Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[N:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:12]([O-])([O-])=O.[Cs+].[Cs+].CI.ClC1C=CC2C(=C(I)N(C)N=2)N=1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([I:11])=[N:9][N:10]([CH3:12])[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2[nH]nc(I)c2n1
Reactant: O=C([O-])[O-]
Agent: Cn1nc2ccc(Cl)nc2c1I
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(I)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-chloro-3-iodo-1H-pyrazolo[4,3-b]pyridine (102 mg, 0.365 mmol) in DMF (3 mL), was added Cs2CO3 (237 mg, 0.73 mmol), MeI (35 μL, 0.55 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and water, the organic phase was dried over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product containing the isomer 5-chloro-3-iodo-2-methyl-2H-pyrazolo[4,3-b]pyridine (in about 1.5:1 ratio). LCMS-ESI+: calc'd for C7H5Cl1N3: 293.9 (M+H+); Found: 294.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1.[CH:25](I)([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:25]([O:1][C:2]1[CH:24]=[N:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[CH:3]=1)([CH3:27])[CH3:26]
Reactant: CC(C)I
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(O)cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: 80 °C
Yield: 45.4 %

Procedure:
To a solution of 6-hydroxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2.1 g, 6.3 mmol) in DMF (20 mL) was added isopropyl iodide (2.14 g, 12.6 mmol) followed by K2CO3 (1.74 g, 12.6 mmol). The reaction was heated at 80° C. for 2 h, cooled to RT, diluted with water (100 mL) then extracted with EA (3×100 mL). The combined organic layers were washed with water (100 mL) then brine (100 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography to give 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.08 g, 46% yield over 3 steps) as a solid. 1H NMR (CDCl3) δ: 8.34 (d, J=3.1 Hz, 1H), 7.90 (d, J=3.1 Hz, 1H), 4.69-4.51 (m, 2H), 4.10-4.30 (m, 2H), 3.90-3.78 (m, 2H), 3.69 (s, 3H), 3.51), 3.40-3.70 (m, 2H), 2.01 (dd, J=13.4, 6.7 Hz, 2H), 1.86-1.45 (m, 6H), 1.38 (d, J=6.1 Hz, 6H), 1.26 (t, J=7.1 Hz, 2H). LCMS: [MH+-THP] 294 and TR=1.668 min.
Reaction SMILES: [CH2:1]([N+:5]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[N:19]([CH:29]1[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[C:20](=[O:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[K].C([N+](CCCC)(CCCC)CCCC)CCC.O=C1C(N(Cl)C([O:64][CH2:65][C:66]2C=CC=[CH:68][CH:67]=2)=O)CN1S([O-])(=O)=O>>[CH2:14]([N+:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH3:17].[CH2:65]([O:64][C:29]1([NH:19][C:20](=[O:28])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:32][N:31]([S:33]([OH:36])(=[O:35])=[O:34])[C:30]1=[O:37])[CH2:66][CH2:67][CH3:68]
Reactant: O=C(Cc1ccccc1)N(Cl)C1CN(S(=O)(=O)O)C1=O
Reactant: O=C(OCc1ccccc1)N(Cl)C1CN(S(=O)(=O)[O-])C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K]
Product: CCCCOC1(NC(=O)Cc2ccccc2)CN(S(=O)(=O)O)C1=O

