Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-:2].[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]=[CH:18][C:17]1=[O:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C>[CH2:9]([N:16]1[C:20](=[O:21])[CH:19]2[CH:18]([NH:2][N:1]=[C:3]2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:17]1=[O:22])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)C1=NNC2C(=O)N(Cc3ccccc3)C(=O)C12
Reaction time: 18 h
Yield: 100 %

Procedure:
Ethyl diazoacetate (13 g, 114 mmol) in diethyl ether (100 ml) was added dropwise to a solution of N-benzylmaleimide (10 g, 53 mmol) in diethyl ether (250 ml). The resulting mixture was allowed to stir for 18 hours; the solvent was then removed in vacuo, and the resulting residue partitioned between methylene chloride and water. The organic layer was dried over sodium sulfate, filtered and concentrated to provide the title product as a white solid, mp 145°-146° with decomposition (16 g, 53 mmol, 100% yield). 1H NMR (CDCl3): 7.31 (m, 5H), 7.02 (bs, 1H), 4.89 (dd, J=11, 2 Hz, 1H), 4.65 (s, 2H), 4.55 (d, J=10 Hz, 1H), 4.36 (q, J=7 Hz, 2H), 1.37 (t, J=7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[S:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:29](Cl)Cl.CCN(C(C)C)C(C)C.FC(F)(F)S(OC)(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]([C:12]2[N:13]=[N:14][S:15][C:16]=2[CH2:17][O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])[S:11][CH3:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: ClCCl
Reactant: CC(C)[Si](OCc1snnc1C(=S)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=Nc1ccc(F)c(Cl)c1)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.08 h

Procedure:
To a solution of N-(3-chloro-4-fluorophenyl)-5-[(triisopropylsilyl)oxy]methyl-1,2,3-thia-diazole-4-carbothioamide (0.18 g, 0.00039 mol) in anhydrous DCM (3 mL, 0.04 mol) under N2 was added DIPEA (82 μL, 0.00047 mol) followed by methyl trifluoromethanesulfonate (47 μL, 0.00043 mol). The reaction was stirred for 5 minutes and then concentrated in vacuo. The crude material was used in the next step. The product amount was estimated (185 mg, 100%). MF=C20H29ClFN3OS2Si; LCMS calculated for C20H30ClFN3OS2Si (M+H)+: m/z=474.1.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.O=[C:41]1[CH2:46][CH2:45][CH2:44][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42]1>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:45]2[CH2:46][CH2:41][CH2:42][N:43]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:44]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(=Cc2ccc(F)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirring solution of (4-fluorophenylmethyl)-triphenylphosphonium chloride (17.68 g, 43.5 mmol) in dry tetrahydrofuran (60 mL) at −78° C. was added 2.5 M n-butyllithium in hexane (14.6 mL, 36.5 mmol). The reaction was warmed to 0° C. for 1 hr and t-Butyl 3-oxo-1-piperidinecarboxylate (3.46 g, 17.4 mmol) in tetrahydrofuran (60 mL) was added. The mixture was stirred at room temperature for 1 hr and the heated to reflux for 16 hr. The reaction was cooled to room temperature and quenched by the addition of saturated aqueous ammonium chloride. The reaction was extracted with ethyl acetate three times (100 mL). The organic layers were combined, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, hexane:ethyl acetate 9:1) to yield 3.82 g of a mixture of E and Z isomers as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.22-7.14 (m, 2H), 7.04-6.98 (m, 2H), 6.36 (s, 0.33H), 6.28 (s, 0.67H), 4.14 (s, 1.34H), 4.00 (s, 0.66H) 3.50 (t, J=5, 2H), 2.47 (t, J=5, 0.66H), 2.39 (t, J=5, 1.34H), 1.75-1.68 (m, 1.34H), 1.65-1.57 (m, 0.66H), 1.48 (s, 9H).
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.[Br:10][CH2:11][C:12](Br)=[O:13]>ClCCl.O>[Br:10][CH2:11][C:12]([N:3]1[CH2:4][CH:5]2[CH2:8][CH2:9][CH:1]([CH2:7][CH2:6]2)[CH2:2]1)=[O:13]
Reactant: C1CC2CCC1CNC2
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: O
Product: O=C(CBr)N1CC2CCC(CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.8 %

