Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[S:19][C:20]=1[Cl:21])\[C:13]([NH:32][C@@H:33]1[C:40](=[O:41])[N:39]2[C@@H:34]1[S:35][CH2:36][C:37]([CH2:58][Cl:59])=[C:38]2[C:42]([O:44][CH:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:43])=[O:14])([CH3:9])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)O)c(Cl)s1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CCl)CS[C@H]23)c(Cl)s1
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a suspension of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (20 g, 39.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (18.59 g, 41.2 mmol) in Dichloromethane (DCM) (300 mL) at −30° C. was added phenyl phosphorodichloridate (7.15 mL, 47.1 mmol), followed by dropwise 4-methylmorpholine (12.94 mL, 118 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (120 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-45% EtOAc/Hexanes) to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (29.9 g, 34.7 mmol, 89% yield) as a light yellow foaming solid. LCMS: (M+H)+: 860.3
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C@H:14]([C@@H:27]([OH:29])[CH3:28])[C:15]([NH:17][NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])=[CH:5][CH:4]=1)#[N:2].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>C1COCC1>[OH:29][C@@H:27]([CH3:28])[C@@H:14]([NH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:15]1[O:16][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:18][N:17]=1
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)C(=O)NNC(=O)c1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](Nc1ccc(C#N)c2ccccc12)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Yield: 27.9 %

Procedure:
The crude material of N′-((2R,3S)-2-(4-cyanonaphthalen-1-ylamino)-3-hydroxybutanoyl)benzohydrazide (intermediate 13b) (602 mg, 1.5501 mmol) was added to THF (100 mL) stirred at room temperature. PS-BEMP (2.11 g, 4.65 mol base) was added to the solution followed by slow addition of p-TSCl (355 mg, 1.8601 mmol). The reaction mixture was stirred for 2 h and the progress of the reaction was monitored by TLC. After the completion of the reaction the BEMP reagent was filtered off and the solution concentrated to get the crude material. The crude material was chromatographed with hexanes:EtOAc (6:4) to give the product (160 mg, 28%). 1H NMR(500 MHz, CDCl3, δ in ppm) 8.11 (d, J=9Hz, 1H), 8.01 (d, J=9Hz, 1H), 7.83 (d, J=9 Hz, 2H), 7.69 (d, J=9 Hz, 1H), 7.62 (t, J=9 Hz, 1H), 7.52 (t, J=9 Hz, 1H), 7.45 (t, J=9Hz, 1H), 7.36 (t, J=9 Hz, 2H), 6.64 (d, J=9 Hz, 1H), 6.20 (d, J=9 Hz, 1H), 4.93 (dd, J=5.0, 9.0 Hz, 1H), 4.70 (m, 1H), 4.06 (d, J=5 Hz, 1H), 1.47 (d, J=6 Hz, 3H).
Reaction SMILES: [Na][Na].N[C:4]1C=C[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[C:13](O)=[O:14].[NH2:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=O>>[CH3:4][C:5]1[C:13](=[O:14])[N:16]([C:17]2[CH:18]=[C:19]3[C:26](=[O:27])[O:28][C:21](=[O:23])[C:20]3=[CH:24][CH:25]=2)[C:7](=[O:8])[C:6]=1[CH3:10]
Reactant: Nc1cccc(C(=O)O)c1C(=O)O
Reactant: Nc1ccc(C(=O)O)c(C(=O)O)c1
Agent: [Na][Na]
Product: CC1=C(C)C(=O)N(c2ccc3c(c2)C(=O)OC3=O)C1=O

Procedure:
If instead of 22.5 g of the disodium salt of 3-aminophthalic acid, an equivalent amount of the disodium salt of 4-aminophthalic acid is employed and in other respects the procedure indicated in the above example is followed, 4-(di-methylmaleinimidyl)-phthalic anhydride of melting point 197° C. is obtained.
Reaction SMILES: [C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([OH:12])=O)[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2].C[N+](C)=CCl.[Cl-].ClCCl.[CH3:28][NH:29][CH2:30][C:31]1[N:38]2[C:34]([S:35][CH:36]=[CH:37]2)=[CH:33][N:32]=1>>[C:1]([S:4][C@H:5]1[CH2:9][C@@H:8]([C:10]([N:29]([CH2:30][C:31]2[N:38]3[C:34]([S:35][CH:36]=[CH:37]3)=[CH:33][N:32]=2)[CH3:28])=[O:12])[N:7]([C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CNCc1ncc2sccn12
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)N(C)Cc1ncc2sccn12
Yield: 47.4 %

