Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N: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)=[N:6][CH:7]=1.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:2]1[C:3]2[N:4]([N:21]=[CH:22][N:23]=2)[C:5]([N: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)=[N:6][CH:7]=1
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)c3ncnn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3cccs3)c3ncnn23)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(8-bromo-[1,2,4]triazolo[1,5-c]pyrimidin-5-yl)piperazine-1-carboxylate (0.6 g, 1.57 mmol), thiophene-2-boronic acid (0.35 g, 2.74 mmol), tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.21 mmol), Cs2CO3 (2 g, 6.36 mmol), 1,4-dioxane (20 mL) and water (5 mL). After the air was purged by bubbling N2 into the solution, the resulting mixture was stirred at 100° C. under N2 overnight. Work-up: the reaction mixture was diluted with water and extracted with CH2Cl2 (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 0.5 g (82%) of the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:16][N:15]=[CH:14][CH:13]=1.CS(O[CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)(=O)=O>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:13]=[CH:14][N:15]([CH2:22][CH2:23][NH2:24])[N:16]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccn[nH]1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Product: COc1cc([N+](=O)[O-])ccc1-c1ccn(CCN)n1

Procedure:
The title compound was prepared from 5-(2-Methoxy-4-nitrophenyl)-1H-pyrazole (1.00 g) and 2-(tert-butoxycarbonylamino)ethyl methanesulfonate (1.42 g) using the method of Example 37(c). Yield 0.24 g (as HCl-salt). 1H-NMR (400 MHz; d6-DMSO): δ 3.32 (t, 2H), 4.02 (s, 3H), 4.47 (t, 2H), 6.94 (d, 1H), 7.88-7.93 (m, 3H), 8.12 (br s, 2H), 8.22 (d, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]([C:13]1[N:14]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[S:16][C:17]=1[C:18]([OH:20])=O)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH:5]2[CH2:4][CH2:3][NH:2][C:18](=[O:20])[C:17]3[S:16][C:15]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][C:13]2=3)=[CH:11][CH:10]=1
Reactant: NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCC(c2ccc(Cl)cc2)c2nc(N3CCOCC3)sc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[3-amino-1-(4-chlorophenyl)propyl]-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylic acid hydrochloride (0.264 g, 0.631 mmol) in DCM (12.7 mL) was added 1-hydroxybenzotriazole (0.103 g, 0.763 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.239 g, 1.24 mmol) and N,N-diisopropylethylamine (0.320 mL, 1.84 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM, then the layers were separated and the organic layer was washed with water then brine and dried over anhydrous sodium sulfate then concentrated. The residue was purified using column chromatography on silica gel (12 gr Analogix column, gradient DCM to 10% MeOH in DCM over 15 minutes) to give the product. The racemic product was then separated into enantiomers on a Chiralpak IA 20×250 mm column using 70/10/20 hexane/IPA/EtOH mixture, with retention time 10.4 min for peak 1 (53 mg, 23%) and 14.5 min for peak 2 (53 mg, 23%). Absolute configuration for the enantiomers is unknown. LCMS: (AA) ES+ 364, 366. 1H NMR (400 MHz, d6-DMSO) δ: 7.95 (t, J=4.4 Hz, 1H), 7.34 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 4.34 (dd, J=7.1, 5.3 Hz, 1H), 3.64-3.57 (m, 4H), 3.31-3.24 (m, 4H), 3.14-3.01 (m, 2H), 2.28-2.13 (m, 1H), 2.04-1.84 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:19])=[O:20])=[CH:15][CH:14]=1
Reactant: COc1ccccc1B(O)O
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: COc1ccccc1-c1ccc(S(=O)(=O)n2cccc2)s1
Yield: 74 %

Procedure:
N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C using 2-methoxyphenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole, 74% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11](=[O:14])(=[O:13])[NH2:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])=[C:22](Cl)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:19]=1.CCOC(C)=O>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:21]=[C:22]([NH:12][S:11](=[O:13])(=[O:14])[NH:10][C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:23]=1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][CH3:32]
Reactant: CC(C)c1ccc(NS(N)(=O)=O)cc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)Nc1ccc(C(C)C)cc1
Temperature: 45 °C
Reaction time: 60 h
Yield: 26.7 %