Procedure:
To a solution of 3-azabicyclo[3.2.2]nonane (1.25 g) in dichioromethane (20 ml) and water (0.75 ml) was added dropwise a solution of bromoacetyl bromide (2.02 g) in dichloromethane (10 ml) at, 5°-10° C. The mixture was allowed to warm to room temperature and stirred for 1 hour at the same temperature. The reaction mixture was washed with a saturated sodium bicarbonate aqueous solution (10 ml) and a brine (10 ml). The organic layer was dried over magnesium sulfate. Filtration and evaporation gave N-bromomethylcarbonyl-3-azabicyclo[3.2.2]nonane (1.15 g). The compound was used in a following reaction step without further purification.
Reaction SMILES: C([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Br)[S:21][C:17]=2[C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=O)C(C)(C)C.[Br:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.CO.[OH-].[Na+]>O1CCOCC1>[Br:33][C:34]1[CH:35]=[C:36]([C:20]2[S:21][C:17]3[C:16]([C:26]4[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[C:15]([C@H:9]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:8][OH:7])[C:24]([CH3:25])=[CH:23][C:18]=3[N:19]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc2nc(Br)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc2nc(-c3cccc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 90 °C
Yield: 35.9 %

Procedure:
To a solution of (S)-2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (310 mg, 0.577 mmol) in dioxane (5 mL), was added 3-bromophenylboronic acid (173 mg, 0.865 mmol), Ph(PPh3)4 (33 mg, 0.029 mmol) 2N K2CO3 (850 μL) in sealed tube. The reaction mixture was heated at 90° C. for 3hs. Then the reaction was cooled down and to the mixture was added MeOH (5 mL), 2N NaOH (1.5 mL) and heated at 45° C. After the reaction was finished, the reaction was washed by water, extracted by EtOAc. The organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product (110 mg, 36%). LCMS-ESI+: calc'd for C26H25BrClNO2S: 530.0 (M+H+); Found: 530.2 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:11])[NH:6][CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[CH3:12]I>[Zn].C(O)(=O)C>[CH3:12][O:11][C:5]1[C:4]([NH2:1])=[C:9]([CH3:10])[CH:8]=[CH:7][N:6]=1
Reactant: Cc1cc[nH]c(=O)c1[N+](=O)[O-]
Reactant: CI
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1nccc(C)c1N

Procedure:
3-Nitro-4-methyl-2-pyridone was methylated with methyl iodide and reduced with zinc and acetic acid to give 2-methoxy-3-amino-4-methylpyridine. This material was coupled with 2-(4-(1-methylpropyl )phenoxynonanoic acid according to the procedure of Example 25 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:22][O:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[CH3:22][O:23][C:24]([NH:1][C:2]1[N:6]2[CH:7]=[C:8]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1)=[O:25]
Reactant: COC(=O)Cl
Reactant: Nc1cnc2ccc(Sc3ccccn3)cn12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1cnc2ccc(Sc3ccccn3)cn12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.0 g. of 3-amino-6-(2-pyridylthio) imidazo [1,2-a] pyridine in 25 ml. of chloroform containing 0.401 g. of triethyl amine is treated dropwise with 0.378 g. of methylchloroformate. The reaction mixture is stirred for 3 hours at room temperature. The chloroform is removed in vacuo and the residue is triturated with water. The solids are collected by filtration, washed well with water and dried. Recrystallization from dimethylformamide-ethane yields pure 3-(methoxycarbonylamino) 6-(2-pyridylthio) imidazo [1,2-a] pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:10]([OH:12])=O)[S:8][CH:9]=1)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH2:29]2.C(O)(=O)C>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([C:35]([NH2:37])=[O:36])[C:30](=[O:38])[CH:29]2[C:10](=[O:12])[C:7]1[S:8][CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Reactant: COC(=O)c1csc(C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)c1csc(C(=O)C2C(=O)N(C(N)=O)c3ccc(Cl)cc32)c1
Yield: 67.9 %