Procedure:
Following the procedure of Example 80, but substituting N-chloro-N-(2-oxo-1-sulfo-3-azetidinyl)-2-phenylacetamide, tetrabutylammonium salt (see Example 47A for preparation of the corresponding potassium salt) for 2-oxo-3-[N-chloro-N-[(phenylmethoxy)carbonyl]amino]-1-azetidinesulfonic acid, tetrabutylammonium salt, yields the title compound as an oil: nmr (CDCl3) 3.62 (s, 2H, C6H5CH2), 4.03 (ABq, 2H, ν=7 cps, C-4 CH2), 6.98 (s, 1H, NH) and 7.30 ppm (S, 5H, C6H5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.[CH3:24][CH:25]([CH3:29])[C:26](=[S:28])[NH2:27]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:28][C:26]([CH:25]([CH3:29])[CH3:24])=[N:27][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Reactant: CC(C)C(N)=S
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 45.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14 mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by a procedure analogous to Intermediate 1, 5.74 g of the title compound was obtained. MS (ESI): 415 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]=[CH:7][CH:8]=1.S(=O)(=O)(O)O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:10][S:9][C:5]=2[CH:4]=1
Reactant: CCCCCC(=O)CSc1cccc(OC)c1
Agent: O=S(=O)(O)O
Product: CCCCCc1csc2cc(OC)ccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.5 %

Procedure:
To a stirred solution of 3-methoxythiophenolate (45 g) in water (100 mL) at 15° C. was added dropwise over 20 minutes 1-bromo-2-heptanone (54.4 g). The reaction was stirred for 1 hour at room temperature then was extracted with diethyl ether (2×250 mL) and the ether extracts were washed in turn with water (2×100 mL) and 1N hydrochloric acid (2×100 mL). The dried (MgSO4) organic layers were combined and evaporated to yield crude 1-(3-methoxyphenylthio)-2-heptanone (71 g). The crude 1-(3-methoxyphenylthio)-2-heptanone (65 g) was added over 30 minutes with stirring to sulfuric acid at -10° C. After 30 minutes at -5° C., the reaction mixture was diluted carefully with ice (200 g) and the resulting solid was filtered off, washed with water and dried. Crystallization of the crude product from hexane gave 18.4 g of 6-methoxy-3-pentylbenzo[b]thiophene, mp 43°-45° C. A small sample was recrystallized from hexane to provide the analytical specimen, mp 45°-47° C. Anal. Calcd for C14H18OS: C, 71.75; H, 7.74; S, 13.68 Found: C, 71.81; H, 7.60; S, 13.37
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>N1C=CC=CC=1>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCSCC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 142 %

Procedure:
To a solution of 4.1 g (0.015 mole) of tetrahydro-4H-thiopyran-4-ol in 40 mL of pyridine, cooled in an ice bath, was added 2.90 g (0.15 mole) of 4-methylphenylsulfonyl chloride, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was poured into a mixture of ice and water, and the whole extracted with diethyl ether. The organic phase was washed with water then with a 10% aqueous solution of sodium hydroxide, dried, and concentrated to give 5.8 g of product as an oil.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:34])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH3:33])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.ClCCl.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[CH3:33][C@@H:30]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:34])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1CN=C(c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)CO)c3)[nH]2)O1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
(5S)-2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-5-methyl-4,5-dihydro-1,3-oxazole (280 mg, 0.58 mmol) synthesized in Example (31b) was dissolved in dichloromethane (10 mL) and cooled to −78° C., and a 1.0 mol/l boron tribromide dichloromethane solution (0.61 mL, 0.61 mmol) was added under nitrogen atmosphere. After the temperature was raised naturally and the solution was stirred at room temperature for 30 minutes, a saturated aqueous sodium hydrogencarbonate solution was added to neutralize the reaction solution, followed by extraction with dichloromethane (60 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate) to afford the desired product (222 mg, yield 82%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([CH:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[CH3:10]>O>[CH2:9]([CH:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1)[CH3:10]
Reactant: CCC1CCCN1
Reactant: Nc1cccc(F)n1
Solvent: O
Product: CCC1CCCN1c1cccc(N)n1
Temperature: 205 °C
Yield: 66.8 %