Procedure:
To a solution of 4-i-propyl-phenyl sulfamic acid amide (642 mg; Referential Example 17) in DMF (9 ml) was added sodium hydride (250 mg). The mixture was warmed to 45° C. for 30 min. Then, 4,6-dichloro-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (1.044 g) was added and the reaction mixture was stirred for 60 h at r.t. After acidic work up and chromatography over silicagel with Hex/EtOAc=2/5, 4-i-propyl-phenyl sulfamic acid-[6-chloro-5-(o-methoxy-phenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-amide (0.42 g) can be isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH:15]1[CH2:17][O:16]1)[C:10]([O:12]C)=O.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[NH:19][NH2:20]>CC(O)C.C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:15]([OH:16])[CH2:17][N:20]([NH:19][C:18](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]1=[O:12]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)C(CC1CO1)c1ccc(F)cc1Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O

Procedure:
To a solution of methyl 2-(2-chloro-4-fluorophenyl)-3-(oxiran-2-yl)propanoate (4.56 g, 17.6 mmol) in 2-propanol (20 mL) was added tert-butyl carbazate (2.3 g, 17.6 mmol) and the reaction heated to reflux for 16 hours. The reaction was then concentrated to dryness, redissolved in toluene (20 mL) and 1,5,7-triazobicylo(4.4.0)dec-5-ene (0.6 g, 4.4 mmol) was added and the mixture heated to reflux for 3 hours. The reaction was then diluted with ethylacetate, washed with 1 N HCl, dried with sodium sulfate and the solvent was evaporated in vacuo. The residue was recystallised from hot ethyl acetate to afford the title compound was obtained as a colourless solid (1.7 g, 26%). The mother liquor contained the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[I:22][C:23]1[CH:24]=[C:25]([CH2:29]C#N)[CH:26]=[CH:27][CH:28]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]4=[N:19][O:21][C:29]([C:25]5[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=5)=[C:17]4[CH:18]=3)[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(I)c1
Reactant: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2(c3ccc4noc(-c5cccc(I)c5)c4c3)OCCO2)cc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
2-(4-Chlorophenyl)-2-(4-nitrophenyl)-1,3dioxolane (38.7 g, 127 mMol) was suspended in 190 mL of methanol (MeOH) under an atmosphere of dry N2. To this solution was added (3-iodophenyl)acetonitrile (46.3 g, 190 mMol) and 25.4 g (625 mMol) of sodium hydroxide (NaOH). The solution was then heated to reflux and reacted at this temperature for 2 hours. The reaction mixture was cooled to ambient temperature and the MeOH was removed under vacuum. The resulting red oil was partitioned between dichloromethane (DCM) and 0.1 N aqueous NaOH. The DCM layer was washed successively with 0.1 N aqueous NaOH and then brine. The DCM layer was dried over MgSO4, filtered and concentrated under vacuum to give a dark red oil. The oil was stirred in MeOH and the titled compound precipitated out as a yellow solid. The yellow solid was washed with MeOH and dried under vacuum to give 52.4 g of the titled compound which was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[CH3:21]>>[CH2:20]([N:22]([CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH3:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: CCNCc1ccncc1
Product: CCc1cc(-c2cncc(C(=O)N(CC)Cc3ccncc3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and ethyl-pyridin-4-ylmethyl-amine to afford the title compound. MS: m/e=377 (M+H).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([CH:8](O)[C:9]#CC2C=CC=CC=2)[CH:7]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=[CH:26][C:23]=1[CH:24]=[O:25]>>[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=[CH:26][C:23]=1[CH:24]([OH:25])[C:9]#[C:8][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Reactant: COc1c(C=O)ccc([N+](=O)[O-])c1OC
Product: COc1c(C(O)C#Cc2ccccc2)ccc([N+](=O)[O-])c1OC
Yield: 91 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 2,3-dimethoxy-4-nitro-benzaldehyde was reacted to give the title compound as a colourless oil (1.42 g, 91%). LCMS (Method G): RT=3.66 min, [M−OH+H]+=297.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OC)(OC)OC.[BH4-].[Na+]>CO>[CH2:18]([O:25][C:26](=[O:33])[NH:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[CH:10][CH:11]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)NCc1ccc(CNCCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 64.3 %

