Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1)[CH2:11][CH2:12][CH2:13][C:14](OCC)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[O:15]=[C:14]1[CH2:13][CH2:12][CH2:11][CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[N:9]1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCC(NNC(=O)OC(C)(C)C)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NN1C(=O)CCCC1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
Ethyl 5-(N′-tert-butoxycarbonylhydrazino)-5-(3-trifluoromethylphenyl)pentanoate (323 mg) was dissolved in methanol (7 mL). A 1 N sodium hydroxide solution (5 mL) was added and the mixture was stirred at room temperature for two hours and 30 minutes. 1 N hydrochloric acid (5 mL) and ethyl acetate were added to the reaction solution, and the organic layer was separated and dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (8 mL). 1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (317 mg) and 1-hydroxybenzotriazole (223 mg) were added and the mixture was stirred at room temperature for 13 hours. 1-Ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (317 mg) was added to the reaction solution, and the mixture was further stirred for one hour. Diethyl ether and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (214 mg). The property values of the compound are as follows.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[CH3:12])[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:18]#[C:19]Br>CO>[F:11][C:7]1[C:6]([CH3:12])=[C:5]([CH:2]2[CH2:3][O:4][C:19]([NH2:18])=[N:1]2)[CH:10]=[CH:9][CH:8]=1
Reactant: Cc1c(F)cccc1C(N)CO
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(F)cccc1C1COC(N)=N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.7 %

Procedure:
To a stirred, cooled (0° C.) solution of (RS)-2-amino-2-(3-fluoro-2-methyl-phenyl)-ethanol (1.82 g) and sodium acetate (1.72 g) in methanol (17 ml) was added dropwise a solution of cyanogen bromide (1.18 g) in methanol (8 ml) over 10 min. The mixture was then stirred for 1 h at 0° C., then was allowed to warm to at r.t. and stirring continued for 2 h. The mixture was concentrated in vacuo and the residue was resuspended in water and made basic by addition of 1 M aq sodium hydroxide solution. The mixture was then extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (SiO2; gradient: dichloromethane/methanol) to give (RS)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine (0.85 g, 41%) as a light yellow solid. MS (ISP): 195.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[Br:20]Br>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[C:6](=[O:16])[CH:7]([Br:20])[O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)COc1ccc(Cl)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
26 g (0.091 mol) of 4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 150 ml of carbon tetrachloride. 4.7 ml (0.091 mol) of bromine in 50 ml of carbon tetrachloride were added dropwise at room temperature at such a rate that the bromine was steadily consumed. The mixture was then stirred for 30 minutes at room temperature. After distilling off the solvent in vacuo, 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester was obtained quantitatively and could directly be reacted further.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:12]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N@:23]1([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH:24]1[C:26]([O:28][CH3:29])=[O:27].B(F)(F)F.O(CC)CC>C(Cl)Cl>[CH2:33]([O:32][C:30]([NH:23][C@@H:24]([CH2:25][O:14][CH2:13][C@H:12]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C@@H:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][OH:11])[C:26]([O:28][CH3:29])=[O:27])=[O:31])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1
Reactant: COC(=O)C1CN1C(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@H](COC[C@H](OCc1ccccc1)[C@H](CO)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
To a solution of (2S,3S)-2,3-bis(benzyloxy)butane-1,4-diol (283 mg, 0.935 mmol), prepared as disclosed in Journal of Organic Chemistry 1991, 56(3), 1321-1322, and (S)-1-benzyl 2-methyl aziridine-1,2-dicarboxylate (110 mg, 0.468 mmol) in CH2Cl2 (1.5 mL) at −78° C. was added BF3-OEt2 (10 μL, 0.081 mmol), and the reaction mixture was stirred at −78° C. for 1 h, slowly warmed to 0° C., and then stirred at 0° C. for 3 h. The reaction mixture was directly purified by flash chromatography (SiO2) to afford the title compound as a colorless oil (208 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 7.45-7.20 (m, 16H), 5.70 (d, J=8.5 Hz, 1H), 4.70-4.54 (m, 6H), 4.53-4.46 (m, 1H), 3.93 (dd, J=9.5, 3.2 Hz, 1H), 3.80-3.53 (m, 9H), 2.09-1.96 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 170.72, 156.04, 138.16, 138.08, 136.24, 128.54, 128.49, 128.47, 128.20, 128.13, 127.99, 127.91, 127.89, 127.86, 79.03, 78.10, 73.09, 72.88, 71.40, 71.08, 67.08, 61.40, 54.46, 52.60; ESIMS m/z 538.4 ([M+H]+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([C:16]#[CH:17])[CH:8]=1.C([Sn]([N:31]=[N+:32]=[N-:33])(CCCC)CCCC)CCC>>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([C:16]2[CH:17]=[N:33][NH:32][N:31]=2)[CH:8]=1
Reactant: C#Cc1cc(C2OCCCO2)c2occc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Product: c1cc2cc(-c3cn[nH]n3)cc(C3OCCCO3)c2o1
Yield: 27.3 %