Procedure:
A mixture of 6-fluoropyridin-2-amine (0.5 g, 4.46 mmol) and 2-ethylpyrrolidine (0.664 g, 6.7 mmol) in water (0.3 mL) was heated to 205° C. for 0.5 h in a microwave oven then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, ethyl acetate:petroleum ether=1:30) to afford 6-(2-ethylpyrrolidin-1-yl)pyridin-2-amine (0.57 g, 67%) as a yellow oil. LC-MS: [M+1]+=192, tR=1.100 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[C:6]([F:23])[CH:5]=1)[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([F:23])[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(N2CCNCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-Ethoxy-2-fluoro-phenyl)-piperazine-1-carboxylic acid, tert.-butyl ester (12 mmol) in CH2Cl2 (150 ml), TFA (29 ml) is added at 0° C. The reaction mixture is stirred at room temperature for 1 h. The solvent is removed by evaporation and dried to give crude product, 1-(4-ethoxy-2-fluoro-phenyl)-piperazine. To the crude product in DMF (50 ml), potassium carbonate (30 mmol) is successively added at 0° C. The mixture is stirred at 0° C. for 15 min. 6-Bromomethyl-7-(2,2-dimethyl-propyl)-7.H.-pyrrolo[2,3-.d.]pyrimidine-2-carbonitrile (12 mmol) is added to the mixture at 0° C. The reaction mixture is stirred at room temperature for 3 h and quenched with saturated ammonium chloride. The mixture is extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=2:1 (v/v).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:19]([CH3:21])[CH3:20])[C:15]=1[N:16]([CH3:18])[CH3:17])[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:26]([CH2:33][CH2:34][C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[NH:26]([CH2:33][CH:34]([CH2:6][C:5]1[CH:13]=[C:14]([N:19]([CH3:20])[CH3:21])[C:15]([N:16]([CH3:18])[CH3:17])=[C:3]([N:2]([CH3:1])[CH3:22])[CH:4]=1)[C:35]#[N:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N(C)C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)CNc2ccccc2)cc(N(C)C)c1N(C)C

Procedure:
A mixture of 8.96 g. of 3,4,5-tris(dimethylamino)-α-[(methylsulfonyl)methyl]benzyl alcohol, 2.56 g. of sodium methylate and 6.6 g. of β-anilinopropionitrile in 70 ml. of dimethylsulfoxide was stirred at room temperature under nitrogen for 50 minutes. The mixture was poured into 500 ml. of ice water, the separated oil extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethanol, there was obtained α-(anilinomethyl)-3,4,5-tris(dimethylamino)hydrocinnamonitrile having a melting point of 179°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15])[CH3:11].C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]([CH3:16])([C:13]([O:12][CH2:10][CH3:11])=[O:18])[CH3:15])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C(C)(C)Br
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Nc1ccc(Cl)c(Cl)c1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 61.9 %

Procedure:
A 15-mL sealed tube equipped with a magnetic stirring bar was charged with 3,4-dichloroaniline (1.63 g, 10.0 mmol) and treated with ethyl-2-bromoisobutyrate (1.6 mL, 11 mmol), diisopropylethylamine (1.9 mL, 11.0 mmol), and NaT (824 mg, 0.600 mmol). The vessel was sealed tightly, heated to 110° C. and maintained at that temperature for 48 h. After allowing the reaction mixture to cool to room temperature, the reaction was diluted with THF and the solids were filtered off. The filtrate was collected and concentrated under vacuum. The crude oil was purified by silica gel chromatography (35 g Redisep column, silica 40 um, 35 mL/min, A: CH2Cl2, B: MeOH, B: 0% for 20 min, 5% for 5 min, 10% for 5 min; detection at 214 nm) to give 1.71 g (55%) of ethyl N-(3,4-dichlorophenyl)-2-methylalaninate as a brown oil. MS (ES) m/z 276 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:20]1([C:26]2[N:30]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([NH:11][C:12]([N:34]3[CH2:35][CH2:36][N:31]([C:29]4[S:28][N:27]=[C:26]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[N:30]=4)[CH2:32][CH2:33]3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1nc2ccc(NC(=O)OCC(Cl)(Cl)Cl)cc2o1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2ccc(NC(=O)N3CCN(c4nc(-c5ccccc5)ns4)CC3)cc2o1