Procedure:
The compound (951.6 mg) obtained in Example 103-3 was dissolved in anhydrous methanol (38 ml) and added with (4-amino-butyl)-carbamic acid benzyl ester (898.0 mg) and trimethyl orthoformate (1.33 ml), followed by stirring at room temperature for 15.5 hours. After that, the solution was cooled with ice and added with sodium borohydride (458.5 mg), followed by stirring at room temperature for 1.5 hours. After the reaction, the solvent was distilled off and the residue was then added with water, followed by extraction with chloroform. The extract was washed with saturated saline solution and dried with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (1.1479 g) as a colorless oily substance.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:22](=[CH:23][CH:24]=[C:16]3[O:15][CH2:14]2)[NH:21][C:20]([CH3:25])=[CH:19]4)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH:31]=[C:30]([C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:29][CH2:28]1>CS(C)=O.C(OCC)(=O)C>[NH:35]1[C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33]([C:30]2[CH2:31][CH2:32][N:27]([CH2:12][CH:13]3[O:26][C:17]4=[C:18]5[C:22](=[CH:23][CH:24]=[C:16]4[O:15][CH2:14]3)[NH:21][C:20]([CH3:25])=[CH:19]5)[CH2:28][CH:29]=2)=[CH:34]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(C)cc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc2c3c(ccc2[nH]1)OCC(CN1CC=C(c2c[nH]c4ccccc24)CC1)O3

Procedure:
A solution of 0.55 g (1.5 mmole) of [(2R)-8-methyl-2,3-dihydro-7H-[1,4]dioxino[2,3-e]indol-2-yl]methyl 4-methylbenzenesulfonate and 0.50 g (2.5 mmole) of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole in 6.0 mL of DMSO was heated at 65-7° C. for 4 hours. The mixture was diluted with 300 mL of ethyl acetate, washed with 200 ml portions of saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on silica gel with 1% methanol in chloroform as eluant to give 0.21 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 212-215° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32](=[O:44])([O:37][CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[O:33][CH:34](I)[CH3:35].C(OCC)(=O)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:34]([O:33][C:32]([O:37][CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:44])[CH3:35])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 52.9 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl]acetamido]-3-acetoacetoxymethylceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, to the solution is added dropwise 5.0 g of 1-iodoethyl cyclohexyl carbonate, followed by stirring for further 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate. The organic layers are combined and washed with 150 ml each portion of ice water (three times) and saturated aqueous sodium chloride (three times) and then dried over anhydrous magnesium sulfate. The solution is then distilled off under reduced pressure and isopropyl ether is added to the residue. The resultant white powder is collected by filtration, washed with isopropyl ether and dried to obtain 3.3 g of the title compound.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]N)=[CH:10][C:9]=1[F:16].[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=O>O1CCOCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:21]3[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][C:20]=3[C:10]=2[C:9]=1[F:16]
Reactant: NNc1ccc(Cl)c(F)c1
Reactant: CN1CCCCC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(Cl)c(F)c3c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sulfuric acid is added to a solution of 4-chloro-3-fluorophenyl hydrazine hydrochloride (1 equiv.) in dioxane, and stirred for 5 min. at RT. N-Methyl piperidone (0.76-1.4 equiv.) is added and the mixture is heated at 80° C. for 3 h. After completion, as monitored by TLC, the reaction mixture is concentrated under reduced pressure and basified to pH 10 using 10% aqueous KOH solution, extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated under reduced pressure using rotary evaporator to give a mixture or regioisomeric products. For this Example, silica gel chromatography separates the title compound from the other regioisomer (Compound 6) obtained in Example 11.
Reaction SMILES: [CH:1]1[CH:9]=[CH:8][C:7]2[CH2:10][CH2:11][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:4]=13.[N+:18]([O-])([O-:20])=[O:19].[K+]>S(=O)(=O)(O)O>[N+:18]([C:9]1[CH:1]=[C:2]2[C:6]3=[C:7]([CH2:10][CH2:11][N:5]3[C:4]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:3]2=3)[CH:8]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 79.3 %

Procedure:
Following the procedure of Example 1 Step 2, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.2 g, 14 mmol), potassium nitrate (1.5 g, 14 mmol) and concentrated sulfuric acid (50 mL) provided 2-nitro-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indole (3.0 g). MS (ES) m/z 271.2; HRMS: calcd for C16H18N2O2+H+, 271.14410; found (ESI, [M+H]+), 271.1437.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7](=O)[CH:8]([CH3:10])[CH3:9]>>[O:4]1[CH2:5][CH2:6][N:1]([CH:7]=[C:8]([CH3:10])[CH3:9])[CH2:2][CH2:3]1
Reactant: C1COCCN1
Reactant: CC(C)C=O
Product: CC(C)=CN1CCOCC1

