Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][OH:23])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[O:1]1[C:5]2([CH2:6][CH2:7][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][S:34]([CH3:33])(=[O:36])=[O:35])[O:19][C:18]4=[O:24])=[CH:13][C:12]=3[F:25])[CH2:9][CH2:10]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 62.9 %

Procedure:
(5R)-3-(4-(1,4-Dioxa-8-azaspiro[4,5]dec-8-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (4.024 g, 11.43 mM) was dissolved in dichloromethane (200 ml), and treated with triethylamine (1.45 g, 14.4 mM), then cooled under nitrogen to 0°. Methanesulfonyl chloride (1.32 g, 11.5 mM) was added dropwise, and the mixture stirred 18 hours allowing the temperature to rise to ambient. The mixture was washed with water (3×75 ml), concentrated, and purified by chromatography on a 90 g silica Biotage column, eluting with 1% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (3.09 g).
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH:15]([NH2:18])([CH3:17])[CH3:16].[OH-].[Na+]>ClCCl.C(OCC)C.Cl[Ti](Cl)(Cl)Cl>[CH:15]([N:18]=[C:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)[CH3:2])([CH3:17])[CH3:16]
Reactant: CCOC(=O)c1ccc(C(C)=O)cc1
Reactant: CC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(C)=NC(C)C)cc1
Temperature: 25 °C

Procedure:
Tetrachlorotitanium (16.85 mL of 1 M, 16.85 mmol) in dichloromethane was added to a solution of ethyl 4-acetylbenzoate (5.4 g, 28.09 mmol) and isopropyl amine (6.644 g, 9.657 mL, 112.4 mmol) in diethyl ether (100 mL) at 0° C. and the reaction mixture allowed to warm to ambient temperature over 15 hours. The reaction mixture was poured into a biphasic mixture of aqueous 0.5 M sodium hydroxide and diethyl ether (4:1, 150 mL) and the layers separated. The aqueous phase was extracted with diethyl ether (×2) and the combined organic phases dried (MgSO4/K2CO3 10:1), filtered and concentrated in vacuo to give ethyl 4-(1-(isopropylimino)ethyl)benzoate as a pale yellow oil (6.7 g, quantitative). 1H NMR (400.0 MHz, DMSO-d6) δ 1.15 (d, J=6.3 Hz, 6H), 1.33 (t, J=7.2 Hz, 3H), 2.25 (s, 3H), 3.88 (sept, 1H), 4.33 (q, J=7.1 Hz, 2H) and 7.91-7.97 (m, 4H) ppm; LC/MS m/z 234.2 [M+H]+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=2)[C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:23]1([C:27]([C:29]2[CH:34]=[N:33][C:32](Cl)=[CH:31][N:30]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:23]1([C:27]([C:29]2[N:30]=[CH:31][C:32]([O:22][C:20]3[CH:19]=[C:9]([CH:8]=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:21]=3)[C:10]([NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[O:11])=[N:33][CH:34]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC3CCCC3)c2)n1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(OC3CCCC3)c2)n1
Temperature: 120 °C
Yield: 91 %

Procedure:
3-(Cyclopentyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.67 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (159 mg, 0.80 mmol) and potassium carbonate (184 mg, 1.33 mmol) were dissolved/suspended in acetonitrile (3.5 mL). The reaction mixture was heated for 4 hours at 120° C. in a microwave reactor. The mixture was cooled, filtered and concentrated in vacuo. The crude product was chromatographed on silica, eluting with 0-5% methanol in DCM, to give the required product as a white foam (282 mg).
Reaction SMILES: [CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][CH:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C:19]([S:21][CH3:22])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B1([O-])O[O:28]1.O.O.O.O.[Na+].[OH-].[Na+]>CC(O)=O>[CH:1]1([C:7]2[CH:26]=[CH:25][C:10]([O:11][CH2:12][C@H:13]3[O:24][C:16]4=[N:17][C:18](=[O:23])[C:19]([S:21]([CH3:22])=[O:28])=[CH:20][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [O-]B1OO1
Reactant: CSc1cn2c(nc1=O)OC(COc1ccc(C3CCCCC3)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1cn2c(nc1=O)O[C@H](COc1ccc(C3CCCCC3)cc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.7 %

