Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)CCO.CON(C)[C:22]([CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23]>CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])[N:3]=1
Reactant: Clc1ccccn1
Reactant: CON(C)C(=O)C1CCN(C)CC1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(C(=O)c2cccc(Cl)n2)CC1
Reaction time: 1 h
Yield: 47.6 %

Procedure:
Add 2-chloropyridine (1 g, 8.8 mmole) to a mixture of n-butyl lithium (1.6 M in hexane) (22 mL, 35.2 mmole) and 2-dimethylamino-ethanol (1.56 g, 17.6 mmole) in hexane (20 mL at −78° C.) and stirred for 1 hour. Then add 1-methyl-piperidine-4-carboxylic acid methoxy-methyl-amide (3.2 g, 17.6 mmole) in hexane (5 mL) and stir the mixture for 1 hour. Quench the reaction mixture with water and extract twice with ethyl acetate, dry the organic layer with anhydrous sodium sulfate, evaporate the solvent and purify the residual product by chromatography on a silica gel column to give about 1 g of the title product.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[F:16][CH:17]([F:30])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]([NH2:28])[CH3:27])=[CH:22][C:21]=1[CH3:29]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:28]([CH:26]([C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:30])[F:16])=[C:21]([CH3:29])[CH:22]=3)[CH3:27])[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1cc(C(C)N)cnc1OCC(F)F
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Agent: Cl
Product: Cc1cc(C(C)N2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)F
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (134 mg, colorless amorphous solid) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (400 mg, 1.4 mmol, Step-1 of Intermediate-6, racemate) and 1-(6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)ethanamine hydrochloride (399 mg, 1.6 mmol, Amine-5, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: C([O-])=O.[NH4+].[C:5]([O:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([N+:21]([O-])=O)=[CH:18][CH:19]=2)[C:14]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].CO>[Pd].O>[NH2:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:12]([C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[N:13]=[C:14]2[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 82.3 %

Procedure:
5-Amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole can be obtained in the following way: 0.12 g of 10% palladium-on-charcoal and 0.68 g of ammonium formate are added to a solution of 0.8 g of N-tert-butoxycarbonyl-5-nitro-3-phenyl-1H-indazole and of 14 ml of methanol. The suspension is maintained with stirring for 18 hours at a temperature in the region of 20° C. 50 ml of distilled water are added to the reaction medium which is extracted with 50 ml and 25 ml of ethyl acetate. The organic phases are pooled, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residue obtained is purified by chromatography on a silica column with dichloromethane as eluent. 0.6 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole is thus obtained in the form of an off-white solid melting at 191° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:11][C:12]([F:23])([F:24])[O:13][C:14]1[CH:15]=[C:16]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1cccc2[nH]ccc12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)Oc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 75 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
To a mixture of 4-bromoindole (4.50 g, 22.95 mmol), and 4-trifluoromethoxyphenylboronic acid (4.73 g, 22.95 mmol) in THF (78 mL)) were added Palladium catalyst Pd(PPh3)4 (795.6 mg, 0.69 mmol) and the freshly prepared sodium hydroxide solution (2.75 g, 68.9 mmol in 32 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 75° C. oil bath for 16 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 5.56 g (78%) of the product 4-(4-trifluoromethoxy-phenyl)-1H-indole.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10]C2C=CC(O)=CC=2)=[N:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5](=[O:10])[NH:4][CH:3]=1
Reactant: N#Cc1nc(F)cnc1Oc1ccc(O)cc1
Agent: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)c[nH]c1=O
Reaction time: 0.25 h

Procedure:
In a mixture of 7.5 mL of acetonitrile and 3 mL of water was dissolved 0.45 g of 6-fluoro-3-(4-hydroxyphenoxy)-2-pyrazinecarbonitrile. Then, 1.17 g of diammonium cerium nitrate was added at room temperature, and stirred at the same temperature as above for 15 minutes. A mixture of 10 mL of ethyl acetate and 5 ml of 5% aqueous solution of sodium thiosulfate was added to the reaction mixture, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].C[Si]([N:20]=[C:21]=[O:22])(C)C.ClCCl>CN(C)C=O>[NH2:20][C:21]([NH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14])=[O:22]
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)c1sc(-c2ccccc2)cc1N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)Nc1cc(-c2ccccc2)sc1C(N)=O