Procedure:
Morpholine (21.78 g, 0.25 mol) and isobutyraldehyde (18.02 g, 0.25 mol) were heated to reflux as a neat mixture, in a 100 ml round bottom flask with a Dean Stark Trap attached. After the mixture was refluxed overnight, the reaction mixture was purified by vacuum distillation. The pure enamine product (15.01 g, 0.10 mol, 42%) had a 1H-NMR (CDCl3): 5.32 (s, 1H), 3.72 (t, 4H), 2.87 (t, 4H), 1.81 (s, 3H), 1.68 (s, 3H) It had LC-MS (ES+): 142 [MH]+ m/e.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]3[CH2:24][CH2:23]3)[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 200 mg), cyclopropylboronic acid (100 mg), potassium phosphate (410 mg) and tetrakis(triphenylphosphine)palladium(0) (65 mg) in dioxane (5 mL) was heated under reflux for 23 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (114 mg) as a colorless viscous oil.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)[CH2:6]CCC[CH2:2]1.[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[S:28])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[S:28])=[CH:22][C:18]=1[C:19]([O:21][CH:1]([CH3:6])[CH3:2])=[O:20]
Reactant: CC(C)OC(=S)Nc1ccc(Cl)c(C(=O)O)c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)OC(=O)c1cc(NC(=S)OC(C)C)ccc1Cl

Procedure:
This is the preparation of compound 32 using 1,3-dicyclohexylcarbodiimide. A mixture of 2-chloro-5-[[(1-methylethoxy)thioxomethyl]amino]benzoic acid (2 g, 0.007 mol), isopropyl alcohol (1.3 g, 0.02 mol), 4-dimethylaminopyridine (0.85 g, 0.007 mol) in 25 ml methylene chloride was stirred in an ice bath and 1,3-dicyclohexylcarbodiimide (1.7 g 0.008 mol) added. The mixture was allowed to come to ambient temperature and stirred overnight. The precipitated solid was filtered off and the filtrate washed with dilute hydrochloric acid and aqueous 5% sodium bicarbonate. After drying over magnesium sulfate, filtering and removing the methylene chloride, the product was crystallized from toluene/petroleum ether. Yield 1.2 g m.p. 89° C. A mixed m.p. with authentic compound 32 also gave m.p. 89°-90° C. The N.M.R. spectrum was identical with that of authentic compound 32.
Reaction SMILES: Cl.[CH2:2]([NH:9][OH:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:11](=O)(O)[O-:12].[K+].C(OCC(F)(F)F)=O>C(OC)(C)(C)C>[CH2:2]([N:9]([OH:10])[CH:11]=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ONCc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: O=COCC(F)(F)F
Agent: [K+]
Solvent: COC(C)(C)C
Product: O=CN(O)Cc1ccccc1
Yield: 96 %

Procedure:
A suspension of N-benzyl-N-hydroxylamine hydrochloride (1.0 g, 6.26 mmol; Aldrich Chemical Company, Milwaukee, Wis.) in methyl tert-butyl ether (10 mL) was vigorously stirred 10% potassium bicarbonate solution and separated into an aqueous fraction and an organic fraction. The organic fraction was treated with the 2,2,2-trifluoroethyl formate reagent (92% (w/w), 4.35 g, 31.3 mmol, 5 equiv), and heated at reflux for 6 hours. The mixture was washed sequentially with water, 15% potassium bicarbonate, and 15% brine, then concentrated to provide 0.90 g (96%) of the desired product as a mixture of rotamers. 1H NMR (300 MHz, CDCl3) δ 8.28, 7.86 (2s, 1H total), 7.35-7.15 (m, 5H total), 7.10, 6.90 (2 br s, 1H total), 4.64, 4.56 (2s, 2H total).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:29])[C:6]([NH:20][C:21]2([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:36]>CCO.CS(C)=O>[C:26]([C:21]1([NH:20][C:6]2[C:5]([F:29])=[CH:4][C:3]([C:1]([NH2:2])=[O:36])=[C:8]([NH:9][C:10]3[CH:11]=[N:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:7]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)(=[O:27])[NH2:28]
Reactant: N#Cc1cc(F)c(NC2(C(N)=O)CCCC2)nc1Nc1cnc2ccccc2c1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1cc(F)c(NC2(C(N)=O)CCCC2)nc1Nc1cnc2ccccc2c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)cyclopentanecarboxamide in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred for 1 h. HOAc (0.5 mL) was added. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (41 mg). MS 409.4 (M+H); UV 224.1, 243.7, 302.6, 324.8 nm; t 0.495 min.