Procedure:
A mixture of 7-[1,3]dioxan-2-yl-5-ethynyl-benzofuran (247 mg) and tributylstannanyl azide (717 mg) was heated at 140° in a sealed vessel for 24 h. Purification by FCC eluting with hexane:ethyl acetate 2:1 gave the title compound as a yellow oil (80 mg).
Reaction SMILES: C(NCCCN[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH3:21])C.C(OC(N(CCCN(C(OC(C)(C)C)=O)[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][CH2:45][CH2:46][N:47](C(OC(C)(C)C)=O)[CH2:48][CH3:49])CC)=O)(C)(C)C.Cl>CO>[C:41]1([CH2:42][NH:43][CH2:44][CH2:45][CH2:46][NH:47][CH2:48][CH2:49][CH2:8][CH2:9][CH2:10][CH2:11][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCN(CCCN(CCCCCCCN(CCCN(CC)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CCNCCCNCCCCCCCNCCCNCC
Agent: Cl
Solvent: CO
Product: c1ccc(CNCCCNCCCCCCCCNCCCNCc2ccccc2)cc1
Reaction time: 8 h

Procedure:
N,N'-Bis[3-(ethylamino)propyl]-1,7-heptanediamine Treat 3,7,15,19-tetra(t-butoxycarbonyl)-3,7,15,19-tetraazaheneicosane (1.68 gm, 0.0024 mol) with HCl in methanol (50 ml, 1.0N) and stir overnight. Filter the mixture and recrystallize the title compound from methanol/water (20:80, v/v) to yield 0.5 gm of the title compound. Rf is 0.39 on silica gel plates eluted with 40% ammonia (concentrated) in methanol; mp 322-23° C. with degradation.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[N:15])[CH2:9]1>C1COCC1>[NH2:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:8]([OH:7])[CH2:9]1
Reactant: N#CCN1CC[C@H](O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(O)C1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 52.6 %

Procedure:
1M Solution of LAH in THF (4.38 mL, 4.38 mmol) was added to a solution of (S)-2-(3-hydroxypyrrolidin-1-yl)acetonitrile (Bio. org. Med. Chem. 15 (2007) 5369-538) (460 mg, 3.65 mmol) in THF (15 mL) at −78° C. and allowed the reaction mixture to stir at 25-35° C. for 10 minutes. The reaction mixture was refluxed for 3 h. The reaction mixture was quenched with saturated aqueous sodium sulphate solution at 0° C., heated to reflux, filtered the solid precipitate; filtrate collected was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 250 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:28][CH3:29].Cl>C(#N)C>[CH2:28]([N:18]1[CH2:19][CH2:20][CH:15]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])[C:2]=2[F:1])[CH2:16][CH2:17]1)[CH3:29]
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.11 g, 0.35 mmol), acetonitrile (4 ml), potassium carbonate (0.063 g, 0.7 mmol) and 1-iodoethane (0.055 g, 0.35 mmol). Yield: 0.068 g (57%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 189-191° C. MS m/z (relative intensity, 70 eV) 339 (M+, 8), 325 (15), 324 (bp), 205 (6), 191 (15).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:6]([C:8]2[N:9]=[C:10]([NH2:15])[N:11]=[C:12]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH:13]=2)[CH:7]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Reactant: Nc1ccc(Cl)cc1
Product: Nc1nc(Nc2ccc(Cl)cc2)cc(-c2cc(Br)ccc2OCCN2CCOCC2)n1
Yield: 83 %