Procedure:
The procedure of Synthesis Example 1 is repeated, except that 260 mg of (3S,5S)-3-acetylthio-1-allyloxycarbonylpyrrolidin-5-carboxylic acid, 0.95 ml of a 1.1 M Vilsmeier reagent/dichloromethane solution, and 159 mg of 5-(N-methylaminomethyl)imidazo[5,1-b]thiazole. Thus, 190.6 mg of the title compound is prepared as a slightly yellow amorphous material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:12]=[C:11]([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[CH:30]([F:32])[F:31])[N:10]=1.O>CS(C)=O>[F:32][CH:30]([F:31])[C:22]1[N:21]([C:11]2[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)[N:14]=[C:9]([NH:1][C:2]3[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=3)[N:10]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1
Reactant: Cn1cc(N)cn1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(Nc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cn1
Temperature: 125 °C
Yield: 17.9 %

Procedure:
A mixture of 0.405 g (4.27 mmol) of 4-amino-1-methylpyrazole and 0.695 g (1.90 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in DMSO (5 mL) was heated at 125° C. for 15 min. The reaction mixture was cooled to room temperature and water was added. The solid was collected by filtration, washed with water, and dried. Chromatography on alumina, eluting with hexanes/EtOAc (1:1) gave a brown powder. Recrystallization from ethanol/CH2Cl2 gave 0.145 g (18% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(1-methyl-1H-pyrazol-4-yl)-6-(4-morpholinyl)-1,3,5-triazin-2-amine: mp 225-226° C.; 1H NMR (DMSO-d6) (rotamers) δ 10.00 (s, 1H), 9.73 (s, 0.2H), 8.60 (d, J=8.0 Hz, 1H), 8.29 (d, J=7.6 Hz, 0.2H), 7.92 (t, JHF=52.8 Hz, 1H), 7.86-7.80 (m, 2.6H), 7.68 (t, JHF=52.6 Hz, 0.2H), 7.59 (s, 1H), 7.52-7.42 (m, 2.9H), 3.85-3.82 (m, 8.4H), 3.75-3.73 (m, 4.8H); Anal. Calcd. for C19H19F2N9O 0.06EtOAc 0.24H2O: C, 52.9; H, 4.6; N, 28.8. Found: C, 52.9; H, 4.5; N, 28.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:20][C:21]([C:23]3[O:27][C:26]([C:28](C)=[CH2:29])=[N:25][CH:24]=3)=[O:22])[CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:31]=[O+][O-]>C(Cl)Cl.CO>[C:28]([C:26]1[O:27][C:23]([C:21]([NH:20][C@H:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=2)[CH2:16][C:17]([OH:19])=[O:18])=[O:22])=[CH:24][N:25]=1)(=[O:31])[CH3:29]
Reactant: C=C(C)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ncc(C(=O)N[C@@H](CC(=O)O)Cc2ccc(-c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-4-(3′-chlorobiphenyl-4-yl)-3-(2-(prop-1-en-2-yl)oxazole-5-carboxamido)butanoic acid (60 mg, 0.14 mmol) in DCM (2 mL) and MeOH (2 mL) at −78° C. is bubbled ozone for 30 seconds. After 30 seconds ozone is removed and oxygen is bubbled for 10 minutes. After bubbling oxygen for 10 minutes the −78° C. bath is removed and the reaction is quenched with polymer supported triphenylphosphine and the reaction is stirred at room temperature for 2 hours. After 2 hours the reaction is filtered to remove triphenylphosphineoxide on supported polymer and the filtrate is collected and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(2-acetyloxazole-5-carboxamido)-4-(3′-chlorobiphenyl-4-yl)butanoic acid (13 mg). HPLC retention time=1.67 minutes (condition D); MS (m+1)=427.0; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.53-2.59 (m, 2H) 2.60 (s, 3H) 2.87 (dd, J=10.9, 3.3 Hz, 1H) 2.94 (dd, J=10.9, 5.1 Hz, 1H) 4.46-4.60 (m, 1H) 7.31 (d, J=8.1 Hz, 2H) 7.36-7.43 (m, 1H) 7.47 (t, J=7.8 Hz, 1H) 7.62 (d, J=8.3 Hz, 3H) 7.69 (t, J=1.9 Hz, 1H) 7.94 (s, 1H) 8.86 (d, J=8.6 Hz, 1H) 12.31 (br. s., 1H).
Reaction SMILES: B.C1COCC1.[I:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([C:18](O)=[O:19])[CH2:12][CH2:11]2.O.C([O-])(O)=O.[Na+]>C1COCC1>[I:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C@@H:13]([CH2:18][OH:19])[CH2:12][CH2:11]2
Reactant: O=C(O)[C@H]1CCc2cc(I)ccc2O1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CCc2cc(I)ccc2O1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A solution of borane-THF complex (1M in THF, 23.4 mmol, 1.2 eq) was added dropwise to a solution of (2R)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, 19.5 mmol, 1.0 eq.) in THF (45 mL) at 10° C. The resulting reaction mixture was stirred at 45° C. for 1.5 hours and was then cooled to 10° C. Next, water was added followed by saturated NaHCO3 solution. The resulting two-phase mixture was separated and aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, concentrated to afford the product as a white solid in quantitative yield that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([P:8]([O-:12])[O:9][CH2:10][CH3:11])[O:5][CH2:6][CH3:7])[CH3:2].[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([CH:18]=[CH:19][C:20]#[N:21])=[CH:16][CH:15]=1.[H-].[Na+].C(O)(=O)C>C(O)C>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]([P:8]([CH:4]([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])(=[O:12])[O:9][CH2:10][CH3:11])[CH2:19][C:20]#[N:21])=[CH:22][CH:23]=1
Reactant: CCOC(OCC)P([O-])OCC
Reactant: N#CC=Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(OCC)P(=O)(OCC)C(CC#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 25.8 g of ethyl (diethoxymethyl)phosphonite and 18.0 g of 4-chlorocinnamonitrile in 100 ml of ethanol is added to a stirred mixture of 1.2 g of sodium hydride (50% dispersion in oil) in 30 ml of ethanol at 0° C. under an atmosphere of nitrogen. The reaction mixture is allowed to warm to room temperature and stirred for 4 hours. 1 ml of glacial acetic acid is added and the mixture is concentrated under reduced pressure. The resulting crude product is dissolved in 50 ml of ethyl acetate, washed twice with 25 ml of water and the organic extract is dried over magnesium sulphate, and then concentrated under reduced pressure. The crude product is distilled under reduced pressure to give ethyl 1-(4-chlorophenyl)-2-cyanoethyl(diethoxymethyl)phosphinate, b.p. 180°-200° C./0.02 mbar, 31 p=+37.9 and +35.8 ppm (CDCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=S)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:12]#[C:13][NH2:14].[Na].Cl.CN(C)CCCN=C=NCC.[CH2:28]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([CH2:36][N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:31]1)[CH3:29]>C(O)C.CN(C)C=O>[C:13]([N:14]=[C:10]([N:40]1[CH2:39][CH2:38][N:37]([CH2:36][C@@H:32]2[CH2:33][CH2:34][CH2:35][N:30]([CH2:28][CH3:29])[CH2:31]2)[CH2:42][CH2:41]1)[NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:12]
Reactant: CCN1CCC[C@@H](CN2CCNCC2)C1
Reactant: N#CN
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCN1CCC[C@@H](CN2CCN(C(=NC#N)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.6 %