Procedure:
The title compound was prepared according to the procedure of Example 55. To a solution of 1.50 g (8.06 mmoles) of 4-methoxycarbonyl-2-thiophenecarboxylic acid (prepared as described in Example 9) in 15 ml of N,N-dimethylformamide was added 1.57 g (9.67 mmoles) of 1,1'-carbonyldiimidazole. After two hours the reaction contents were slowly added to 1.54 g (7.32 mmoles) of 5-chloro-2-oxindole-1-carboxamide and 2.66 g (21.75 mmoles) of 4-(N,N-dimethylamino)pyridine in N,N-dimethylformamide. Acidic workup of this reaction followed by filtration, drying and trituration with hot acetic acid furnished 1.88 g (4.97 mmoles, 68% yield) of title compound as a yellow solid, m.p. 244°-246° C.
Reaction SMILES: [CH2:1]([Zn]CC)C.C([Si]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:22])=[CH2:21])=[CH:16][CH:15]=1)(C)C)(C)(C)C.ICI.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>ClC(Cl)C>[CH3:1][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC[Zn]CC
Reactant: C=C(C)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ICI
Solvent: CC(Cl)Cl
Product: CC1(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Diethylzinc (1.0 M in hexanes, 69 mL, 69 mmol) was added to a solution of tert-butyl-(4-isopropenyl-phenoxy)-dimethyl-silane (6.85 g, 27.6 mmol) in dichloroethane at 0° C. Diiodomethane (11.2 mL, 138 mmol) was then added dropwise to the solution and the resultant mixture was stirred at 0° C. for 0.5 h and allowed to warm to rt for 2 h. The opaque mixture was quenched with saturated aqueous NH4Cl. The aqueous phase was extracted with CH2Cl2 and the combined organic layers were washed with saturated aqueous NaHCO3. The organic layers were dried over sodium sulfate, filtered through celite, and concentrated. The crude TBS ether was dissolved in THF (50 mL) and TBAF (1.0 M in THF, 28 mL, 28 mmol) was added at rt. The solution was stirred for 2 h and then quenched with aqueous 1.0 M HCl. The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered and concentrated. Purification by silica-gel chromatography (1% 2-propanol/12% ethyl acetate in hexanes) provided 4-(1-methyl-cyclopropyl)-phenol (2.77 g, 68%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][N:4](CC2C=CC=CC=2)[C:3]=1[C:24]([O:26]CC1C=CC=CC=1)=[O:25].[K]>O1CCCC1.O>[Br:1][C:2]1[C:3]([C:24]([OH:26])=[O:25])=[N:4][CH:5]=[C:6]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:7]=1[O:8][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)c1c(Br)c(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ncc(OCc2ccccc2)c(OCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.8 g of 3-Bromo-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, phenylmethyl ester and 0.54 g potassium hydroxyde were dissolved in 30 ml tetrahydrofuran and 3 ml H2O. After stirring for 24 hours at room temperature, the THF was distilled off and 20 ml H2O were added to the residue. The pH was adjusted to 3.5 with 2NHCl. Crystals of the title compound were formed and filtered off, washed with 20 ml H2O and dried; yield 3 g of the title compound white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:21][C:20]1[CH:22]=[CH:23][C:17]([O:16][C:15]([F:14])([F:24])[F:25])=[CH:18][CH:19]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1cc(F)ccc1Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1cc(F)ccc1Cl)Nc1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
2.99 g (0.015 mol) of 2-chloro-5-fluoro-benzoyl isocyanate are added to 2.66 g (0.015 mol) of 4-trifluoromethoxyaniline in 30 ml of dry toluene, at 60° C., in the absence of moisture. The mixture is stirred for one hour at 80° C. and cooled to 20°-25° C. The precipitated product is filtered off under suction and dried in vacuo at 100° C. 5.6 g (100% of theory) of 1-(2-chloro-5-fluoro-benzoyl)-3-(4-trifluoromethoxyphenyl)-urea of melting point 199° C. are obtained.
Reaction SMILES: [C-:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14].N1C=CC=CC=1.[C:21](Cl)(=[O:25])[C:22]([CH3:24])=[CH2:23]>CCOCC>[C:21]([O:8][CH2:7][CH2:6][C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)(=[O:25])[C:22]([CH3:24])=[CH2:23].[CH-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:14]
Reactant: C=C(C)C(=O)Cl
Reactant: OCC[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCC[c-]1cccc1
Reaction time: 4 h

