Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([OH:12])[CH3:11])[CH3:3].CN([P:16](N(C)C)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)C>C1(C)C=CC=CC=1>[CH3:3][CH:2]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH:10]([CH3:11])[O:12][P:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:1]1
Reactant: CC(O)c1ccccc1C(C)O
Reactant: CN(C)P(c1ccccc1)N(C)C
Solvent: Cc1ccccc1
Product: CC1OP(c2ccccc2)OC(C)c2ccccc21

Procedure:
A solution of 1-[2-(1-Hydroxy-ethyl)-phenyl]-ethanol (1.0 g, 6.02 mmol) and bis-(dimethylamino)phenylphosphine (1.18 g, 6.02 mmol) in toluene (5 ml) was heated at reflux under a nitrogen atmosphere until all of the bis-(dimethylamino)phenylphosphine had been consumed (31P-NMR, 24 h). The solvent was then removed in vacuum to leave the product as a colourless oil in almost quantitative yield. 1H/13C-NMR (CDCl3, 300 MHz, HSQC/HMBC/NOE): δ/δ 1.59 (d, 3H, J=6.7 Hz)/21.77 (d, J=2.2 Hz) Ph anti-CH3; 1.90 (d, 3H, J=6.4 Hz)/23.51 (d, J=7.0 Hz) Ph syn-CH3; 5.41 (p, 1H, JP,H≈7 Hz)/70.72 (d, J=6.1 Hz) Ph syn-CHCH3); 5.63 (p, J=JP,H≈6.4 Hz)/74.72 (d, J=9.6 Hz) Ph anti-CHCH3); 7.19/126.65 ortho-CH); 7.30/126.65 ortho-CH); 7.21/127.35 meta-CH); 7.28/127.58 meta-CH); 7.41/128.33 (d, J=4.6 Hz) Ph meta-CH); 7.68/129.80 (d, J=20.1 Hz) Ph ortho-CH); 7.41/130.28 (d, J=0.6 Hz) Ph p-CH); 141.03 (d, J=0.9 Hz) ipso-C); 141.65 (d, J=32.6 Hz) Ph ipso-C); 142.54 (d, J=0.6 Hz) ipso-C). 31P-NMR: δ 154.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2C=O)[CH2:3][CH2:2]1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.CO.[O:27]1[CH2:32][CH2:31][O:30][CH2:29]C1>>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([CH2:16][NH:15][C:32](=[O:27])[CH:31]([O:30][CH3:29])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:18][CH:19]=1)#[N:22]
Reactant: C1COCCO1
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=Cc1ccccc1N1CCOCC1
Solvent: CO
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1N1CCOCC1

Procedure:
Morpholinobenzaldehyde was reacted according to general procedure A using methanol/dioxane as a solvent. The product of this reaction was subsequently coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-(2-morpholin-4-yl-phenyl)-acetamide. Orange oil.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]1)(=O)=O.[C-:21]#[N:22].[Na+]>CS(C)=O>[C:21]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]1)#[N:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC#N)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of {trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}methyl methanesulfonate (1.48 g, 4.81 mmol) and sodium cyanide (0.46 g, 9.4 mmol) in dimethyl sulfoxide (20 mL) was stirred at 90° C. for 4 h. After cooling, the mixture was partitioned between EtOAc and brine. The organic layer was washed with water, concentrated and purified on silica gel (eluting with 50% EtOAc in hexanes) to give tert-butyl [trans-4-(cyanomethyl)cyclohexyl]carbamate. LCMS calculated for C13H22N2O2Na (M+Na)+: m/z=261.2. Found: 261.1. A solution of the Boc-protected intermediate in methylene chloride (20 mL) was treated with trifluoroacetic acid (3 mL, 40 mmol) and the resulting mixture was stirred at room temperature for 2 h, then concentrated to give the desired product as TFA salt. LCMS calculated for C8H15N2 (M+H)+: m/z=139.1. Found: 139.1.
Reaction SMILES: CN(C=O)C.[NH:6]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:7]([C:15]([O:17]N1C(=O)CCC1=O)=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35].CCN(CC)CC>>[NH:6]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C@H:7]([C:15]([NH:32][C@H:33]([C:36]([OH:38])=[O:37])[CH2:34][OH:35])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: N[C@@H](CO)C(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CO)C(=O)O
Yield: 31 %