Procedure:
3-Amino-5-phenyl-2-thiophenecarboxamide (0.5 g), trimethylsilylisocyanate (3 mL), dichloromethane (15 mL) and dimethylformamide (3 mL) were heated at reflux for 3 days.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1Cl.[CH3:30][CH:31]([OH:33])[CH3:32].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][C:15]=3[CH3:29])[N:10]=2)[CH:5]=[N:6][C:7]=1[O:33][CH:31]([CH3:32])[CH3:30]
Reactant: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(Cl)c(Cl)c2)n1
Reactant: CC(C)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(CCC(=O)OC(C)(C)C)ccc1-c1noc(-c2cnc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a solution of 138 mg (0.32 mmol) of tert-butyl 3-(4-(5-(5,6-dichloropyridin-3-yl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate and 36.5 μL (0.48 mmol) of 2-propanol in 10 mL of THF was added 477 μL (0.48 mmol) of sodium bis(trimethylsilyl)amide (1.0 M in THF). The mixture was refluxed overnight, cooled to rt and concentrated. Chromatography on a Biotage 40S cartridge using 1:19 v/v EtOAc/hexanes as the eluant gave 106 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.43 (s, 9H), 1.44 (d, J=6.2, 6H), 2.58 (t, J=7.8, 2H), 2.65 (s, 3H), 2.95 (t, J=7.7, 2H), 5.49 (m, 1H), 7.17-7.18 (m, 2H), 8.00 (d, J=8.4, 1H), 8.38 (d, J=2.0, 1H), 8.86 (d, J=2.3, 1H).
Reaction SMILES: C(O[C@H]1CNC[C@H]1NC1C(CC)=NC(C2C(C)=NC(OC)=CC=2)=C(CC)N=1)C.[CH3:29][O:30][C:31]1[C:36]([C:37]2[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]3[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][N:48](C(OCC4C=CC=CC=4)=O)[CH2:47]3)=[N:41][C:42]=2[CH2:43][CH3:44])=[CH:35][CH:34]=[C:33]([O:66][CH3:67])[N:32]=1>>[CH3:29][O:30][C:31]1[C:36]([C:37]2[N:38]=[C:39]([CH2:64][CH3:65])[C:40]([NH:45][C@H:46]3[C@@H:50]([O:51][CH2:52][CH3:53])[CH2:49][NH:48][CH2:47]3)=[N:41][C:42]=2[CH2:43][CH3:44])=[CH:35][CH:34]=[C:33]([O:66][CH3:67])[N:32]=1
Reactant: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC
Agent: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2OC)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting benzyl (3R,4S)-3-{[5-(2,6-dimethoxypyridin-3-yl)-3,6-diethylpyrazin-2-yl]amino}-4-ethoxypyrrolidine-1-carboxylate provided the title compound as an amber oil. 1H NMR (400 MHz, CDCl3) δ) 7.53, 6.42, 5.29, 4.52, 4.04, 3.98, 3.92, 3.66, 3.51, 3.40, 3.21, 3.12, 2.91, 2.72, 2.48, 1.28, 1.18; IR (liq.) 2972, 2418 (w), 2184 (w), 2036 (w), 1993 (w), 1603, 1581 (s), 1564, 1477 (s), 1423, 1395, 1376 (s), 1313 (s), 1233, 1022 cm−1 HRMS (ESI) calcd for C21H31N5O3+H1 402.2505. found 402.2516.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C1OCCOCCOCCOCCOC1.CS(O[CH:25]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])(=O)=O.C(Cl)Cl>CN(C=O)C>[N:1]([CH:25]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:26][CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=1[C:31]([O:33][CH3:34])=[O:32])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccccc1CCCC(Cc1ccccc1)OS(C)(=O)=O
Agent: C1COCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1CCCC(Cc1ccccc1)N=[N+]=[N-]
Temperature: 85 °C

Procedure:
Sodium azide (1 g, 15.4 mmol) and 15-crown-5 (0.17 g, 0.77 mmol) were added to a stirred solution of 30e (2.9 g, 7.7 mmol) in DMF (60 mL). The mixture was heated at 85° C. for 24 h under argon atmosphere. Then DCM (300 mL) was added, the solution was washed with a saturated NaHCO3 solution (2×150 mL) and brine (3×200 mL), and dried over Na2SO4. After removal of the solvent under reduced pressure, the desired product was obtained as yellow oil, which was used without further purification in the next step.
Reaction SMILES: CC1(C)CO[C:5]2([CH2:12][CH2:11][CH:10]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=3[O:21][CH3:22])[CH2:9][CH2:8]2)[O:4]C1.C(O)=O>CC(C)=O>[O:4]=[C:5]1[CH2:8][CH2:9][CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[O:21][CH3:22])[CH2:11][CH2:12]1
Reactant: COc1c(OC2CCC3(CC2)OCC(C)(C)CO3)ccnc1C
Solvent: O=CO
Solvent: CC(C)=O
Product: COc1c(OC2CCC(=O)CC2)ccnc1C

