Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](/[C:14](/[CH3:26])=[CH:15]/[C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=3)=[CH:11][CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3C(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(C)(C)c2cc(/C(C)=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 48 h

Procedure:
To a solution of 0.1 g (0.265 mmol) of methyl 4[(E)-2-(N-acetyl-4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-methylvinyl]benzoate in 10 ml of dioxane was added, with stirring, 0.8 ml (1.6 mmol) of 2N sodium hydroxide, with the temperature maintained at 25° C. Stirring was continued for 48 hours, and then the reaction mixture was diluted with 25 ml of water. It was then acidified to pH 2 with 2N hydrochloric acid and extracted with dichloromethane. The combined extracts were dried using sodium sulfate and then evaporated in vacuo to give the title compound as a white solid. The solid was recrystallized from methanol-hexane to give 70 mg of the title compound, mp 200°-202° C.
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[N:3]=1.C(ON=O)CC(C)C>C1COCC1>[CH2:10]([O:9][C:7]([C:6]1[CH:2]=[N:3][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)[CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cn(-c2cccc(Br)c2)nc1N
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2cccc(Br)c2)c1
Temperature: 25 °C

Procedure:
To a solution of the ester from Step 1 (0.5 g, 1.61 mmol) in THF (4.3 mL) was added isoamylnitrite (0.434 mL, 3.23 mmol), and the mixture was refluxed for 16 hours. It was cooled to room temperature, concentrated, dried and used as such for the subsequent step without any purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O(CCN1CCOCC1)C1C=CC=CC=1.[Cl:32][S:33](O)(=[O:35])=[O:34]>ClCCl>[N:10]1([CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:33]([Cl:32])(=[O:35])=[O:34])=[CH:4][CH:3]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc(OCCN2CCOCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[2-(Morpholin-4-yl)ethoxy]benzene-4-sulfonyl chloride was prepared using N-(2-phenoxyethyl) morpholine by similar reaction described above. For example, 7.2 g of N-(2-phenoxyethyl)morpholine HCl salt was resuspended in 20 ml of dichloromethane and 7 ml of chlorosulfonic acid was slowly introduced with cooling by ice-jacket. The reaction mixture was stirred at 0° C. for 2 hr, then, at room temperature overnight. Dichloromethane (350 ml) was added to the reaction mixture and excess chlorosulfonic acid was destroyed by adding icy water(about 100 g). Aqueous layer was adjusted to pH 8.5 by concentrated sodium carbonate solution with cooling by ice. Dichloromethane was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 8.1 g of [2-(morpholin-4-yl)ethoxy]benzene-4-sulfonyl chloride. M.P. 48-50° C.
Reaction SMILES: O[N:2]=[C:3]([CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)C(O)=O.O>C(OC(=O)C)(=O)C>[C:13]1([C:11]2[CH:12]=[C:8]([CH2:7][C:3]#[N:2])[S:9][CH:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C(Cc1cc(-c2ccccc2)cs1)=NO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCc1cc(-c2ccccc2)cs1
Temperature: 25 °C
Yield: 72.8 %

Procedure:
2-(Hydroxyimino)-3-(4-phenylthiophen-2-yl)propanoic acid (0.8 g, 3.1 mmol) was heated in acetic anhydride (5 mL) for 1.5 h. The reaction mixture was cooled to room temperature and treated with water. The product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel 60-120 mesh, eluent 10-15% EtOAc in petroleum ether) to afford 2-(4-phenylthiophen-2-yl)acetonitrile (0.45 g, yield 73%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.57-7.53 (m, 2H), 7.43-7.39 (m, 2H), 7.37-7.36 (m, 2H), 7.34-7.30 (m, 1H), 3.96 (s, 2H).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:42])[F:41])=[CH:35][N:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:28]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[C:38]([Cl:39])=[CH:37][C:36]([C:40]([F:43])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.70 g of desired compound.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([O:30]C)[C:14]=3[C:15](=[O:24])[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].B(Br)(Br)Br>C(Cl)Cl>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][C:13]3[C:28]([Cl:29])=[CH:27][CH:26]=[C:25]([OH:30])[C:14]=3[C:15](=[O:24])[C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1ccc(Cl)c2oc(-c3ccc(S(N)(=O)=O)cc3)c(-c3ccc(F)cc3)c(=O)c12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-c2oc3c(Cl)ccc(O)c3c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 2-(4-(aminosulfonyl)phenyl)-8-chloro-3-(4-fluorophenyl)-5-methoxy-4H-1-benzopyran-4-one(0.03 g, 0.07 mmol) in CH2C2(5 ml) was added 1.0M BBr3(0.2 ml) at a temperature of 0° C. The mixture was stirred for 4 hours at room temperature and diluted with CH2Cl2(10 ml). After being washed with water and brine, the solution was dried over anhydrous MgSO4. The crude product was purified by flash chromatography to yield the title compound as a solid(0.02 g, 74%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:6]([CH:26]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15][C:16]1[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=1)=[O:8].[CH:32]1(B(O)O)[CH2:34][CH2:33]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:32]1([C:2]2[CH:3]=[CH:4][C:5]([N:27]3[N:31]=[CH:30][CH:29]=[N:28]3)=[C:6]([CH:26]=2)[C:7]([NH:9][C@H:10]2[CH2:14][CH2:13][CH2:12][C@@H:11]2[NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)=[O:8])[CH2:34][CH2:33]1
Reactant: OB(O)C1CC1
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(Cl)ccc1-n1nccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1cc(C2CC2)ccc1-n1nccn1