Procedure:
3,4-Dichlorophenylisothiocyanate (204 mg) and sodium hydrogen cyanamide (70 mg) were refluxed in ethanol (20 ml) for three hours. The mixture was allowed to cool to room temperature then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg), 1-{[(3R)-1-ethylpiperidin-3-yl]methyl}piperazine (220 mg) and N,N-dimethylformamide (2 ml) were added and the reaction left to stir for 18 hours then concentrated in vacuo. The crude product was subjected to reverse phase HPLC using a gradient of 95% water/acetonitrile/0.1% TFA through to 50% water/acetonitrile/0.1% TFA. The combined product fractions were concentrated in vacuo then separated between dichloromethane (50 ml) and saturated sodium bicarbonate solution (100 ml). The dichloromethane layer was separated, dried over magnesium sulphate, filtered and concentrated in vacuo to give the title compound (159 mg).
Reaction SMILES: C(OP([CH2:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])(OCC)=O)C.[H-].[Na+].[CH:22]1([C:28]2[CH:43]=[CH:42][C:31]([CH2:32][O:33][C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3[CH:36]=O)=[CH:30][CH:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)C1C(=CC=CC=1)O.C1(C2C=CC(CCl)=CC=2)CCCCC1>C1COCC1.O>[CH:22]1([C:28]2[CH:43]=[CH:42][C:31]([CH2:32][O:33][C:34]3[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=3/[CH:36]=[CH:9]/[C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:30][CH:29]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CCOP(=O)(CC(=O)CCCCC(=O)OC)OCC
Reactant: O=Cc1ccccc1OCc1ccc(C2CCCCC2)cc1
Agent: ClCc1ccc(C2CCCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=Cc1ccccc1O
Solvent: O
Product: COC(=O)CCCCC(=O)/C=C/c1ccccc1OCc1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, a solution of 3.00 g (10.19 mmol) of methyl 7-(diethoxyphosphoryl)-6-oxo-heptanoate XIIb in 10 ml of THF was added dropwise to a suspension of 0.25 g (10.19 mmol) of sodium hydride in 20 ml of THF. After 30 min, a solution of 2.50 g (8.49 mmol) of 2-[(4-cyclohexylbenzyl)oxy]benzaldehyde (obtainable from salicylaldehyde and 4-cyclohexylbenzyl chloride in 10 ml of THF was added dropwise. The mixture was stirred at room temperature for 2 days. Water was added, the mixture was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4. The product was purified chromatographically (silica gel, cyclo-hexane/ethyl acetate 10:1).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][S:6][CH3:7])C.Cl.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=2)=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>>[CH3:7][S:6][CH2:5][CH2:4][NH:26][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:12])([F:27])[F:28])=[CH:15][CH:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(CSC)OCC
Reactant: Nc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CSCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 1 h
Yield: 45.1 %