Procedure:
A solution of 2,2,2-trichloroethyl (2-methyl-1,3-benzoxazol-6-yl)carbamate (200 mg, 0.618 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (152 mg, 0.618 mmol), diisopropylethylamine (0.215 ml, 1.24 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 75.6 mg (29.1%) of the desired product as a solid.
Reaction SMILES: [C:1]1(=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][CH2:2]1.C1(=O)CCCCCC1>>[CH:1]1[CH2:2][CH:3]=[C:4]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCC2=C1CCCCC2
Agent: O=C1CCCCCC1
Product: C1=C2CCCCCC2=CC1
Yield: 98 %

Procedure:
14 grams of 2,4,5,6,7,8-hexahydroazulene, (compound Ia with n=5) are obtained with a yield of 98% from the product (VI) and of 40% from the starting cycloheptanone, which has the following NMR spectrum: 1H-NMR (CDCl3, δ ppm rel. TMS): 5.96 (s, br, 2H); 2.84 (t, 2H, J=2Hz); 2.47 (m, 4H); 1.61 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21]Cl)([CH3:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[CH:17]([N:20]([CH2:23][CH2:24][C:25]#[N:26])[S:21][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:19])[CH3:18]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: CC(C)N(CCC#N)SCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(CCC#N)SN(C)C(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 0 °C

Procedure:
2.2 g (0.01 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate and 1.8 g (0.01 mole) of N-isopropyl-N-cyanoethylaminosulfenyl chloride were dissolved in 30 ml of methylene chloride, and the solution was cooled to 0° C. 1.2 g (0.012 mole) of triethylamine was dropwise added thereto with stirring, and allowed to react for 2 hours at the same temperature. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities.
Reaction SMILES: C(O)(=O)C.C(#N)C.C([O-])(=O)C.[Na+].[C:13]([C:21]1[NH:22][CH:23]=[CH:24][C:25]=1[CH2:26][CH2:27][CH:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C.[Mn+3].C([O-])(=O)C.[Mn+3].C([O-])(=O)C.C([O-])(=O)C>[C:13]([C:21]1[N:22]2[C:27](=[CH:26][CH:25]=1)[C:28]([C:34]([O:36][CH2:37][CH3:38])=[O:35])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]2)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Agent: [Mn+3]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CCOCC
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21

Procedure:
To a warm, preferably 60°-80° C., mixture of a high valence metal ion, preferably a manganese(III) salt, and more preferably manganese(III) acetate, in an alkanoic acid, preferably acetic acid, or a polar aprotic solvent such as acetonitrile, is added a weak base, preferably sodium acetate, and a compound of formula IV, preferably 2-benzoyl-[3,3-di(ethoxycarbonyl)propyl]pyrrole. The reaction is stirred, preferably at 50°-70° C. until the reaction is complete. The reaction mixture is diluted with a polar solvent, such as diethyl ether, and filtered. The resulting solution is washed with water and aqueous base, preferably 10% sodium hydroxide, dried, and concentrated under reduced pressure. The product, a compound of formula I, preferably diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate, may be isolated by conventional means.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[C:8]2[N:9](C=C(C)[N:15]=2)[CH:10]=[CH:11][CH:12]=1.ClC1C=CC(COC2C3N(C=C(C)N=3)C=CC=2)=CC=1>>[NH2:15][C:8]1[C:7]([O:6][CH2:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Cc1cn2cccc(OCc3ccc(Cl)c(Cl)c3)c2n1
Agent: Cc1cn2cccc(OCc3ccc(Cl)cc3)c2n1
Product: Nc1ncccc1OCc1ccc(Cl)c(Cl)c1