Procedure:
2-ferrocenylethyl alcohol obtained from Example 1 (0.8 g) is dissolved in 300 ml anhydrous ether and 0.4 g of pyridine are added. The solution of 0.5 ml methacryloyl chloride in 30 ml ether is added dropwise and the reaction is continued for four hours. The precipitate is removed by filtration and the ether solutions are combined, washed with 5% sodium bicarbonate, 5% hydrochloric acid, sodium bicarbonate again and dried. The ether is evaporated, leaving a brown viscous oil that is further purified by chromatography over silica (ether as eluent).
Reaction SMILES: C([Li])CCC.[CH:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:8])[CH3:7].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)OC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)OC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
11.7 cm3 of a 1.6M solution of n-butyllithium in hexane is added at -70° C. to a solution of 2.5 g of 5-isopropyloxy pyrrolidin-2-one in 60 cm3 of tetrahydrofuran, while maintaining the temperature between -70° C. and -65° C. Agitation is carried out for 30 minutes under these conditions then a solution of 2.46 g of benzoyl chloride in 8 cm3 of tetrahydrofuran is added, maintaining the temperature between -65° C. and -70° C. The temperature is allowed to return to the ambient over 2 hours. After evaporation to dryness and then chromatography on silica (eluent: ethyl acetate-n-hexane 1-3), 2.78 g of the product sought is obtained.
Reaction SMILES: CI.Cl[CH2:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8].[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=O)[C:15]=2[CH:14]=[CH:13][CH:12]=1.[Cl-].[NH4+]>CCOCC>[CH3:10][C:11]1[C:21]2[CH2:20][CH2:19][C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[C:16](=[CH:4][CH2:5][CH2:6][N:7]([CH3:9])[CH3:8])[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: CN(C)CCCCl
Reactant: Cc1cccc2c1CCc1ccccc1C2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1cccc2c1CCc1ccccc1C2=CCCN(C)C
Temperature: 45 °C
Reaction time: 10 h

Procedure:
10 g. of Gilman alloy are covered with 30 ml. of dry ether and treated with 0.5 ml. of methyl iodide. After the vigorous reaction has subsided somewhat, 40 ml. of 1-chloro-3-dimethylaminopropane in 120 ml. of dry ether are added dropwise in such a way that the reaction mixture is maintained at boiling. The mixture is heated at 45° C. under reflux conditions for an additional 3 hours, then cooled with ice water and treated dropwise over a period of one hour with a solution of 21.8 g. of 1-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (J. Med. Pharm. Chem. 4, 335-49, 1961) in 400 ml. of dry ether. Subsequently, the mixture is stirred at 45° C. under reflux conditions for an additional 10 hours, then cooled with ice water and decomposed with a cold saturated ammonium chloride solution. The organic layer is removed by separation. The aqueous phase is shaken twice with 100 ml. portions of ether and the combined ether extracts are dried over sodium sulfate and evaporated. The residual 1-methyl-10,11-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene has a melting point of 154°-155° C. after recrystallization from high-boiling petroleum ether.
Reaction SMILES: [C:1]([O-:7])(=O)[CH2:2][C:3]([CH3:5])=[O:4].[Li+].C(N(CC)CC)C.[CH2:16]([NH:19][CH2:20][CH:21]1[CH2:23][CH2:22]1)[CH2:17][CH3:18].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClC(Cl)C>[CH:21]1([CH2:20][N:19]([CH2:16][CH2:17][CH3:18])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH2:23][CH2:22]1
Reactant: CC(=O)CC(=O)[O-]
Reactant: CCCNCC1CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(CC1CC1)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
A stirred mixture of lithium acetoacetate (scheme 2: (G)) (1.00 g, 9.26 mmoles), triethylamine (2.58 mL, 18.5 mmoles), and n-propylcyclopropylmethyl amine (scheme 2: (E)) (1.32 mL, 9.26 mmoles) in dry dichloroethane (60 mL) was treated with bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl) (2.36g, 9.26 mmoles). The mixture was stirred overnight at room temperature, and then acidified (pH˜1) with 1M hydrochloric acid. The mixture was extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over MgSO4. Concentration in vacuo and purification by silica gel chromatography (30% ethyl acetate/hexane) gave 900 mg of a yellow oil.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23](N2CCOCC2)=[O:24])[CH:20]=1>C1COCC1>[CH:1]1([CH2:7][C:23](=[O:24])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:32])[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCC1CCCCC1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of cyclohexylmethyl bromide (0.26 g) in THF (1 mL) cooled to −70° C. under argon, tert-butyl lithium (1.7 M in pentane, 1.8 mL) was added dropwise over 5 minutes. The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.33 g) in THF (1 mL) was added all at once and the mixture was stirred for one hour. The reaction temperature rose to approximately coming to −20° C. The reaction was quenched with EtOH (0.3 mL), and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (eluent: hexanes-methylene chloride gradient) gave the title compound as an oil (0.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:10]>C1(C)C=CC=CC=1>[Br:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[CH2:8][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Product: O=C(CN1CCOCC1)c1ccc(Br)cc1
Yield: 101.3 %

