Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:27]=[C:26]3[C:21]([C:22]([NH2:28])=[N:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[C:13](=[O:29])[CH:12]1[CH2:30][O:31][CH3:32])=[O:10])C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:64][C:65]1[S:69][C:68]([O:70][CH2:71]C(O)=O)=[CH:67][CH:66]=1>CN(C=O)C>[NH2:28][C:22]1[C:21]2[C:26](=[CH:27][C:18]([CH2:17][N:14]3[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH2:71][O:70][C:68]4[S:69][C:65]([Cl:64])=[CH:66][CH:67]=4)[C@@H:12]([CH2:30][O:31][CH3:32])[C:13]3=[O:29])=[CH:19][CH:20]=2)[N:25]=[CH:24][N:23]=1
Reactant: COCC1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)OCc1ccccc1
Reactant: O=C(O)COc1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C(=O)N(Cc2ccc3c(N)ncnc3c2)CCN1C(=O)COc1ccc(Cl)s1
Reaction time: 16 h

Procedure:
To a solution of 4-(4-amino-quinazoline-7-ylmethyl)-2-methoxymethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, EXAMPLE 75, (0.69 g, 2.29 mmol) in 9 mL of DMF is added N,N-diisopropylethyl amine (0.89 g, 6.87 mmol), TBTU (0.76 g, 2.36 mmol), and 5-chloro-2-thienyloxyacetic acid, EXAMPLE 24, (0.40 g, 2.08 mmol). The solution is stirred for 16 hours. After this time the solution is concentrated. The crude material is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 80% CH3CN/H2O (0.1% TFA). The product fractions are lyophilized to give product as a white solid (1.0 g, 1.57 mmol). 1H NMR (d6-DMSO, 300 MHz) δ9.70 (bs, 2H), 8.78 (s, 1H), 8.29 (m, 1H), 7.55 (m, 2H), 6.72 (m, 1H), 6.22 (m, 1H), 4.80 (m, 4H), 3.78 (m, 4H), 3.59 (m, 3H), 3.31 and 3.2 (s, 3H rotational isomers).MS (ion spray) M+H=476. Elemental Analysis: C21H22ClN5O4S.1.4CF3CO2H cal: C=45.03%, H=3.68%, N=11.04%; found C=44.98%, H=3.71%, N=11.02%.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:21])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO.C(#N)C>[NH2:28][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]#[N:20])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:21])[CH:5]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(C#N)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(C#N)C1
Temperature: 65 °C

Procedure:
A mixture of 1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidine-3-carbonitrile (0.016 g, 0.053 mmol) and ammonium acetate (0.0411 g, 0.534 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, sodium cyanoborohydride (0.010 g, 0.16 mmol) was added. The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H18ClN4 (M+H)+: m/z=301.1; Found: 301.1.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[CH:26][CH:25]=1>>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:40]1[CH2:39][CH2:38][N:37]([C:34]2[CH:33]=[CH:32][C:31]([CH2:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)=[CH:36][CH:35]=2)[CH2:42][CH2:41]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=C(CCCCCBr)Nc1ccccc1Cc1ccccc1
Product: O=C(CCCCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1Cc1ccccc1

Procedure:
The compound (12) synthesized in Reference Example 12 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1>C(Cl)Cl.C(OCC)C>[Cl:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[O:23])=[CH:15][CH:14]=1
Reactant: OCCCCCOc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCCCCOc1ccc(Cl)cc1
Reaction time: 3 h