Procedure:
A solution of 5-chloro-2-(2H-1,2,3-triazol-2-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]benzamide (Example 52; 100 mg, 0.22 mmol), cyclopropylboronic acid (CAS number 411235-57-9; 29 mg, 0.33 mmol), bis(triphenylphosphine)palladium(II) dichloride (3 mg, 4.43 μmol) and potassium carbonate (31 mg, 0.22 mmol) in 1,4-dioxane (1.3 ml) and water (0.13 ml) was sealed and degassed with nitrogen. The reaction was subjected to microwave irradiation at 130° C. for 30 minutes. To this was then added bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)-dichloropalladium(II) (157 mg, 0.22 mmol) and the reaction was subjected to microwave irradiation at 130° C. for a further 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with water and brine, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:8]=1[CH3:16])(=O)=O.[CH:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)=[O:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH:19]([C:21]1[CH:26]=[C:25]([C:7]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]#[N:15])=[CH:9][C:8]=2[CH3:16])[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Cc1cc(C#N)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(C#N)cc(C)c1-c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Trifluoromethanesulfonic anhydride was dropwise added, under ice-cooling, to a mixture of 4-hydroxy-3,5-dimethylbenzonitrile, pyridine and dichloromethane, followed by stirring at room temperature for 2 hours to obtain 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate. In an atmosphere of nitrogen, a mixture of 4-cyano-2,6-dimethylphenyl trifluoromethanesulfonate, (3-formylphenyl)boronic acid, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at room temperature for 6 hours to obtain 3′-formyl-2,6-dimethylbiphenyl-4-carbonitrile.
Reaction SMILES: [C:1]([Si:5]([CH3:34])([CH3:33])[O:6][CH2:7][CH2:8][N:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([OH:32])=O)=[CH:24][CH:23]=1)[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.CN([P+](O[N:53]1N=[N:60][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C1(N)C=CC=CC=1N.[NH4+].[Cl-]>CN(C=O)C>[NH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[NH:60][C:30](=[O:32])[CH:29]=[CH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:34])[CH3:33])[CH2:10][CH2:11][C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)=[CH:23][CH:24]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(C=CC(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(CCc1c[nH]c2ccccc12)Cc1ccc(C=CC(=O)Nc2ccccc2N)cc1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a stirred solution of 4 (1.30 g, 2.72 mmol) in anhydrous DMF (20 mL) at room temperature under nitrogen were added Et3N (330 μl, 3.26 mmol) and BOP reagent (1.32 g, 2.99 mmol), respectively. After 30 min, a solution of 1,2-phenylenediamine (352 mg, 3.26 mmol), Et3N (1.14 mL, 8.15 mmol) in anhydrous DMF (3 mL) was added dropwise. After 3 h the reaction mixture was poured into saturated aqueous solution of NH4Cl, and extracted with AcOEt. The extract was washed with saturated NH4Cl, water and brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography on silica gel (MeOH/CH2Cl2, 5/95 plus several drops of NH4OH), to afford the title compound 5 (1.49 g, 2.62 mmol, 96% yield) as a yellow sticky foam. 1H NMR (300 MHz, DMSO-d6) δ(ppm): 10.78 (s, 1H), 9.40 (s, 1H), 7.59 (d, J=8.0 Hz, 2H), 7.58 (d, J=15.8 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.40 (t, J=7.7 Hz, 2H), 7.35 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.07 (t, J=7.5 Hz, 1H), 7.05-6.85 (m, 3H), 6.79 (d, J=7.9 Hz, 1H), 6.62 (t, J=7.5 Hz, 1H), 4.98 (bs, 2H), 3.80 (s, 2H), 3.71 (t, J=6.2 Hz, 2H), 2.95-2.75 (m, 4H), 2.71 (t, J=6.2 Hz, 2H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[I:21]I.[Cl-].[NH4+]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([I:21])=[CH:12][CH:11]=[CH:10][C:9]=1[F:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1I
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a cooled (−78° C.) solution of (2-fluoro-phenyl)-carbamic acid tert-butyl ester (38.0 g, 180 mmol) in THF (700 mL) under nitrogen was added tert-butyllithium (1.7 M, 240 mL, 408 mmol). The mixture was stirred for 1 h at −78° C. and then a solution of iodine (60.8 g, 240 mmol) in THF (150 mL) was added slowly. The reaction mixture was stirred for further 1 h. Saturated aqueous ammonium chloride (100 mL) was added slowly and the mixture was warmed to RT. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic fractions were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography (5% ethyl acetate:hexanes) to afford 39.1 g (65%) of the title compound as a while solid. 1H NMR (300 MHz, CDCl3): δ 1.50 (s, 9H), 5.98 (br. s, 1H), 6.92-6.99 (m, 1H), 7.08-7.15 (m, 1H), 7.62 (dt, J=7.8, 1.2 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:17]([NH:16][C:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:15])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNC(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCCCNC(=O)N1CCNCC1
Yield: 116.8 %