Procedure:
Morpholine (4.35 g) in dry toluene (8 ml) was stirred during the addition of aliquots of 2-bromo-1-(4-bromophenyl)ethanone (6.95 g) in dry toluene (70 ml). The resulting precipitate was removed by filtration and the filtrate evaporated to give the product (J. Amer. Chem. Soc., 1940, 62, 2882) as a pale yellow solid (7.2 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[CH:9][CH:10]=[O:11].[CH3:13][C:14]1[O:15][CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1>C(#N)C>[CH3:13][C:14]1[O:15][C:16]([CH:8]=[CH:9][CH:10]=[O:11])=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:18]=1
Reactant: Cc1cc(-c2ccc(F)cc2)co1
Reactant: CN(C)C=CC=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1cc(-c2ccc(F)cc2)c(C=CC=O)o1
Temperature: -23 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
A solution of 1.1 mL (11.9 mmol) of phosphorus oxychloride in 15 mL of acetonitrile was allowed to react with 1.2 mL (11.9 mmol) of 3-dimethylaminoacrolein at -23° C. After 0.25 hour at -23° C., 1.4 g (7.9 mmol) of 2-methyl-4-(4'-fluorophenyl)furan in 10 mL of acetonitrile was added dropwise. The reaction mixture was stirred at -23° C. for 0.15 hour then at 24° C. for 2 hours. The reaction was quenched upon treatment with 20 mL of 1M NaOH and extracted three times with CHCl3. The CHCl3 layers were combined, dried (MgSO4) and concentrated under reduced pressure. Column chromatography (3:1 hexanes-diethyl ether) of the residue on silica gel produced 1.76 g (97%) of 3-(5-methyl-3-p-fluorophenyl-furan-2-yl)acrylaldehyde as a solid (m.p. 89°-90° C.), homogeneous by TLC and spectroscopic criteria; Rf 0.58 (1:1 hexanes-diethyl ether); IR (KBr) 1655, 1600, 1205, 1118, 1095 cm-1 ; 1HNMR (300 MHz, CDCl3) 9.60 (d, 1H, J=10.5 Hz), 7.41 (m, 2H), 7.27 (d, 1H, J=15 Hz), 7.18 (t, 2H, J=9.0 Hz), 6.64 (dd, 1H, J=10.5 Hz, 15 Hz), 6.32 (s, 1H), 2.42 (s, 3H).
Reaction SMILES: CN([CH:4]=[C:5]1[C:13](=O)[C:12]2[N:11]([CH3:15])[N:10]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]=2[C:7]([CH3:22])([CH3:21])[CH2:6]1)C.[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]([NH2:40])=[NH:39])[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]([NH:37][C:38]2[N:40]=[CH:4][C:5]3[CH2:6][C:7]([CH3:21])([CH3:22])[C:8]4[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10][N:11]([CH3:15])[C:12]=4[C:13]=3[N:39]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1
Reactant: CN1CCN(c2ccc(NC(=N)N)cc2Cl)CC1
Reactant: CCOC(=O)c1nn(C)c2c1C(C)(C)CC(=CN(C)C)C2=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C)c2c1C(C)(C)Cc1cnc(Nc3ccc(N4CCN(C)CC4)c(Cl)c3)nc1-2
Reaction time: 37 h
Yield: 88.2 %

Procedure:
A solution of ethyl 6-[(dimethylamino)methylene]-1,4,4-trimethyl-7-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylate (0.50 g, 1.6 mmol) and N-[3-chloro-4-(4-methylpiperazin-1-yl)-phenyl]-guanidine (0.48 g, 1.8 mmol) in anhydrous dimethylformamide was heated to 100° C. and kept at this temperature for 37 hours. After cooling, the mixture was diluted with water (50 mL) and the resulting precipitate was collected by filtration and dried to give the title compound (0.72 g, 85% yield) as a yellow solid.