Procedure:
To a solution of 2-(4-cyclohexyl-phenoxymethyl)-6-methylsulfanyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (0.284 g, 0.763 mmol), prepared in accordance with the procedures set forth in Example 98, in HOAc (6 mL) was added sodium perborate tetrahydrate (0.313 g, 2.04 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then neutralized with NaOH (2N) to PH˜9 after which it was extracted with EtOAc three times. The organic phase was washed with brine and dried (Na2SO4). Silica gel chromatography (0-8% EtOH/CH2Cl2) provided 0.03 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfonyl-2,3-dihydro-oxazolo[3,2a]pyrimidin-7-one, 0.042 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfinyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (Diastereomer 1) and 0.011 g of (S)-2-(4-cyclohexyl-phenoxymethyl)-6-methanesulfinyl-2,3-dihydro-oxazolo[3,2-a]pyrimidin-7-one (Diastereomer 2).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH:23]=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27]CC)=O)=[CH:18][CH:17]=1)#[N:15]>CCCCCC>[CH2:33]([O:32][C:30]([C:24]1[CH:23]=[N:22][C:19]2[C:18]([C:25]=1[OH:27])=[CH:17][C:16]([C:14]#[N:15])=[CH:21][CH:20]=2)=[O:31])[CH3:34]
Reactant: CCOC(=O)C(=CNc1ccc(C#N)cc1)C(=O)OCC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2ccc(C#N)cc2c1O
Yield: 94.8 %

Procedure:
To 100 mL vigorously refluxing diphenyl ether (Aldrich) was added in open air, in portions over the course of one hour, 10.5 g (36.5 mmol) diethyl 2-(4-cyanophenylamino)methylenemalonate. The solution was refluxed for one additional hour. After allowing the solution to cool to below 100° C., it was poured into 200 mL hexane. The resulting precipitate was filtered and washed well with hexane to yield 8.39 g (34.6 mmol, 94%) of the title compound as a light brown solid: MH+: 243, mp>265° C.
Reaction SMILES: C([Li])CCC.[C:6]1([S:12]([OH:15])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[P:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.FC(F)(F)C(O)=O>O1CCCC1>[CH:24]1([P:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:12]([OH:15])(=[O:14])=[O:13])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Reactant: O=S(=O)(O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(O)c1ccccc1P(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
n-Butyllithium (manufactured by Kanto Chemical Co., Inc., 1.65 M hexane solution, 5.1 ml, 8.4 mmol) was added to a tetrahydrofuran (THF) solution (20 ml) of benzenesulfonic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.66 g, 4.2 mmol) at 0° C. under argon atmosphere and the mixture was stirred for 2.5 hours at room temperature. After cooling the reaction container to −78° C., chlorodicyclohexylphosphine (manufactured by Sigma-Aldrich, 0.89 mg, 3.8 mmol) was added thereto at −78° C. and stirred for 24 hours at room temperature. After ceasing the reaction with trifluoroacetic acid (manufactured by Tokyo Chemical Industry Co., Ltd., 0.50 M THF solution, 8.4 ml, 4.2 mmol), the precipitate formed was collected by filtration and dried under reduced pressure to obtain 2-(dicyclohexylphosphino)benzenesulfonic acid (compound 1a). The yield was 0.66 g (85%).
Reaction SMILES: [Br:1][C:2]1[C:6]([CH:7]=O)=[C:5](Br)[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:20][SH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:6]2[CH:7]=[C:20]([C:19]([O:23][CH2:24][CH3:25])=[O:22])[S:21][C:5]=2[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1
Reactant: COc1ccc(Cn2nc(Br)c(C=O)c2Br)cc1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc2c(Br)nn(Cc3ccc(OC)cc3)c2s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
3,5-Dibromo-1-(4-methoxybenzyl)-1H-pyrazole-4-carbaldehyde (1.3301 g, 3.56 mmol), ethyl thioglycolate (0.419 ml, 3.73 mmol), and sodium carbonate (0.761 g, 7.18 mmol) were dissolved in ethanol (35 ml) at 25° C. under Ar in a sealed heavy-walled reaction vessel. The reaction mixture was warmed to 80° C. and allowed to stir for 4 h. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (40 mL), and the mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with saturated aqueous sodium chloride (1×20 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash Rf purification system eluting with ethyl acetate-hexanes (0-25%). The title compound (1.2063 g, 3.05 mmol, 86% yield) was recovered as a white solid. LC-MS [M+1]=395.2.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[N+:23]([O-])([OH:25])=[O:24].O.[OH-].[Na+]>C(O)(=O)C>[N+:23]([C:5]1[CH:4]=[CH:3][C:2]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)=[C:1]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)([O-:25])=[O:24]
Reactant: c1ccc(-c2ccccc2OCCCN2CCOCC2)cc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(OCCCN2CCOCC2)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-[3-(Biphenyl-2-yloxy)-propyl]-morpholine (t, 500 mg, 1.46 mmol) was dissolved in 3 mL acetic acid and the reaction mixture was cooled in an ice bath. Concentrated nitric acid (3 mL) was added dropwise and the mixture was stirred for 15 minutes at 0° C., then at room temperature for one hour. The reaction was subsequently poured into 100 mL water and the pH of the reaction mixture was raised to >7 with 2N NaOH. The aqueous solution was extracted with ethyl acetate and dried. The solvent was then removed to afford 500 mg 4-[3-(5-nitro-biphenyl-2-yloxy)-propyl]-morpholine (u) which was used without further purification: m/e: 342.15, MS (ES+): 343.1; 1H NMR (500 MHz, CDCl3): 8.2-6.8 (m, 9H), 4.1(m, 2H), 3.7 (m, 4H), 2.5 (m, 6H) and 1.8 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f46) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][C:19]([CH2:20][CH3:21])=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:8]2=[O:17]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=C(Cc1cccc(F)c1)c1cc(Br)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(Br)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 38.6 %