Procedure:
10% Palladium-on-carbon (250 mg) was added to a solution of 2.8 g of 1-benzyl-4-butylaminocarbonylpiperazine in 15 ml of ethanol, and catalytic reduction was carried out until cessation of hydrogen absorption. The catalyst was then filtered off, and the filtrate was concentrated under reduced pressure to give 2.2 g of 1-butylaminocarbonylpiperazine. This product was submitted to the next step without purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH2:15])[CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[IH:16].CS[C:19]1[C:27]2[CH:28]=[CH:29][CH:30]=[C:25]3[C:26]=2[C:21](=[CH:22][CH:23]=[CH:24]3)[N:20]=1.C([O-])(=O)C.[Na+]>C(O)C>[IH:16].[C:1]1([C:7]2[N:8]([CH2:12][CH2:13][CH2:14][NH:15][C:19]3[C:27]4[CH:28]=[CH:29][CH:30]=[C:25]5[C:26]=4[C:21](=[CH:22][CH:23]=[CH:24]5)[N:20]=3)[CH:9]=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCCn1ccnc1-c1ccccc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: CC(=O)[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2nccn2CCCNC2=Nc3cccc4cccc2c34)cc1

Procedure:
A mixture of 4.0 g of 3-(2-phenyl-1H-imidazol-1-yl)propanamine, 6.5 g of 2-(methylthio)benz[cd]indole hydroiodide, 1.8 g of sodium acetate and 250 ml of ethanol was reacted as described in Example 11. The crude product was recrystallized from a mixture of ethanol and isopropanol giving 3.8 g of the desired product, mp 153° C.-155° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[CH:17][C:7]2[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1.[CH3:19][N:20]([CH3:39])[C:21]1[CH:38]=[CH:37][C:24]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28]2)=[CH:23][CH:22]=1>CCCCCC.CS(C)=O>[F:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]([C@@H:30]3[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:24]4[CH:23]=[CH:22][C:21]([N:20]([CH3:19])[CH3:39])=[CH:38][CH:37]=4)[CH2:31]3)[C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C:6]=2[CH:5]=1
Reactant: CN(C)c1ccc(CCN2CC[C@H](OS(C)(=O)=O)C2)cc1
Reactant: Fc1ccc2c(c1)COc1ccccc1N2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: CN(C)c1ccc(CCN2CC[C@@H](N3c4ccc(F)cc4COc4ccccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (100 mg, 2.5 mmol) was washed with hexane in argon stream and then suspended in dimethyl sulfoxide (8 ml), and the obtained suspension was stirred at room temperature for 30 minutes. 2-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (538 mg, 2.5 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes and then at 50° C. for additional 40 minutes. A solution of (S)-1-(4-dimethylaminophenethyl)-3-methanesulfonyloxypyrrolidine (312 mg, 1.0 mmol, prepared by a method disclosed in International Patent No. 0040570A1) in dimethyl sulfoxide (3 ml) was added dropwise to the obtained solution, and they were stirred at 50° C. for 13 hours. The reaction mixture was poured into ice/water and then subjected to the extraction with ethyl acetate. The organic layer was dried and then the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-2-fluoro-5,11-dihydro-5-[1-(4-dimethylaminophenethyl)pyrrolidin-3-yl]dibenzo-[b,e][1,4]oxazepine in the form of a light yellow oily substance (140 mg, 32%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N)[CH3:2].Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl.O>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4]1[C:5]2[NH:10][C:16]3[CH2:17][CH2:18][NH:13][CH2:14][C:15]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: O=C1CCNCC1
Reactant: CCOc1ccccc1NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CCOc1cccc2c3c([nH]c12)CCNC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.8 %