Procedure:
To a suspension of 33 g (0.15 mmol) of pyridinium chlorochromate in 450 ml of methylene chloride is added 21.4 g (0.1 mol) of 5-(4-chlorophenoxy)-1-pentanol. The mixture is maintained with stirring for 3 hours, diluted with 900 ml of ethyl ether and stirred for an additional 1 hour.
Reaction SMILES: [F:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[N:3]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:4]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[CH2:7][OH:8]
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc(CO)c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A solution (20 mL) of ethyl 2-fluoro-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (390 mg) in tetrahydrofuran was cooled to −70° C., and a 1.5 mol/L solution (3.5 mL) of diisobutylaluminum hydride in toluene was added dropwise by small portions. The mixture was further stirred at −70° C. for 1 hr, 1 mol/L hydrochloric acid (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a pale-red oil (yield 330 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[I:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([I:28])[N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(I)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridyl)-pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 mL of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (2 eq.). The mixture was stirred at −78° C. for 30 min and N-iodosuccinimide (2.2 eq.) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hour. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1 N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 2-(4-fluorophenyl)-7-iodo-3-pyridin-4-ylpyrazolo[1,5-α]pyridine as a yellow solid. 1H NMR (CDCl3): δ 8.54 (d, 2H, J=5.8 Hz), 7.50–7.57 (m, 3H), 7.37 (d, 1H, J=7.1 Hz), 7.20 (d, 2H, J=5.8 Hz), 7.00 (t, 2H, J=8.6 Hz), 6.90 (t, 1H, J=7.8 Hz); MS m/z 416 (M+1).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[N:18]1([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH:31]=2)[CH:29]=O)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>C1COCC1>[N:18]1([C:24]2[CH:31]=[C:28]([CH:29]=[CH:3][C:1]#[N:2])[CH:27]=[N:26][CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cncc(N2CCOCC2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC=Cc1cncc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a solution of diethyl cyanomethylphosphonate (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) cooled at 0° C. was added 1.0 M potassium tert-butoxide in THF (0.50 mL) dropwise. The cold bath was removed and the reaction was warmed to room temperature over 30 minutes. The reaction was cooled to 0° C. and a solution of 5-morpholin-4-ylnicotinaldehyde (70 mg, 0.0004 mol) in THF (2 mL, 0.02 mol) was added dropwise. The reaction was stirred at room temperature for 4 h, quenched with water and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give (2E & Z)-3-(5-morpholin-4-ylpyridin-3-yl)acrylonitrile (75 mg, 100%) as a mixture of isomers; LC/MS: 216 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.CC(O)C.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>O>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[N:7]=1
Reactant: Cc1cc(C)c(Nc2ccnc(Cl)n2)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(C)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(C)c1
Temperature: 42.5 °C
Yield: 85.5 %

Procedure:
A mixture of intermediate 49 (0.082 mol) and 5.4 N HCl in 2-propanol (0.086 mol) in water (300 ml) was stirred and warmed to 40-45° C. over 30 minutes. 4-Amino-benzonitrile (0.242 mol) was added at 40-45° C. The reaction mixture was stirred and refluxed for 4.5 hours, then cooled to room temperature. The mixture was alkalized by portionwise addition of NaHCO3. This mixture was extracted with ethylacetate. The organic layer was separated, washed with brine, dried, filtered, and the solvent was evaporated. This fraction was stirred in ethanol p.a. (100 ml), filtered off, washed with ethanol (50 ml), then dried, yielding 23.1 g (86%) 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 52).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5](C(=O)C(F)(F)F)[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2
Reactant: CN1c2ccccc2CN(C(=O)C(F)(F)F)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1c2ccccc2CNc2ccccc21
Yield: 94.7 %