Procedure:
Following the method described in Example 4, 4-[5-bromo-2-(2-morpholin-4-yl-ethoxy)-phenyl)-6-chloro-pyrimidin-2-ylamine and 4-chloro-phenylamine provided the title compound (83% yield). 1H NMR (CDCl3) δ 2.47 (m, 4H, 2CH2), 2.68 (t, 2H, J=5.6 Hz, CH2), 3.67 (m, 4H, 2CH2), 4.09 (t, 2H, J=5.7 Hz, CH2), 4.95 (s, 2H, NH2), 6.72-6.84 (m, 3H, Ar), 7.28-7.33 (m, 2H, Ar), 7.42-7.45 (m, 1H, Ar), 7.99 (s, 1H, Ar).
Reaction SMILES: [NH2:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:30]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:31]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:69]([NH:71][C@H:72]([C:76](O)=[O:77])[C@@H:73]([CH3:75])[OH:74])=[O:70])[CH2:67][OH:68])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][C:52](=[O:54])[NH2:53])=[O:48])[CH2:45][OH:46])=[O:42])[CH2:32][S:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[NH:30]([C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[C@H:31]([C:41]([NH:43][C@H:44]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][C@H:66]([C:69]([NH:71][C@H:72]([C:76]([NH:1][C@H:2]([C:12]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C:27]([OH:29])=[O:28])[CH2:23][CH:24]([CH3:25])[CH3:26])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:77])[C@@H:73]([CH3:75])[OH:74])=[O:70])[CH2:67][OH:68])=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[CH2:51][C:52](=[O:54])[NH2:53])=[O:48])[CH2:45][OH:46])=[O:42])[CH2:32][S:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CSCc1ccccc1)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CSCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
3.90 g (6 mmols) of H-Cys(Bzl)-Val-Leu-OH, 1.15TFA are dissolved in freshly distilled dimethylformamide, treated with 4.48 g (5.5 mmols) of BOC-Cys(Bzl)-Ser-Asn-Leu-Ser-Thr-OH and stirred at room temperature until all is dissolved. The solution is then cooled to 0°C, 1.26 g (11 mmols) of N-hydroxysuccinimide and 0.98 ml of triethylamine in 45 ml of dimethylformamide are added, followed by cooling to -22°C and the addition of 1.13 g (5.5 mmols) of dicyclohexylcarbodimide in 10 ml of dimethylformamide. The batch is stirred for 1 hour at -22°C, then at room temperature for 3 days, filtered to remove precipitated dicyclohexylurea, and evaporated to dryness. The residue is stirred twice with a mixture of 200 ml of ethyl acetate and 20 ml of 5% citric acid solution, then once with a mixture of 200 ml of ethyl acetate and 20 ml of 5% sodium bicabonate solution. The resulting product is filtered off and dried at 40°C in a high vacuum. Melting point: 218°-221°C; [α]D20 -28.5° (c = 2 in dimethylformamide); Rf8 = 0.43.
Reaction SMILES: C(OC1C=CC(NN)=CC=1)(C)(C)C.C1(CC2CCCCN2CCCC(=O)C)CCCCC1.[CH:33]1([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][N:41]2[CH2:46][CH2:47][C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])[CH:55]=3)[NH:50][C:49]=2[CH3:62])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[H-].[Na+].[Na].[C:66](Cl)(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C(O)C.CN(C=O)C>[C:66]([N:50]1[C:51]2[C:56](=[CH:55][C:54]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[CH:53][CH:52]=2)[C:48]([CH2:47][CH2:46][N:41]2[CH2:42][CH2:43][CH2:44][CH2:45][CH:40]2[CH2:39][CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)=[C:49]1[CH3:62])(=[O:73])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: Cc1[nH]c2ccc(OC(C)(C)C)cc2c1CCN1CCCCC1CC1CCCCC1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)CCCN1CCCCC1CC1CCCCC1
Agent: CC(C)(C)Oc1ccc(NN)cc1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1c(CCN2CCCCC2CC2CCCCC2)c2cc(OC(C)(C)C)ccc2n1C(=O)c1ccccc1