Procedure:
In a 10 ml solution of DMF containing 500 mg (1.38 mmol) of Boc-Phe-OSu was added 5 ml of an aqueous solution of H-Ser-OH.Et3N [preparation from 290 mg (2.76 mmol) of H-Ser-OH and 384 μl (2.76 mmol) of Et3N] and the mixture was stirred for 14 hr. The reaction mixture was evaporated and the residue was dissolved in ethyl acetate and washed with 1N-HCl and saturated sodium chloride aqueous solution, successively, together with salting out. The resultant solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure, and the resulting residue was purified with a silica gel column chromatography (CHCl3:MeOH). The eluate was mixed with ether and n-hexane to give crystals of 150 mg of the title compound with yield of 31%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15](N(CC)CC)[CH3:16].BrCC[CH2:25][C:26]([CH3:31])([CH3:30])[C:27]([O-:29])=[O:28]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:29][C:27](=[O:28])[C:26]([CH3:25])([CH3:30])[CH3:31])[CH2:11][CH2:10]1
Reactant: CC(C)(CCCBr)C(=O)[O-]
Reactant: CCN(CC)CC
Reactant: COc1ccccc1N1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCOC(=O)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N-(2-methoxyphenyl)piperazine (3.64 g, 0.019 mol) and triethylamine (6 g, 0.06 mol) in 80 mL of DMF was added 2-bromoethylpivalate (4 g, 0.019 mol). The reaction mixture was stirred overnight at room temperature. The DMF was removed under reduced pressure and the residue was dissolved in 100 mL of methylene chloride. The organic layer was washed with water, dried (anhydrous Na2SO4) and evaporated. The desired product was separated by preparative HPLC and converted to the dihydrochloride salt, mp.=193°-195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:5]([C:4]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[CH:3]=1)=[O:7])[CH2:47][CH2:48][CH3:49]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: CCCC[n+]1nc(C)sc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3,5-dimethylbenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.87-0.96 (m, 3 H) 1.28-1.39 (m, 2 H) 1.68-1.80 (m, 2 H) 2.33 (s, 6 H) 2.47 (s, 3 H) 4.21 (t, 2 H) 6.66 (s, 1 H) 7.14 (s, 1 H) 7.62 (s, 2 H); MS (ESI) m/z 303 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([N:18]3[CH:27]([CH3:28])[CH2:26][C:25]4[C:20](=[CH:21][C:22]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:23][CH:24]=4)[CH2:19]3)[N:15]=[C:14]([NH2:35])[N:13]=2)[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.[CH3:45][N:46]([CH3:50])[C:47](Cl)=[O:48]>C(#N)C.CO>[NH2:35][C:14]1[N:15]=[C:16]([N:18]2[CH:27]([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH:29]4[CH2:30][CH2:31][N:32]([C:47]([N:46]([CH3:50])[CH3:45])=[O:48])[CH2:33][CH2:34]4)=[CH:23][CH:24]=3)[CH2:19]2)[CH:17]=[C:12]([N:9]2[CH2:10][CH2:11][N:6]([CH3:5])[CH2:7][CH2:8]2)[N:13]=1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC1Cc2ccc(C3CCN(C(=O)N(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride (17 mg) HCl salt in acetonitrile (0.50 mL) was treated with N,N-diisopropylethylamine (42 uL, 0.24 mmol). To the solution was added N,N-Dimethylcarbamoyl chloride (3.59 uL, 0.0390 mmol). The mixture was stirred at r.t. for 2 h. The mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=493.4.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:11]=[C:10]([CH3:12])[C:7]([C:8]#[N:9])=[C:6]([I:13])[C:5]=1[O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C)c(C#N)c(I)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(C(C)=O)cc(C)c(C#N)c1I
Temperature: 60 °C
Yield: 93.3 %