Procedure:
1-(10,11-Dihydro-5-methyl-dibenzo[b,e][1,4]diazepin-10-yl)-2,2,2-trifluoroethanone of Step B (1.0 g) in ethanol (25 mL) was treated with 1 N sodium hydroxide (10 mL). The reaction mixture was refluxed for five hours, cooled, all volatiles removed in vacuo and the residue triturated with water. The resulting solid was filtered off, redissolved in dichloromethane and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® which was eluted with several additional volumes of dichloromethane. The total effluent was evaporated to dryness to provide the title compound as an off-white crystalline solid (0.65 g), m.p. 115-117° C.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1.C([Li])CCC.[CH:32](=[O:34])[CH3:33]>O1CCCC1>[OH:34][CH:32]([C:2]1[N:3]=[C:4]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[N:5]([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=1)[CH3:33]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)cn2CCN2CCCC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)c1cn(CCN2CCCC2)c(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Combine tert-butyl 4-(4-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate (40.00 g, 82.63 mmol) and tetrahydrofuran (600 mL). Cool to −70° C. under nitrogen. Add 2.5 M n-butyllithium in hexanes (67.76 mL, 2.1 eq) dropwise. Add acetaldehyde (23.22 mL, 5.0 eq) and stir for 15 minutes. Quench over aqueous saturated ammonium chloride (75 mL). Separate the layers. Wash the aqueous phase with methyl tert-butyl ether. Wash the organics with water and aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Dissolve in ethanol. Add 85% aqueous phosphoric acid dropwise to achieve a suspension. Stir the mixture overnight at room temperature. Filter and dry the resulting off-white solid under vacuum to give tert-butyl 4-(4-(1-hydroxyethyl)-1-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazol-2-yl)piperidine-1-carboxylate; phosphoric acid (28.00 g, 69%). MS (ES) m/z=393 [M]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:22][C:23](=[O:25])[NH2:24])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:22][C:23]([NH2:24])=[O:25])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CC(N)=O)Cc2ccc(Cl)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[carbamoylmethyl-(4-chloro-benzyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g, 1.32 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification ESI-MS m/z: 267 (M+1), UV retention time: 0.82 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15]O)[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12].[CH3:23][NH:24]CCC(C1C=C2C(=CC=1)NC=C2C#N)C1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH2:15][NH:24][CH3:23])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]#[N:12]
Reactant: CNCCC(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Reactant: N#Cc1c[nH]c2c(F)cc(C(CCO)c3ccccc3)cc12
Product: CNCCC(c1ccccc1)c1cc(F)c2[nH]cc(C#N)c2c1

Procedure:
7-Fluoro-5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXXXIX (197 mg) was prepared from 7-fluoro-5-(3-hydroxy-1-phenyl-propyl)-1H-indole-3-carbonitrile using the procedure described above for preparation of 5-(3-Methylamino-1-phenyl-propyl)-1H-indole-3-carbonitrile LXVI (Example 16). MS (M+H)=308.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[BH4-].[Na+]>CO.O>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
240 mg (1.2 mmol) of 4-(4-oxo-piperidin-1-yl)-benzonitrile (reference example 116) was dissolved in 5 ml of methanol, 23 mg (0.6 mmol) of NaBH4 was added and stirred 3 h at room temperature. A few drops of water were added, methanol evaporated then 20 ml of water were added and extracted with DCM (3×), dried with Na2SO4, filtered and evaporated to give 230 mg (95% yield) of the title compound. 1H NMR (CDCl3): d 7.47 (d, 2H), 6.85 (d, 2H), 3.93 (bs, H), 3.70 (m, 2H), 3.11 (m, 2H), 1.95 (m, 2H), 1.62 (m, 2H). MS (ion spray) m/z 202 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]([N:6]1[CH2:11][CH2:10][CH:9](N(C2CC2)C(C2C=NC(N3C=CN=C3CC)=NC=2)=O)[CH2:8][CH2:7]1)#[N:5].C(N(C(C)C)C(C)C)C>C(O)C>[OH:3][NH:2][C:4]([N:6]1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[NH:5]
Reactant: CCc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(C#N)CC2)cn1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N=C(NO)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Hydroxylamine hydrochloride (36 mg) is added to 2-(2-ethyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (180 mg, Intermediate 32) and ethyldiisopropylamine (0.1 mL) in ethanol (30 mL) and the mixture is refluxed for 4 h. Another 10 mg hydroxylamine hydrochloride is added and the mixture is refluxed for 1 h and stirred at room temperature for 12 h. The solvent is removed in vacuo to yield the respective (N-hydroxycarbamimidoyl)-piperidine derivative as an intermediate. Subsequently 50 mg of the aforementioned intermediate are added to tetrahydrofuran (10 mL) followed by ethyldiisopropylamine (32 μL) and cyclopropanecarbonyl chloride (11 μL). The mixture is stirred at room temperature for 1.5 h. Acetonitrile is added and the mixture is refluxed for 5 h. The mixture is concentrated and 1,2-dicholorethane (2.0 mL) and (methoxycarbonylsulfamoyl) triethylammonium hydroxide (Burgess reagent, 75 mg) are added and the mixture is heated in a microwave oven to 130° C. for 15 min. The solvent is removed in vacuo and the residue is purified by HPLC (MeOH/H2O/TFA) to yield the desired product. LC (method 9): tR=1.09 min; Mass spectrum (ESI+): m/z=449 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[S:11]C#N.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC.O1CCCC1>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([OH:9])[C:5]([CH3:10])=[CH:4][C:3]=1[SH:11]
Reactant: Cc1cc(SC#N)c(C)c(C)c1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(S)c(C)c(C)c1O
Temperature: 0 °C
Yield: 103.4 %