Procedure:
1 g of 4-(3,3-dimethyl-1,5-dioxaspiro[5.5]undecan-9-yloxy)-3-methoxy-2-methylpyridine is stirred with 20 ml of formic acid and 5 ml of acetone for 5 hours. The residue which remains after concentrating is purified by chromatography on silica gel using ethyl acetate. 0.3 g=41%; m.p.: 56° to 57° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]([C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([O:22][C@@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:32][C:31]([CH2:55][C:56]#[N:57])([N:33]4[CH:37]=[C:36]([C:38]5[C:39]6[CH:46]=[CH:45][N:44](COCC[Si](C)(C)C)[C:40]=6[N:41]=[CH:42][N:43]=5)[CH:35]=[N:34]4)[CH2:30]3)[CH2:25][CH2:24]2)[CH:13]=1)([CH3:11])[CH3:10].[OH-].[NH4+].O>CC#N.O.C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:8][C:9]([C:12]1[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([O:22][C@@H:23]2[CH2:24][CH2:25][C@H:26]([N:29]3[CH2:32][C:31]([CH2:55][C:56]#[N:57])([N:33]4[CH:37]=[C:36]([C:38]5[C:39]6[CH:46]=[CH:45][NH:44][C:40]=6[N:41]=[CH:42][N:43]=5)[CH:35]=[N:34]4)[CH2:30]3)[CH2:27][CH2:28]2)[CH:13]=1)([CH3:10])[CH3:11]
Reactant: CC(C)(O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
Methylene chloride (2.0 mL) and trifluoroacetic acid (0.40 mL, 5.2 mmol) were added to {1-(cis-4-{[6-(1-hydroxy-1-methylethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, stirred for 2 hours, and then concentrated to remove trifluoroacetic acids. LCMS showed clean conversion to the hydroxymethyl intermediate (M+2H 320). To the residue was added methanol (2.0 mL), then 15.0 M ammonium hydroxide in water (1.8 mL, 27 mmol). The solution was stirred 2.5 hours. LCMS showed the reaction was complete. The product was isolated by preparative LCMS using a Waters Fraction-Linx instrument and a 30 mm×100 mm Sunfire C18 column (5% CH3CN—H2O (0.1% TFA), 4.0 minutes; 8.0 min gradient to 30%; 60 mL/min; 8 runs; retention time 11.0 minutes). The eluent was concentrated by 50%, then freeze-dried to give white solid. 1H NMR (300 MHz, MeOH-D4): δ 8.99 (s, 1H); 8.82 (s, 1H); 8.57 (s, 1H); 7.71 (m, 1H); 7.20 (s, 1H); 7.16 (m, 1H); 5.48 (m, 1H, OCH); 5.06 (d, 2H azetidine) 4.8 (d, 2H, azetidine); 3.70 (s, 2H, CH2CN); 3.50 (m, 1H, NCH); 2.30 (m, 2H); 2.01 (m, 2H); 1.80 (m, 2H); 1.75 (m, 2H); 1.50 (s, 6H). MS: 582 (M+H)
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH:29]=O>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:29][C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc2ccccc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 2-naphthaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.87 min.; [M+H]+: 362.35 g/mol.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1>[Pd]>[F:23][C:18]([F:24])([C:15]1[CH:14]=[CH:13][C:12]([C@H:6]2[O:7][C@@H:3]([CH2:1][OH:2])[CH2:4][CH2:5]2)=[CH:17][CH:16]=1)[C:19]([F:20])([F:22])[F:21].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]([F:23])([F:24])[C:19]([F:20])([F:21])[F:22])=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd]
Agent: FC(F)(F)C(F)(F)c1ccc(Br)cc1
Product: OC[C@H]1CC[C@@H](c2ccc(C(F)(F)C(F)(F)F)cc2)O1

Procedure:
The requisite {cis-5-[4-(pentafluoroethyl)phenyl]tetrahydrofuran-2-yl}methanol was prepared via Suzuki reaction of (5-formylfuran-2-yl)boronic acid with 1-bromo-4-(pentafluoroethyl)benzene, followed by hydrogenation over palladium on carbon. 1-Bromo-4-(pentafluoroethyl)benzene was prepared according to the method of W. Lambert et al., PCT Int. Appl., 2011017513, Feb. 10, 2011.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N+:12]([O-:14])=[O:13])\[CH3:11].Cl.[CH3:16][O:17][NH2:18].C(N(CC)CC)C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:18][O:17][CH3:16])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11]
Reactant: C/C(=C\c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Reactant: CON
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CONC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a stirred yellow solution of the 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene (1.0 mmol, 0.232 g), in methanol (3 ml) under N2 was added at 0° C. O-methylhydroxylamine hydrochloride (2.0 mmol, 0.167 g) and triethylamine (3.0 mmol, 0.30 g). After stirring for 0.5 h at 50° C., the colourless liquid cooled to ambient temperature and water (20 ml) was added. The aqueous solution was extracted with dichloromethane (20 ml), the organic layers were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.23 g (82.4% of theory) of N-[1-(2,4-dichloro-phenyl)-2-nitro-propyl]-O-methyl-hydroxylamine in the form of liquid, as a mixture of diastereomeres.
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.CO.[BH4-].[Na+]>[OH-].[Na+].O>[CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH:6]([OH:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: CC1c2ccccc2CC(=O)Cc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1c2ccccc2CC(O)Cc2ccccc21

