention time 2.91 minutes.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[H-].[Na+].[Cl:18][C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CN(C=O)C>[ClH:18].[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH2:32][CH2:33][O:34][CH3:35])[N:22]=[CH:21][N:20]=[C:19]2[CH:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([S:3]([NH:2][CH3:1])(=[O:5])=[O:4])[CH:7]=2)[NH:11][C:10]1=[O:15]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1ccc2c(c1)C(c1ncnc3cc(OCCOC)c(OC)cc13)C(=O)N2
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of 5-methylaminosulphonyloxindole (252 mg, 1.1 mmol), (prepared as described for the starting material in Example 69), in DMF (2.5 ml) was added dropwise to a suspension of sodium hydride (45 mg, 1.1 mmol, prewashed with hexane) in DMF (1.5 ml). The mixture was stirred for 30 minutes at ambient temperature and 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (100 mg, 0.37 mmol), (prepared as described for the starting material in Example 2), was added as a solid. The mixture was then stirred for 45 minutes at 60° C. and was then partitioned between ether and water. The aqueous layer was separated and was adjusted to pH7-8 with 1M hydrochloric acid. The precipitate was collected by filtration, washed with water and ether, and dried under vacuum. The solid was suspended in methylene chloride/methanol (1/1) and 2.2M ethereal hydrogen chloride (1.5 ml) was added. The mixture was stirred for 10 minutes at ambient temperature and the volatiles were removed by evaporation. The solid residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-methylaminosulphonyloxindol-3-yl)quinazoline hydrochloride (123 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH:20]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)C(OC(C)(C)C)=O)=[O:18])=[N:6][CH:7]=1.[F:35][C:36]([F:41])([F:40])[C:37]([O-:39])=[O:38]>>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17]([O:19][CH2:20][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:18])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C(OC(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)C1CCNCC1
Reactant: O=C([O-])C(F)(F)F
Product: O=C(Nc1ccccc1C(=O)Nc1ccc(Cl)cn1)OCC1CCNCC1
Product: O=C(O)C(F)(F)F
Yield: 99 %

Procedure:
Using a similar procedure to that described in Example 9-B, N-(5-chloropyridin-2-yl)-2-[(1-tert-butoxycarbonylpiperidin-4-ylmethoxycarbonyl)amino]benzamide (300 mg, 0.615 mmol) yielded 308 mg (99%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: [C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[OH:26])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.[I-].[K+]>C1COCC1.CN(C=O)C>[C:1]1([C:7]([NH:20][C@@H:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[O:26][CH2:40][C:39]2[CH:42]=[CH:43][C:36]([C:28]3[O:27][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)=[CH:37][CH:38]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1ccc(C(N[C@@H]2CCC[C@H]2OCc2ccc(-c3nc4ccccc4o3)cc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a mixture of trans-2-triphenylmethylaminocyclopentanol (4.76 g; 13.85 mmol), is added Nail (60%; 0.83 g; 20.78 mmol) in 100 ml THF and 20 ml DMF. This mixture is stirred for 1 hr. and then 4-(benzoxazol-2-yl)benzyl bromide (3.99 g; 13.85 mmol) is added followed by potassium iodide (pinch). The reaction mixture is stirred for 72 hrs., quenched with water, concentrated in vacuo and flash chromatographed using 9:1; hexane:EtOAc to obtain trans-2-triphenylmethylamino-[4-(benzoxazol-2-yl)benzyloxy]cyclopentane which is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][OH:14])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:12][CH2:13][O:14][S:29]([CH3:28])(=[O:31])=[O:30])[CH:7]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2=[O:20]