Procedure:
2,3,5-Trimethyl-4-hydroxyphenylthiocyanate (2 g, 10.35 mmol) was dissolved in 100 mL of anhydrous ether containing 25 mL of anhydrous tetrahydrofuran. This solution was added dropwise over 1 h to 100 mL of anhydrous ether containing LiAlH4 (0.9 g, 24 mmol) at room temperature. After a further hour at 20° C., the unreacted LiAlH4 was destroyed by cooling the heterogeneous mixture to 0° C. and adding moist ether (50 mL), H2O (50 mL), and 1 N HCl (50 mL). A further 50 mL of water was added and the organic phase was separated and washed with water (2×50 mL), NaHCO3 solution (2×50 mL), water (2×50 mL), and saturated NaCl (50 mL). The organic phase was dried over anhydrous MgSO4 and filtered and the solvent removed under reduced pressure. Silica gel column chromatography with 5% ethyl acetate in hexane gave 1.8 g (90%) of 2,3,5-trimethyl-4-hydroxybenzenethiol as a white powder, mp 86° C. [Lit. 1 mp 86° C.].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)[CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=3)[CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(C(F)(F)F)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(trifluoromethyl)phenyl]amino]piperidine (688 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[C@@H:13]1[CH2:15][O:14]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl([O-])(=O)(=O)=O.[Li+]>C(#N)C>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:15][C@H:13]([OH:14])[C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc2nccc([C@@H]3CO3)c2c1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: COc1ccc2nccc([C@@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.4 %

Procedure:
(R)-2-(6-Methoxyquinolin-4-yl)oxirane (Example 3a) (4.30 g, 21.37 mmol) was dissolved in acetonitrile (30 mL). To the solution was added piperazine-1-carboxylic acid tert-butyl ester (7.17 g, 38.47 mmol) and lithium perchlorate (2.27 g, 106.4 mmol). The resulting slurry was stirred at room temperature for 10 hours and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic phase dried over magnesium sulfate. Concentration in vacuo afforded a colourless oil which was subjected to purification by column chromatography on silica gel using a dichloromethane/methanol gradient. This provided the desired compound as a colourless oil (7.65 g, 92%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]3[C:26]4[NH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]=4[CH2:17][CH2:16][N:15]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Br[CH2:35][C:36]#[N:37].O>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH:14]3[C:26]4[N:25]([CH2:35][C:36]#[N:37])[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[C:18]=4[CH2:17][CH2:16][N:15]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c([nH]c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CC#N)c3ccccc23)C1C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
60% Sodium hydride suspension in mineral oil (0.412 g, 10.3 mmol) in dry dimethylformamide (25 mL) was stirred at room temperature under an atmosphere of nitrogen. tert-Butyl 1-[1-(4-chlorophenyl)cyclobutyl]-1,3,4,9-tetrahydro-2H-b-carboline-2-carboxylate (3.0 g, 6.87 mmol) was added in small portions. After 30 min stirring at room temperature 2-bromoacetonitrile (1.235 g, 10.3 mmol) in dimethylformamide (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for two days. Water was added (1 mL). The reaction mixture was concentrated in vacuo, dichloromethane (100 mL) was added and the organic solution successively washed with water (50 mL), saturated NaHCO3 solution (30 mL) and water (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane). Yield: 2.7 g (83%).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH2:12][OH:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CCOCC1>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCc1c[nH]c(-c2ccccc2)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=Cc1c[nH]c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.6 %

Procedure:
To a solution (45 mL) of (5-phenyl-1H-pyrrol-3-yl)methanol (1.51 g) in acetonitrile were added tetra-n-propylammonium perruthenate (0.46 g), N-methylmorpholine N-oxide (2.36 g) and molecular sieves 4A powder (4.5 g), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→41:1) to give the title compound as a pale-yellow powder (yield 0.92 g, 62%).