Procedure:
1-Benzoyl-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-t-butoxy-2-methylindole is prepared by reaction of 4-t-butoxyphenylhydrazine with 1-(2-cyclohexylmethylpiperidino)pentan-4-one in ethanol and reaction of the resulting 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-t-butoxy-2-methylindole with sodium hydride in DMF followed by reaction of the resulting sodium salt with benzoyl chloride all according to the procedure described above in Example 1.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:16].[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[CH:12][C:13]=2[F:15])[CH2:8][CH2:7][C:6]1=[O:16]
Reactant: CN(C)CCN1C(=O)CCc2cccc(F)c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])cc(F)c21
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
1-(2-(Dimethylamino)ethyl)-8-fluoro-3,4-dihydroquinolin-2(1H)-one (2.86 g, 12.11 mmol) was weighed into a round bottom flask equipped a stir bar. To this was added concentrated sulfuric acid (30 mL) and the flask was cooled to −5° C. in an ice/salt bath. To this stirring solution was added nitric acid (90%, 615.5 μL, 13.2 mmol) and the resulting mixture was stirred for 30 min. The reaction mixture was then quenched with ice and NaOH(aq). The product was extracted with CH2Cl2 (3×). The combined organics were dried, filtered and concentrated then chromatographed on silica using 0-10% (2M NH3 in MeOH) in dichloromethane, giving the desired product. Yield: 1.1 g, 32%, product still contains some impurities). 1H NMR (CDCl3) δ 2.20 (s, 6H), 2.48 (t, 2H, J=7.0 Hz), 2.67 (t, 2H, J=7.0 Hz), 2.98 (t, 2H, J=7.0 Hz), 4.16 (t, 2H, J=7.0 Hz), 7.89 (m, 2H). ESI-MS: 282 (MH+, 100), 237 (50), 192 (27).
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=2[C:11](=[O:20])[N:10]2[CH2:21][CH2:22][CH2:23][C@H:9]2[C@@H:8]1O)=O>C1COCC1.CCOC(C)=O>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:13]2[N:7]=[CH:8][CH:9]3[CH2:23][CH2:22][CH2:21][N:10]3[C:11](=[O:20])[C:12]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(=O)N1CCC[C@H]1[C@H](O)N2C(=O)OCC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1CCCC1C=N2
Reaction time: 2 h
Yield: 89.3 %

Procedure:
10% Cd/Pb couple (2.50 g, 20 mmol Cd) was added to a rapidly stirring solution of 95 (1.71 g, 4.03 mmol) in a mixture of THF (30 mL) and 1N NH4OAc (30 mL). Upon addition, the solution turned cloudy and after 2 hours TLC showed the reaction to be complete. The reaction mixture was diluted with EtOAc (150 mL) and dried over anhydrous MgSO4. The solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent by rotary evaporation under reduced pressure afforded the product as a yellow solid (0.84 g, 3.6 mmol, 90%).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[CH:10]=1
Reactant: [H][H]
Reactant: Cn1ccc(=O)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: Cn1ccc(=O)c(O)c1