Procedure:
8-(3,4-dichlorobenzyloxy)-2-methylimidazo[1,2-a]-pyridine and 8-(4-chlorobenzyloxy)-2-methylimidazo[1,2-a]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][N:17]([CH3:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([N:17]([CH3:27])[CH3:16])=[CH:19][CH:20]=3)=[O:26])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CN(C)c1ccc(N=C=O)cc1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: CN(C)c1ccc(NC(=O)NC2CCCc3c2[nH]c2ccc(Br)cc32)cc1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-[4-(dimethylamino)phenyl]urea was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 4-dimethylamino phenyl isocyanate in a similar manner as described above to give a tan solid (40% yield). 1H-NMR (DMSO-d6): δ 10.99 (s, 1H), 7.98 (s, 1H), 7.60 (d, 1H), 7.33-7.23 (m, 3H), 7.17 (dd, 1H), 6.71 (d, 2H), 6.44 (d, 1H), 5.00 (m, 1H), 2.84 (s, 6H), 2.67 (m, 2H), 2.04 (m, 1H), 1.94-1.74 (m, 3H); MS m/z 427 (M−1).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:16])([F:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.Br[CH:18]([CH3:22])[CH:19](Br)[CH3:20]>C1COCC1>[F:3][C:4]([F:15])([F:16])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:13]#[N:14])[CH2:20][CH2:19][CH2:18][CH2:22]2)=[CH:10][CH:11]=1
Reactant: N#CCc1ccc(OC(F)(F)F)cc1
Reactant: CC(Br)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC1(c2ccc(OC(F)(F)F)cc2)CCCC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 70.9 %

Procedure:
To sodium hydride (600 mg, 15 mmol) in anhydrous THF (5 mL) at 0° C., was added dropwise 2-(4-(trifluoromethoxy)phenyl)acetonitrile (1006 mg, 5 mmol) and then the reaction mixture was stirred for 5 mins, followed by dibromobutane (1075 mg, 5 mmol) dropwise. The reaction mixture was heated to reflux for 16 h, then cooled to 0° C., quenched with MeOH (1 mL), diluted with EtOAC (50 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to give 1-(4-(trifluoromethoxy)phenyl)cyclopentanecarbonitrile as a yellow oil (905 mg, 71%) (1H NMR (400 MHz, CDCl3) 7.50 (dd, J=2.1, 6.7 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.53-2.49 (m, 2H), 2.10-1.97 (m, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4C=[CH:20][CH:19]=[C:18](C)[C:17]=4OCOC)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.Cl.[O:30]1[CH2:35][CH2:34]OCC1.C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:20])=[C:35]([OH:30])[CH:34]=4)[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: C1COCCO1
Reactant: COCOc1c(C)cccc1CN1CCN(c2nc3ccc(Cl)cc3s2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)cc1O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 6-chloro-2-[4-(2-methoxymethoxy-3-methylbenzyl)piperazine-1-yl]benzothiazole (1.70 g; 4.067 mmol) and 4N hydrochloric acid/dioxane solution (8.5 ml) was stirred at 60° C. for 2 hours. After cooling, the reaction solution was condensed under reduced pressure. To the residue was added saturated aqueous sodium hydrogencarbonate to be alkaline and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and evaporated under reduced pressure. The precipitate was washed with diisopropyl ether to give 5-{[4-(6-chlorobenzothiazole-2-yl)piperazine-1-yl]methyl}-2-methylphenol as colorless crystal (1.33 g; 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[Cl:31][C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[N:37]2>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:45]3[CH2:46][CH2:47][N:42]([C:36]4[CH:35]=[CH:34][C:33]5[C:38](=[CH:39][CH:40]=[CH:41][C:32]=5[Cl:31])[N:37]=4)[CH2:43][CH2:44]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Reactant: Clc1cccc2nc(N3CCNCC3)ccc12
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5c(Cl)cccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 5-chloro-2-piperazin-1-yl-quinoline.