Procedure:
A solution of 2-(methylthio)-acetaldehyde diethyl acetal (0.465 g, 2.83 mmol) in 0.5 M HCl (5.66 mL, 2.83 mmol) was heated to 50° C. and stirred under nitrogen for 1 h. The reaction mixture was allowed to cool and extracted with CH2Cl2 (20 mL). The organic solution was dried (hydrophobic frit), and stood over molecular sieves for 2 h then decanted off into a clean flask. To this solution was added 4′-(trifluoromethyl)-1,1′-biphenyl-3-ylamine (0.67 g, 2.83 mmol) followed by sodium triacetoxyborohydride (1.68 g, 7.93 mmol) and acetic acid (0.162 mL, 2.83 mmol). The resultant mixture was stirred at room temperature under nitrogen for 16 h. The reaction was quenched with sat. NaHCO3 aq. (30 mL) and extracted with CH2Cl2 (2×40 mL), the organic solution was passed through a hydrophobic frit and the solvent removed in vacuo. Purification by Biotage™ chromatography (90 g Silica column) eluted with 1:19 EtOAc:cyclohexane afforded the title compound as a pale yellow oil (397 mg).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[C:12]([CH2:14]C(O)=O)#[N:13].[NH:18]1CCC[CH2:20][CH2:19]1.CN1CCOCC1>>[OH:6][C:5]1[CH:4]=[C:3]([CH:2]([CH2:14][C:12]#[N:13])[CH2:20][C:19]#[N:18])[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: C1CCNCC1
Reactant: COc1ccc(C=O)cc1O
Reactant: N#CCC(=O)O
Solvent: CN1CCOCC1
Product: COc1ccc(C(CC#N)CC#N)cc1O
Temperature: 25 °C
Yield: 590.4 %

Procedure:
To a 500 mL flask containing isovanillin (30.4 gm, 200 mmol) and cyanoacetic acid (68.0 gm, 800 mmol) was charged a solution consisting of 3.0 mL (30 mmol) piperidine and 151 mL N-methylmorpholine. The initially formed yellow slurry was warmed to mild reflux for 21 hours and then cooled to room temperature and concentrated on a rotary evaporator. The resulting brown oil was dissolved in 430 mL ethyl acetate (EtOAc), washed sequentially with water (H2O), five normal hydrochloric acid (5N HCl) and H2O and the combined aqueous washes back extracted with dichloroethane. Combination of the organic layers followed by solvent removal led to a thick orange oil which was crystallized from ethyl acetate/methylene chloride (EtOAc/CH2Cl2) to yield 38.3 gm of orange solids after filtration and drying. Recrystallization from EtOAc/diisopropyl ether gave 35.3 gm (82%) of light yellow solid, m.p. 90-92° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4]Cl.[Cl:6][SiH:7]([Cl:9])[Cl:8]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:6][Si:7]([Cl:9])([Cl:8])[CH2:2][CH2:3][CH2:4][Si:7]([Cl:9])([Cl:8])[Cl:6].[Cl:1][CH2:2][CH2:3][CH2:4][Si:7]([Cl:9])([Cl:8])[Cl:6]
Reactant: ClCCCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: ClCCC[Si](Cl)(Cl)Cl
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 14 %
Yield: 72 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 0.85 g (7.5 mmol) of 1,3-dichloropropane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 10 hrs. The resulting mixture was distilled to give 1.68 g of 1,3-bis(trichlorosilyl)propane (yield; 72%) and 0.22 g of (3-chloropropyl)trichlorosilane (yield; 14%).
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16](O)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.FC(F)(F)C([O-])=O>ClCCl>[CH3:1][N:2]1[CH2:20][CH2:19][C:5]2[N:6]([CH2:14][CH2:15][C:16]([N:21]3[CH2:22][CH2:23][CH:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:25][CH2:26]3)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCC(=O)O)CCN(C)C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CCC(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)CCN(C)C1
Yield: 6.1 %