Procedure:
A mixture of 3-benzyloxy-1-methyl-1H-pyridin-4-one (14.1 g, 65.5 mmol) and 10% Pd/C (1.20 g) in methanol was subjected to hydrogenation in a Parr apparatus under 50 psi pressure of hydrogen for 70 min. The mixture was filtered through a pad of CELITE™, the filtrate was concentrated to dryness, and the residue was triturated with acetone. The solid was then collected by suction filtration. The title compound was obtained as a light-brown powder (7.13 g, 87% yield) after vacuum oven drying. 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.49 (br. s, 1H), 7.38 (s, 1H), 6.12 (br. s, 1H) and 3.63 (s, 3H); MS-ESI (m/z): 125.7 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[C:14]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[NH4+].[Cl-]>CN(C=O)C>[CH2:22]([O:21][C:14](=[O:20])[CH2:15][CH:16]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13])[CH2:17][CH2:18][CH3:19])[CH3:23]
Reactant: CCC/C=C/C(=O)OCC
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(C(CCC)CC(=O)OCC)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 1-isopropenyl-2-benzimidazolinone (2 g, 11.5 mmol) in DMF (10 mL) were added ethyl trans-2-hexenoate (2 g, 14 mmol) and the benzyltrimethylammonium hydroxide (40% in MeOH) (0.4 mL, 2.3 mmol) at room temperature. The solution was heated to 60 C for 12 hours. The solution was cooled down and sat.NH4Cl sol was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4 and filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 20% EtOAc in Hexane to afford the desirable product 3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (2 g, 55%) as an colorless oil.
Reaction SMILES: [C:1]([C@:8]1(C)[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(OC(C)(C)C)=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O>>[CH3:1][C@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)[C@]1(C)CCCCN1C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: C[C@H]1CCCCN1C1CCNCC1
Yield: 94 %

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2S,31R)-2-Methyl-[1,3′]bipyrrolidinyl dihydrochloride by acid hydrolysis of BOC—(S)-2-Methyl-[1,4]bipiperidinyl which was synthesized by condensation of corresponding tosylate with (S)-(−)-2-methylpiperindine to get 1.37 g (94% yield) of the title product as a clear oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:15]=[CH:14][O:13][C:12]([OH:16])=[C:11]1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:25]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([C:37]([F:40])([F:39])[F:38])[CH:28]=1)[CH3:26]>CS(C)=O>[CH2:3]([N:10]1[CH2:15][CH2:14][O:13][C@@H:12]([O:16][CH2:26][CH2:25][C:27]2[CH:28]=[C:29]([C:37]([F:38])([F:40])[F:39])[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=2)[C@@H:11]1[C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC1=C(c2ccc(F)cc2)N(Cc2ccccc2)C=CO1
Reactant: CC(Br)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc([C@H]2[C@H](OCCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)OCCN2Cc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
3.76 g of sodium hydride and 300 ml of dimethylsulfoxide (DMSO) were charged into a clean and dry 4neck round bottom flask under nitrogen atmosphere, followed by heating to about 70° C. and was stirred for about 2 hours. Resultant reaction solution was cooled to about 30° C. and a solution of 30 g of (±)-N-benzyl-3-(4-fluorophenyl)-1,4-oxazin-2-ol of Formula VIII dissolved in 60 ml of dimethyl sulfoxide, a solution of 50 g of 1-(1-bromoethyl) 3,5-bis-trifluoromethyl-benzene of Formula VII dissolved in 60 ml of dimethylsulfoxide were charged followed by stirring for about 3 hours. After completion of the reaction, the reaction mass was quenched with 450 ml of precooled water and 300 ml of toluene. Organic and aqueous phases were separated and the aqueous phase was extracted with 2×300 ml of toluene. Combined organic layer was washed with 3×300 ml of water followed by drying the organic layer over 100 g of anhydrous sodium sulphate and the organic layer was distilled completely at about 60° C. under vacuum to afford 40 g of the title compound.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH:60]([F:62])[F:61])[C:57](=[O:63])[CH2:56][O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:52][C:53]4[N:58]([CH2:59][CH:60]([F:62])[F:61])[C:57](=[O:63])[CH2:56][O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(F)F)C(=O)CO4)cc2)CCC1
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC(F)F)C(=O)CO4)cc2)CCC1
Yield: 99.3 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(1-(2,2-difluoroethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.037 mmol) was reacted to afford the title compound (16 mg). 1H NMR (500 MHz, CH3OD) 7.71 (s, 1H), 7.42 (d, 2H), 7.38 (d, 2H), 7.31 (m, 3H), 7.22 (m, 2H), 6.21 (tt, 1H), 5.01 (s, 2H), 4.50 (dt, 2H), 2.73-2.78 (m, 2H), 2.54-2.59 (m, 2H), 2.21-2.25 (m, 1H), 1.93-1.99 (m, 1H). LCMS (Method D): RT=0.84 min, M+H+=436.