Procedure:
The 4-acetyl-3-hydroxy-2-iodo-6-methylbenzonitrile (5.0 g, 17 mmol) was dissolved in N,N-dimethylformamide (50 mL) and the potassium carbonate (4.6 g, 33 mmol) and methyl iodide (2.1 mL, 33 mmol) were added. The reaction was heated to 60° C. and monitored by LC/MS. After heating for 2 hrs the reaction was complete. This was allowed to cool, diluted with ethyl acetate (300 mL) and filtered to remove the remaining solids. The organic layer was washed with water (3×), brine, dried over magnesium sulfate and concentrated to give the crude product as a dark solid. The product was purified by FCC on silica gel eluting hexane:ethyl acetate gradient to give 4-acetyl-3-methoxy-2-iodo-6-methylbenzonitrile as a pale yellow crystalline solid (5.0 g, 96%). LCMS calculated for C11H11INO2 (M+H)+: m/z=315.9; found: 316.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[C@@H:10](N)[CH2:11]C1C=CC(C2C=CC=C(Cl)C=2)=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[C@H](C)C(OCC)=O)(=O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)OCc1ccccc1
Agent: CCOC(=O)[C@@H](C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of (S)-2-amino-3-(3′-chloro-biphenyl-4-yl)-propionic acid benzyl ester (10.0 g, 24.9 mmol) in dichloromethane (100 mL) was added triethylamine (10.4 mL, 74.6 mmol) at 0° C. After stirred for 10 min, ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) was added at room temperature and stirred for 1 hour. Additional triethylamine (10.4 mL, 74.6 mmol) and ethyl (R)-2-(trifluoromethylsulfonyloxy)propionate (9.3 mL, 49.5 mmol) were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-3-(3′-chloro-biphenyl-4-yl)-2-(S)-1-ethoxycarbonyl-ethylamino)-propionic acid benzyl ester. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, 3H, J=7.3 Hz), 1.27 (d, 3H, J=6.8 Hz), 1.89 (bs, 1H), 2.95-3.07 (m, 2H), 3.38 (dd, 1H, J=6.8, 14.8 Hz), 3.69 (dd, 1H, J=7.1, 7.1 Hz), 4.06-4.17 (m, 2H), 5.06 (d, 1H, J=12.1 Hz), 5.12 (d, 1H, J=12.1 Hz), 7.20-7.25 (m, 4H), 7.28-7.34 (m, 4H), 7.35 (dd, 1H, J=7.6, 7.6 Hz), 7.41-7.46 (m, 3H), 7.53 (dd, 1H, J=1.5, 1.5 Hz); MS: m/z (MH+) 466.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O.O>[N:22]([CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][CH:8]1[C:12](=[O:13])[CH:11]=[C:10]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:9]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COC1=CC(=O)C(Cc2cccc(CCI)c2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC1=CC(=O)C(Cc2cccc(CCN=[N+]=[N-])c2)C1
Temperature: 50 °C
Yield: 76 %

Procedure:
A mixture of 30 (0.044 g, 0.11 mmol) and sodium azide (0.007 g, 0.11 mmol) in dry N,N-dimethylformamide (0.5 mL) was heated to 50° C. for 45 minutes. The reaction mixture was diluted with water and the resulting mixture extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue so obtained was dried under high vacuum to furnish the desired compound. Yield: 76%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:29][C:10]3=[N:11][CH:12]=[CH:13][C:14]([C:15]4[N:20]=[C:19]([NH:21][CH2:22][CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:18]=[CH:17][CH:16]=4)=[C:9]3[CH:8]=2)[CH2:3][CH2:2]1.C=O.O.[C:33]([BH3-])#N.[Na+]>CO.ClCCl>[CH3:33][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:29][C:10]3=[N:11][CH:12]=[CH:13][C:14]([C:15]4[N:20]=[C:19]([NH:21][CH2:22][CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:18]=[CH:17][CH:16]=4)=[C:9]3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1cc(NCC2CCOCC2)nc(-c2ccnc3[nH]c(C4CCNCC4)cc23)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2cc3c(-c4cccc(NCC5CCOCC5)n4)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Example 88C (15 mg, 0.04 mmol) in methanol (2 mL) was treated with 37% formaldehyde in water (12 mg, 0.4 mmol) and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (5 mg, 0.08 mmol) was added and the mixture was stirred at room temperature for 12 hours. The mixture was diluted with dichloromethane and washed with water. The organic phase was concentrated and purified by HPLC (Zorbax C-18, using a 0-100% gradient of water/acetonitrile, containing 0.1% trifluoroacetic acid) to afford the title compound. 1H NMR (400 MHz, DMSO-d6): δ 1.17-1.38 (m, 2H), 1.64-1.73 (m, 2H), 1.77-1.96 (m, 4H), 2.34 (d, J=13.56 Hz, 4H), 2.83 (d, J=4.75 Hz, 3H), 3.00-3.20 (m, 4H), 3.56 (d, J=11.53 Hz, 2H), 3.88 (dd, J=10.68, 3.22 Hz, 2H), 6.68 (d, J=8.48 Hz, 1H), 6.77-6.83 (m, 1H), 7.18 (d, J=7.80 Hz, 1H), 7.50 (d, J=5.09 Hz, 1H), 7.58-7.63 (m, 1H), 8.24-8.27 (m, 1H). LCMS: 406 (M+H)+.
Reaction SMILES: CI.[C:3](=O)([O-])O.[Na+].[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:17][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:33][S:34][C:35]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH2:17][N:18]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[C:24]2[C:29]([O:31][CH3:32])=[O:30])[CH3:3])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc2c(NC[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(N(C)C[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)cccc12
Temperature: 20 °C
Reaction time: 20 h