Reactant: CCOC(=O)c1cn(CCO)c2ncc(Br)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCOS(C)(=O)=O)c2ncc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of ethyl 6-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 17, 800 mg, 2.34 mmol) and triethylamine (473 mg, 4.69 mmol) in dichloromethane (50 mL) was cooled to 0° C. and methane sulphonyl chloride (400 mg, 3.50 mmol) was added drop wise. The mixture was allowed to stir at room temperature for 3 h. The reaction mixture was washed with water and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 700 mg, (71%) of ethyl 6-bromo-1-{2-[(methylsulfonyl)oxy]ethyl}-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate, which was taken without further purification to next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:10](\[CH3:18])/[C:11]([O:13]C(C)(C)C)=[O:12])[CH:6]=[CH:5][C:4]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1>FC(F)(F)C(O)=O.C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[C:10](\[CH3:18])/[C:11]([OH:13])=[O:12])[CH:6]=[CH:5][C:4]=1[N:19]1[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]1
Reactant: COc1nc(/C=C(\C)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(/C=C(\C)C(=O)O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (400 mg), an allylpalladium chloride dimer (32.8 mg), tri-o-tolylphosphine (54.4 mg), sodium acetate (441 mg), dimethylacetamide (0.640 mL), tert-butyl methacrylate (0.724 mL) and toluene (2 mL) was stirred in a nitrogen atmosphere at 120° C. for 3.5 hours. The reaction solution was left to cool to room temperature. Then, a silica gel was added and the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 313 mg of tert-butyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacrylate. The ester was diluted with trifluoroacetic acid (2.48 mL) and methylene chloride (2.48 mL), and the reaction solution was stirred at room temperature for 3.5 hours. The reaction solution was concentrated under reduced pressure to obtain 260 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])#[N:22]>>[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:25][C:24]=1[F:32])#[N:22]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C#N)c(F)c3)ccn2c1=O
Yield: 105.5 %

Procedure:
Methyl 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 4-cyano-3-fluoro-phenyl-boronic acid (85 mg, 0.51 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (135 mg, 98%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1)#[N:2].Br.[Br:13][CH2:14][CH2:15][CH2:16][NH:17][C@H](C(O)=O)C.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:17][CH2:16][CH2:15][CH2:14][Br:13])=[O:11])=[CH:7][CH:8]=1)#[N:2]
Reactant: C[C@H](NCCCBr)C(=O)O
Reactant: N#Cc1ccc(N=C=O)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NC(=O)NCCCBr)cc1
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To 10.0 g (0.07 mole) 4-cyanophenyl isocyanate in 200 mL methylene chloride at 23° C. was added with stirring 15.2 g (0.07 mole) 3-bromopropylalanine hydrobromide. To this was added 7.08 g (0.07 mole) triethylamine via syringe. After the addition was complete the reaction was allowed to proceed for one hour. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate (2×50 mL), dilute aqueous hydrochloric acid, dried (Na2SO4) and concentrated to give 13.8 g (85%) of desired N-4-cyanophenyl-N'-3-bromopropyl urea contaminated with 15% isocyanate dimer.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([O:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:7][CH:8]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>>[CH:17]([O:16][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][O:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([CH3:29])=[CH:21][CH:22]=2)=[O:28])[CH:4]=1)[C:11]([OH:13])=[O:12])([CH3:18])[CH3:19]
Reactant: CCOC(=O)C(Cc1cccc(CO)c1)OC(C)C
Reactant: Cc1ccc(N=C=O)cc1
Product: Cc1ccc(NC(=O)OCc2cccc(CC(OC(C)C)C(=O)O)c2)cc1

Procedure:
Using ethyl 3-[3-(hydroxymethyl)phenyl]-2-isopropoxypropanoate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 148.