Procedure:
(2-ethoxyphenyl)-hydrazine (1.22 g 8.00 mmol) and 4-piperidone hydrochloride (1.09 g 8.00 mmol) in ethanol (20 mL) were heated to reflux for 1 h. The 4M HCl (1 mL) in dioxane was added (immediate darkening) and heating continued for 4 h. The reaction was cooled to RT. The solvent was evaporated and the residue triturated with ether (c.f. 10 mL) to give a dark brown solid. The solid was slurried with the minimum of water, filtered and dried (MgSO4). This was repeated to give an off white solid (1.19 g, 59%). Material used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[C:18]([C:4]1[CH:3]=[C:2]([NH:1][C:31]([NH:30][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:23]=2[Cl:22])=[O:32])[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:17])[NH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)[N:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc3c(=O)[nH]cnc3c2)n1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3c(=O)[nH]cnc3c2)n1
Yield: 51 %

Procedure:
Using general method A, 7-(5-amino-3-t-butyl-1H-pyrazol-1-yl)quinazolin-4(3H)-one (120 mg, 0.424 mmol) and 2,3-dichlorophenylisocyanate (79 mg, 0.487 mmol) were combined to yield 1-(3-t-butyl-1-(4-oxo-3,4-dihydroquinazolin-7-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (102 mg, 51% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): 9.41 (s, 1H), 8.79 (s, 1H), 8.25-8.23 (s, 1H), 8.16 (s, 1H), 8.08-8.02 (m, 1H), 7.82-7.75 (m, 2H), 7.32-7.30 (m, 2H), 6.46 (s, 1H), 1.30 (s, 9H). MS (ESI) m/e (M+H+) 471.0.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]([C:12]([OH:14])=O)[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(Cl)(=O)C([Cl:18])=O>CCOCC>[CH2:1]([C:9]1[CH:10]([C:12]([Cl:18])=[O:14])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1=CC1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCCCCCCCC1=CC1C(=O)Cl
Reaction time: 1 h
Yield: 85.4 %

Procedure:
A solution of 2-octylcycloprop-2-ene-1-carboxylic acid (350 mg, 1.8 mmol) in ether was treated with 0.45 g (3.5 mmol) of oxalyl chloride at room temperature. The reaction mixture was stirred for one hour then stripped to give 330 mg of 2-octylcycloprop-2-ene-1-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[N:11]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:18][CH2:17][CH2:16][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: OCCN1CCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1OCCN1CCCC1

Procedure:
A mixture of 4-chloro-2-fluoro-benzonitrile (869 mg, 5.58 mmol) and 2-pyrrolidin-1-yl-ethanol (0.80 mL, 6.70 mmol) in THF (30 mL) is treated with a 0.5 M toluene solution of KHMDS (13.4 mL, 6.7 mmol) at 0° C. After completion of the reaction at RT, the reaction mixture is quenched by H2O. EtOAc is added and the organic layer is washed with brine, dried over MgSO4. Concentration in vacuo affords the corresponding 4-chloro-2-(2-pyrrolidin-1-ylethoxy)-benzonitrile. A THF (7 mL) solution of 4-chloro-2-(2-pyrrolidin-1-yl-ethoxy)-benzonitrile is added to a suspension of LAH (293 mg, 7.71 mmol) in THF (50 mL) at 0° C. The reaction is allowed to stir for 2 h at ambient temperature and then quenched by Na2SO4.10H2O, and the product is isolated by filtration with Celite and washed with THF and dried under reduced pressure to give the title compound as oil; ES-MS: M+=255.2; HPLC: AtRet=1.22 min.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([OH:7])[CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
tert-Butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (3.63 g, 11.2 mmol) was dissolved in ethanol (100 mL) then sodium tetrahydroborate (424 mg, 112 mmol) was added to this solution. The reaction mixture was stirred at room temperature for 3 h. LC-MS analysis of the reaction mixture showed no more starting material. The crude reaction mixture was concentrated and the residue was diluted with EtOAc (100 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to yield tert-butyl 4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.46 g, 94%), which was used in the next step directly. m/z: 326 (MH+)