Procedure:
3.6 cm3 of methyl iodide and 7 g of solid sodium hydrogen carbonate are added, with stirring, to a solution of 1.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate in 25 cm3 of dimethyl-formamide. The reaction mixture is stirred for 20 hours at a temperature in the region of 20° C. and then poured onto 200 cm3 of ice. The aqueous phase is extracted 3 times with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The red oil obtained is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (90/10 by volume)]. 0.56 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propyl-N-methylamino)-1-naphthoate is obtained, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([O:13]CC)=O)=[N:6][CH:7]=1.C(O)C.O.[NH2:21][NH2:22]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:9][CH2:10][C:11](=[O:13])[NH:21][N:22]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=C1CCC(c2ccc(Cl)cn2)=NN1
Yield: 81.1 %

Procedure:
To a dry 200 mL flask equipped with magnetic stirrer, and reflux condenser was charged 3.7 g ethyl 4-(5-chloropyridin-2-yl)-4-oxobutanoate (0.0153 mol), 75 mL ethanol, and 0.8 g of hydrazine hydrate (0.0168 mol). The reaction was heated at reflux for about 2 hours. An aliquot was analyzed by GC which indicated no remaining starting material, and one major product. The reaction was cooled and poured into about 200 mL of water to afford a tan solid which was collected by vacuum filtration, washed with water, hexane, and dried overnight in vacuo at 40° C. Isolated 2.6 g of a tan solid. The NMR data is as follows: 300 MHz 1H NMR (CDCl3, TMS=0 ppm) 2.65 (t, 2H); 3.22 (t, 2H), 7.75 (d, 1H); 8.00 (d, 1H); 8.60 (s, 1H); 8.70 (bs, 1H). The sample was stored in the refrigerator and had 81% isolated yield.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[C@@H:9]1[CH3:25])=[O:7])(C)(C)C.CC1C=C(C)N=C(N[C@@H]2CCCN(C([C:43]3[CH:48]=[CH:47][C:46](F)=[CH:45][C:44]=3[N:50]3[N:54]=[CH:53][CH:52]=[N:51]3)=O)[C@H]2C)N=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:51]1[N:50]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][N:16]=3)[C@@H:9]2[CH3:25])=[O:7])[N:54]=[CH:53][CH:52]=1
Reactant: C[C@H]1[C@H](Nc2ccc(C(F)(F)F)cn2)CCCN1C(=O)OC(C)(C)C
Reactant: Cc1cc(C)nc(N[C@@H]2CCCN(C(=O)c3ccc(F)cc3-n3nccn3)[C@H]2C)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@H]1[C@H](Nc2ccc(C(F)(F)F)cn2)CCCN1C(=O)c1ccccc1-n1nccn1

Procedure:
(±)-trans-tert-butyl-2-methyl-3-((5-(trifluoromethyl)pyridin-2-yl)amino)piperidine-1-carboxylate. Prepared analogous to Example 1 substituting (±)-trans-(3-((4,6-dimethylpyrimidin-2-yl)amino)-2-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone with the title compound from Step B, intermediate A-1 with intermediate A-4 and HATU with HBTU. MS (ESI) mass calcd. for C21H21F3N6O, 430.2; m/z found 431.2 [M+H]+. MP=154.7° C. (Mixture of 4 isomers, undefined ratio). 1H NMR (300 MHz, DMSO) δ 8.36 (d, J=21.8 Hz, 0.44H), 8.24 (d, J=12.9 Hz, 0.36H), 8.08 (d, J=1.3 Hz, 1.62H), 7.97 (s, 0.47H), 7.91 (d, J=8.2 Hz, 0.41H), 7.83-7.32 (m, 4.20H), 7.32-7.21 (m, 0.48H), 7.06-6.96 (m, 0.47H), 6.82 (d, J=8.9 Hz, 0.76H), 6.71 (dd, J=13.9, 7.0 Hz, 0.59H), 6.60 (s, 0.10H), 6.15 (d, J=8.8 Hz, 0.10H), 4.93 (d, J=6.0 Hz, 0.12H), 4.68 (q, J=6.8 Hz, 0.39H), 4.41 (t, J=13.4 Hz, 0.65H), 4.17-3.83 (m, 0.78H), 3.81-3.61 (m, 0.73H), 3.20 (d, J=14.4 Hz, 0.35H), 2.94 (t, J=11.7 Hz, 0.52H), 2.85-2.66 (m, 0.46H), 2.19-1.49 (m, 3.53H), 1.49-1.22 (m, 2.07H), 0.74 (d, J=6.9 Hz, 1.40H).
Reaction SMILES: [CH3:1][C:2](=[CH2:10])[CH2:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7].C1N2CCN(CC2)C1>C(O)C.O.CCCCC>[CH3:1][C:2]([CH3:10])=[CH:3][O:4][CH2:5][C:6]([F:9])([F:8])[F:7]
Reactant: C=C(C)COCC(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Solvent: CCCCC
Product: CC(C)=COCC(F)(F)F