Reaction SMILES: [NH2:1][C:2](/[N:4]=[C:5](/[N:7]([CH3:9])[CH3:8])\[CH3:6])=[S:3].[CH3:10][I:11]>C1COCC1>[IH:11].[NH2:1][CH:2]([S:3][CH3:10])/[N:4]=[C:5](/[N:7]([CH3:9])[CH3:8])\[CH3:6]
Reactant: C/C(=N\C(N)=S)N(C)C
Reactant: CI
Solvent: C1CCOC1
Product: CSC(N)/N=C(\C)N(C)C
Product: I
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
A suspension of (1E)-N′-(aminocarbonothioyl)-N,N-dimethylethanimidamide (47.8 g, 0.33 mole) in methyl iodide (150 mL) and THF (350 mL) was stirred for 18 h at room temperature. The mixture was evaporated under reduced pressure. After addition of 5% MeOH and diethyl ether, the compound precipitated and was collected by filtration affording (1E)-N′-[amino(methylthio)methyl]-N,N-dimethylethanimidamide hydrogen iodide salt (91.0 g, 96% yield).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].CN1CCCC1=O.Br[Mg][CH2:23][CH:24]([CH3:26])[CH3:25].Cl>C1COCC1.C(OCC)C.[Fe+3]>[CH2:23]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11])[CH:24]([CH3:26])[CH3:25]
Reactant: N#Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)C[Mg]Br
Agent: [Fe+3]
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: CC(C)Cc1ccc(C#N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)benzonitrile (1 g) and iron(3+) tris[(2Z)-4-oxopent-2-ene-2-oleate] (86 mg), and 1-methylpyrrolidin-2-one (2.8 ml) in THF (30 ml) was added a solution of 2M bromo(isobutyl)magnesium in diethyl ether (2.9 ml) under ice-cooling. The solution was stirred at room temperature for 30 minutes, and diluted with diethyl ether (30 ml), and then 1M HCl was carefully added thereto to complete the reaction. The reaction solution was extracted with EtOAc (100 ml), and the organic layer was dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=100:0 to 95:5) to obtain 4-isobutyl-3-(trifluoromethyl)benzonitrile (320 mg) as a pale yellow liquid.
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11]Br)=[N:8][C:7]=2[CH:13]=1>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH2:11][NH2:1])=[N:8][C:7]=2[CH:13]=1
Reactant: N
Reactant: BrCc1nc2cc(Br)ccc2s1
Solvent: CO
Product: NCc1nc2cc(Br)ccc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Gaseous ammonia is bubbled through a solution of 5-Bromo-2-bromomethyl-benzothiazole (0.850 g, 2.768 mmol) in methanol (16 mL) for 10 minutes at 0° C. then stirred at room temperature for 3 hours. The reaction mixture is dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo. The crude material is washed with n-pentane and hexane to afford the title compound (0.78 g). 1H NMR (400 MHz, DMSO-d6) δ: 4.52 (s, 2H), 7.69-7.72 (dd, J1=1.96 Hz, J2=8.68 Hz, 1H), 7.95 (d, J=8.64 Hz, 1H), 8.46 (d, J=1.96 Hz, 1H). LC-MS (m/z): [M+H]=245.0.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:13]([CH2:17][CH:18]=[CH2:19])[C:14]([OH:16])=O)[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.CN(C=O)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH:37]([CH3:39])[CH3:38])=[C:35]([NH2:40])[CH:34]=[N:33]2)=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CCN(CC)CC>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:36]([CH:37]([CH3:38])[CH3:39])=[C:35]([NH:40][C:14](=[O:16])[CH:13]([N:3]3[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]3[CH3:1])[CH2:17][CH:18]=[CH2:19])[CH:34]=[N:33]2)=[CH:30][CH:31]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Reactant: C=CCC(C(=O)O)n1c(C)nc(C(F)(F)F)c1C=C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCC(C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C)n1c(C)nc(C(F)(F)F)c1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To 2-[2-methyl-4-(trifluoromethyl)-5-vinylimidazol-1-yl]pent-4-enoic acid (120 mg, 0.42 mmol) was added DMF (3 mL), Et3N (500 μL, excess), 1-(4-chlorophenyl)-5-isopropylpyrazol-4-amine (100 mg, 0.42 mmol), and HATU (250 mg, excess) and the resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were then dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to obtain N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-2-[2-methyl-4-(trifluoromethyl)-5-vinylimidazol-1-yl]pent-4-enamide (147 mg, 0.3 mmol, 70% yield).