Procedure:
The title compound, tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate, was obtained as follows. 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoic acid (500 mg, 1.8 mmol) (See Example 54B) was stirred with tert-butyl piperidin-4-ylcarbamate (0.366 ml, 1.8 mmol), EDCI-HCl (0.35 g, 1.8 mmol) and triethyl amine (0.253 ml, 1.8 mmol) in dichloromethane (20 ml) to obtain 50 mg of tert-butyl 1-(3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoyl)piperidin-4-ylcarbamate as a trifluoroacetate salt after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient followed by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:24][C:25](O)=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].[NH:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(#N)C>[CH2:1]([O:3][P:4]([CH2:24][C:25]([N:28]1[CH2:42][CH2:41][CH2:40][C@H:29]1[C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:26])([CH:6]([CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)O)C(CCc1ccccc1)CC(=O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: CC#N
Product: CCOP(=O)(CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)C(CCc1ccccc1)CC(=O)c1ccccc1
Reaction time: 1.5 h
Yield: 74 %

Procedure:
A solution of the product from part (d) (834 mg., 2.15 mmole) in dry acetonitrile (8 ml.) is treated with N,N'-carbonyldiimidazole (375 mg., 2.31 mmole) and stirred at 0° (ice bath) under argon for 1.5 hours. The resulting solution is then treated with L-proline, benzyl ester (455 mg., 2.22 mmole) in acetonitrile and stirred at room temperature for 4 hours. The mixture is evaporated to dryness and the residue is taken up in ethyl acetate. The ethyl acetate solution is washed successively with 5% potassium bisulfate, saturated sodium bicarbonate and saturated sodium chloride, dried over Na2SO4 and evaporated. The residue (1.325 g.) is purified by flash chromatography on silica gel (75 g.) eluting with 1% methanol/dichloromethane to give (±)-1-[[ethoxy[3-oxo-3-phenyl-1-(2-phenylethyl)propyl]phosphinyl]acetyl]-L-proline, phenylmethyl ester (74%) as a colorless glass, Rf (methanol/dichloromethane; 5:95) 0.29.
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[NH2:16][C@H:17]([C:22]([NH2:24])=[O:23])[CH2:18][CH2:19][S:20][CH3:21].C(N(CC)CC)C>CCO>[CH2:1]([CH:3]([CH2:13][CH3:14])[C:4]([N:6]1[CH2:11][CH2:10][C:9]2([NH:24][C:22](=[O:23])[C@H:17]([CH2:18][CH2:19][S:20][CH3:21])[NH:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CSCC[C@H](N)C(N)=O
Reactant: CCC(CC)C(=O)N1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](CCSC)N2

Procedure:
A solution of 1-(2-ethylbutyryl)-piperidin-4-one (1.6 g, 8.1 mmol), (S)-methioninamide hydrochloride (1.5 g, 8.1 mmol), and triethylamine (820 mg, 8.1 mmol) in EtOH (66 mL) was heated under reflux over a period of 16 h. Following removal of the solvent, water (50 mL) and CH2Cl2 (50 mL) were added to the residue and the mixture was basified with concentrated sodium hydroxide solution. The aqueous phase was extracted with CH2Cl2 (3×20 mL) and the combined organic phases were dried over Na2SO4. Following removal of the solvent and vacuum drying, there was obtained the product 8-(2-ethylbutyryl)-3-(S)-(2-methylsulfanylethyl)-1,4,8-triazaspiro[4,5-]-decan-2-one in a yield of 1.8 g (69%).