Procedure:
In 100 ml 20% ethanol/water is added 11 g (71.4 mmol) 2,2,2-trifluoroethyl 2-methyl-2-propenyl ether and 0.59 g (0.642 mmol) 1,4-diazobicyclo(2,2,2)octane. Rhodium tris-triphenylphosphine chloride (16 g, 142.8 mmol) is then added to the stirring mixture, and the solution is heated to 90° for 4 hr. The reaction is then cooled, brought up in pentane, filtered, washed with water and brine and dried over sodium sulfate. The crude product is distilled, yielding 2,2,2-trifluoroethyl 2-methyl-1-propenyl ether.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:8](OC)=[O:9])[CH2:7][CH2:6]1)=[O:4].O>O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>[OH:9][CH2:8][C:5]1([C:3]([NH:2][CH3:1])=[O:4])[CH2:7][CH2:6]1
Reactant: CNC(=O)C1(C(=O)OC)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C1(CO)CC1
Reaction time: 1 h

Procedure:
Methyl 1-(methylcarbamoyl)cyclopropanecarboxylate 5b (942 mg, 6 mmol) was dissolved in 10 mL of tetrahydrofuran in a dry ice-acetone bath, by addition of a solution of diisobutylaluminum hydride in tetrahydrofuran (1 M, 18 mL), then the reaction solution was stirred for 1 h, followed by addition of 3 mL of water. After removing the dry ice-acetone bath, the reaction solution was continuously stirred at room temperature for 1 h. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1-(hydroxymethyl)-N-methyl cyclopropanecarboxamide 5c (800 mg, a yellow solid), which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C-]#N.[Na+].[C:13]1(/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][C:21](=[O:23])[CH3:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CC(=O)/C=C/c1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CC(C(=O)c1cccc(F)c1)c1ccccc1
Reaction time: 1.5 h
Yield: 56.8 %

Procedure:
A solution of 3-fluorobenzaldehyde (2.005 ml, 18.33 mmol) in DMF (5 ml) was added dropwise over the course of 0.5 hours to a mixture of sodium cyanide (0.450 g, 9.18 mmol) in DMF (20 ml) at 35° C. Stirring was then continued for 1.5 hours at 35° C. A solution of (E)-4-phenylbut-3-en-2-one (2.0 g, 13.68 mmol) in DMF (5 ml) was then slowly added dropwise over the course of 0.5 hours at 35° C. Stirring was continued for 3.5 hours at the same temperature. The reaction mixture was treated with twice its volume of water and extracted with DCM. The combined extracts were washed with water and brine, dried with Na2SO4, filtered and concentrated to give a liquid, purified by chromatography on silica gel using an automated Biotage system (EtOAc/Hex, 0-50%) to give 1-(3-fluorophenyl)-2-phenylpentane-1,4-dione (2.1 g, 7.77 mmol, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.75-7.73 (m, 1H), 7.64-7.61 (m, 1H), 7.37-7.12 (m, 7H), 5.03 (dd, 1H), 3.61 (dd, 1H), 2.76 (dd, 1H), 2.19 (s, 3H).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[CH3:12][C:13]([CH3:17])=[CH:14][CH:15]=O.C(O)(=O)CC>>[CH3:12][C:13]([CH3:17])=[CH:14][CH2:15][CH2:3]/[C:2](/[CH3:1])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:8])=[CH:9]/[CH:10]=[O:11]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CC=O
Solvent: CCC(=O)O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Yield: 84 %

Procedure:
100 parts of geraniol, 30 parts of 3,3-dimethylacrolein and 2.5 parts of propionic acid are heated together at refluxing temperature for four hours while stirring. The product is distilled. 83.5 parts of farnesal is obtained having a boiling pointof 120° to 123° C at 0.2 mm. The yield is 84% of theory at a conversion of 63% (based on 3,3-dimethylacrolein).