Procedure:
12-Methyl-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-one (3.6 g., 15.3 mmole) in 25 ml. of methanol was treated with several drops of 1 M sodium hydroxide followed by 0.58 g. (15.3 mmole) of sodium borohydride in 5 ml. of water. The mixture was heated at reflux for 20 minutes, cooled, and concentrated in vacuo. The residue was slurried in water and extracted three times with chloroform. The chloroform fractions were washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo to give 3.7 g. of white solid, m.p. 142°-145° C.
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:9]C(=O)C(C)(C)C)=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20]CC)=O.N1CCCC1>C(O)C>[O:20]=[C:18]1[C:17]([C:16]([O:24][CH2:25][CH3:26])=[O:23])=[CH:1][C:3]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:9]1
Reactant: CC(C)(C)C(=O)Nc1ncccc1C=O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNC1
Product: CCOC(=O)c1cc2cccnc2[nH]c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.5 %

Procedure:
6.57 g (32 mmol) of 3-formyl-2-(pivaloylamino)pyridine was dissolved in ethanol (50 mL), and 10.2 g (64 mmol) of diethyl malonate and 1.6 mL (16 mmol) of pyrrolidine were added to the above solution. The resulting mixture was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, and a solid precipitated therefrom was washed with ethanol. Thus, 2.2 g (yield: 32%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [Li].[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][C:7]([C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=O)=[CH:8][CH:9]=2)[N:4]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+].C(OCC)(=O)C>O1CCCC1>[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][C:7]([CH2:18][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(C(=O)N3CCCC3)cc2n1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(N2CCCC2)c2ccc(CN3CCCC3)cc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
Lithium aluminumhydride (20 mg, 0.52 mmol) was added to a solution of (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-pyrrolidin-1-yl-methanone (example 27, 80 mg, 0.26 mmol) in tetrahydrofuran (1 mL), and the reaction mixture was stirred at room temperature for 3 h, then 1 M aq. potassium sodium tartrate solution (10 mL) and ethyl acetate (10 mL) were added. After 15 min, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) afforded the title compound (31 mg, 41%). Off-white solid, ISP-MS: m/e=337.3 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.C[Si](Cl)(C)C.[O:17]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18]1.C(=O)([O-])O.[Na+]>C(OCC)C>[O:17]1[CH:21]=[CH:20][C:19]([CH:22]([C:6]2[S:5][CH:4]=[N:3][C:2]=2[CH3:1])[OH:23])=[CH:18]1
Reactant: O=Cc1ccoc1
Reactant: Cc1cscn1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ncsc1C(O)c1ccoc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Methylthiazole (3g) in dry diethyl ether was added dropwise to a stirred solution of n-butyllithium (1.6M in hexanes, 21ml) in diethyl ether (20ml) at -78° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (3.9ml) was added and the mixture was then allowed to warm to 0° C. The mixture was then cooled to -78° C. and further n-butyllithium (21ml) was added. The mixture was warmed to 0° C. After 30 minutes the mixture was again cooled to -78° C. and 3-furaldehyde (5g) in diethyl ether (10ml) was added. The mixture was allowed to warm to room temperature and after 30 minutes saturated aqueous sodium hydrogen carbonate was added. The reaction mixture was extracted with diethyl ether in the usual manner to give the crude product which was then purified by flash chromatography on silica gel to give the title compound. M.p. 44°-46° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:27][C@@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1ccc(-c2cc(Cl)cc(Cl)c2)cc1
Product: Clc1cc(Cl)cc(-c2ccc(CN[C@H]3CCCc4ccccc43)cc2)c1

Procedure:
3′,5′-Dichloro[1,1′-biphenyl]-4-carbaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:17][S:18][CH2:19][C@H:20]([NH:44]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])=[CH:28][CH:27]=1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[C:1]([O:14][CH2:15][C@@H:16]([O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:17][S:18][CH2:19][C@H:20]([NH2:44])[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])=[CH:28][CH:27]=1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(3-(diethoxyphosphoryl)propoxy)phenethylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the starting material disappeared. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.