Procedure:
Intermediate 33 (3.0 g, 9.70 mmoles) was taken in a RB flask and to this triethylamine (30 ml) and propionic anhydride (3.94 g, 30.37 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as off-white solid (1.30 g, 39% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 6 8.10(d, J=2.3 Hz, 1H), 7.99(dd, J=8.9,2.4 Hz, 1H), 7.69(d, J=8.9 Hz, 1H), 7.51(q, J=7.9 Hz, 1H), 7.25(dt, J=10.8,2.4 Hz, 1H), 7.15(t, J=12.2 Hz, 2H), 2.57(q, J=7.6 Hz, 2H), 1.20(t, J=7.5 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([CH3:11])[CH:3]=1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][C:4]=1[CH3:11])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1C
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CC(=O)c1ccc(OC(=O)N(C)c2ccccc2)cc1C

Procedure:
The title product was prepared from 4′-hydroxy-2′-methylacetophenone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (76%, white crystals). HPLC-MS: m/z=284.2 (M+1); Rt: 3.95 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:10](#[N:13])[CH:11]=[CH2:12].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[N:1]1([CH2:12][CH2:11][C:10]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C=CC#N
Reactant: c1ccc2[nH]cnc2c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: N#CCCn1cnc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 15.8 grams of 1H-benzimidazole, 8 grams of acrylonitrile and 0.2 ml of benzyltrimethylammonium hydroxide (40% solution in methanol) in 200 ml of dioxane was stirred at room temperature for 24 hours. The solvent was evaporated from the resulting yellow solution under reduced pressure and the residual yellow solid was triturated first with ether and then with water to give 1H-benzimidazole-1-propionitrile melting at about 108°-110° C.
Reaction SMILES: [C:1]1([C:7]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([C:16]([OH:18])=O)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1>ClCCl>[CH:25]1([NH:28][C:16]([C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:15][C:14]=3[NH:13][N:12]=2)=[O:18])[CH2:27][CH2:26]1
Reactant: O=C(O)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C(NC1CC1)c1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 20 °C
Reaction time: 18 h

Procedure:
Starting with a mixture of 1.23 g of 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxylic acid, 0.26 cm3 of cyclopropylamine, 0.86 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 60 mg of hydroxybenzotriazole in solution in 30 cm3 of dichloromethane, and after stirring for 18 hours at a temperature in the region of 20° C., washing with twice 30 cm3 of distilled water and purifying the crude product obtained by flash chromatography on silica gel (30–70 μm), eluting with a cyclohexane/ethyl acetate (60/40) mixture, 0.58 g of (N-cyclopropyl)-6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide is obtained in the form of a yellow solid, the characteristics of which are as follows:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(#N)C.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:25]([CH:27]2[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:34][C:33]3[C:28]2=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:26])[CH2:20][CH2:19]1>O>[CH2:8]([N:18]1[CH2:19][CH2:20][CH:21]([NH:24][C:25]([CH:27]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=3[O:34][C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])[CH2:22][CH2:23]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCI
Reactant: O=C(NC1CCNCC1)C1c2ccccc2Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCN1CCC(NC(=O)C2c3ccccc3Oc3ccccc32)CC1
Temperature: 25 °C

Procedure:
60 mg of potassium carbonate and 25 ml of iodohexane were successively added to 5.0 ml of acetonitrile suspension having 50 mg of N-(piperidin-4-yl)xanthene-9-carboxamide hydrochloride, followed by reflux under heating for 4 hours. After cooled to room temperature, water was added to the reaction solution, followed by extraction with ethyl acetate and drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was purified by preparative thin layer chromatography (Kieselgel™60F254, Art5744 produced by Merck Co.: chloroform/methanol=10/1), and 35 mg of the title compound as a white solid was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][C:19](=S)[N:18]([CH:23]([C:25](OCC)=[O:26])[CH3:24])[C:17]=3[CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:32][NH2:33]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:30]=[C:17]3[C:16](=[CH:15][CH:14]=2)[O:21][CH2:20][C:19]2[N:18]3[CH:23]([CH3:24])[C:25](=[O:26])[NH:32][N:33]=2)[CH2:11]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc21
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc(OC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 49.4 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-azetidine-1-carboxylic acid tert-butyl ester (0.530 g, 1.22 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.486 g, 9.72 mmol) and the mixture was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature, concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with 20% EtOAc in petroleum ether) to give 3-(4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-azetidine-1-carboxylic acid tert-butyl ester (0.234 g, 52%) as a white solid. LC/MS (Table 1, Method 3) Rt=1.332 min.; MS m/z: 389 [M+H]+.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.Cl.Cl.[N:52]1([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1.C(N(CC)CC)C>CN(C)C=O>[N:52]1([CH:56]2[CH2:61][CH2:60][N:59]([C:8]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=6)=[O:47])[CH2:37][CH2:36]5)=[O:34])=[CH:28][C:27]=4[F:48])[CH:22]=[CH:21][N:20]=3)=[O:7])[CH2:58][CH2:57]2)[CH2:55][CH2:54][CH2:53]1
Reactant: C1CN(C2CCNCC2)C1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC(N2CCC2)CC1
Reaction time: 24 h
Yield: 59 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(azetidin-1-yl)piperidine dihydrochloride (85 mg) and triethylamine (0.112 ml) at room temperature, followed by stirring for 24 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether:heptane=1:3 to the resultant residue. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (34.6 mg, 59%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[OH:13][CH2:12][CH2:14][N:15]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCO
Product: O=C1c2ccccc2C(=O)N1CCO

Procedure:
Phthalic anhydride (100 g, 0.67M) was condensed with monoethanol amine (41.2 g, 0.91 M) at 160-178° C. for 4 hours. The reaction mass was quenched in hot water at 95° C., cooled and filtered and washed with water twice and dried at 90-95° C. for 12 hours. Yield 118 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]=[C:15]3[N:10]([CH:11]=[C:12]([CH3:17])[CH:13]=[CH:14]3)[C:9]=2[CH2:18][C:19](N(C)C)=[O:20])=[CH:6][CH:7]=1.[OH-:24].[Na+]>Cl>[CH3:17][C:12]1[CH:13]=[CH:14][C:15]2[N:10]([C:9]([CH2:18][C:19]([OH:20])=[O:24])=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:16]=2)[CH:11]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)N(C)C)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a magnetically stirred solution of zolpidem (8.0 g, 26.0 mmol) at 0° C. under Ar atmosphere was added 6N HCl (80 mL). The reaction mixture was refluxed for 18 h. The mixture was cooled to 0° C., and 20% NaOH was added slowly to a pH of 6.5. The white solids were filtered in vacuo to provide the title compound (6.9 g, 94%) as a white solid. 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.35 (s, 3H), 3.94 (s, 2H), 7.10 (d, J=9.1 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.48 (d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 2H), 8.18 (s, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 18.4, 21.4, 30.8, 114.8, 116.6, 121.6, 122.9, 127.9, 128.2, 129.8, 132.4, 137.3, 143.0, 143.5, 171.8.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([CH2:15][NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[I:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=O)(C)(C)C>C(Cl)Cl>[I:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:17]([NH:16][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)C(Cc1ccccc1I)NCC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1I)NC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (25 ml) was added to ethyl 2-(tert-butoxycarbonylmethylamino)-3-(2-iodophenyl)propionate (6.4 g, 15 mmol) in CH2Cl2 (35 ml). The mixture was stirred at room temperature for 2 h. The reaction solution was concentrated on a rotary evaporator, the residue was taken up in ethyl acetate, washed (NaHCO3 sat.), dried and concentrated The residue obtained in this manner (3.9 g, 79%) was reacted further as a crude product.