Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[C:2]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N+:11]2[CH2:14][CH:15]=[CH2:16])=[CH:6][CH:5]=1)#[N:3].[OH-:17].[K+].O>O1CCOCC1.O.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[O:17]=[C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2)[N:11]1[CH2:14][CH:15]=[CH2:16]
Reactant: C=CC[n+]1cccc2ccc(C#N)cc21
Reactant: [OH-]
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCn1c(=O)ccc2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
A mixture of 7-cyano-1-(2-propen-1-yl)quinolinium iodide (1.75 g, 5.4 mmol), potassium hydroxide (1.33 g, 23.76 mmol) and potassium ferricyanide (3.9 g, 11.9 mmol) in 50% 1,4-dioxane/water was stirred at rt for 2 h. Water (50 ml) was then added and the organic phase was extracted with 10% methanol/DCM (2×100 ml). The combined organic phases were washed with water (100 ml) then dried and evaporated. The residue was chromatographed on silica gel, eluting with 0-5% methanol-DCM to afford the desired compound (0.6 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[NH2:36][CH2:37][CH2:38][OH:39]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[N:36]([CH2:37][CH2:38][OH:39])[CH:11]=[C:12]([C:24](=[O:29])[C:25]([CH3:27])([CH3:26])[CH3:28])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: CC(C)(C)C(=O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reactant: NCCO
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1cn(CCO)c(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Temperature: 60 °C
Reaction time: 11 h

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (113 mg) in tetrahydrofuran (0.7 ml)-ethanol (0.7 ml) was added 2-aminoethanol (0.015 ml) and the mixture was stirred at 60° C. for 11 hr. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=3:1) to give 3-benzyloxy-5-(2,2-dimethylpropionyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (91 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:20](OC(=O)C)(=[O:22])[CH3:21]>>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:22])[CH3:21]
Reactant: CC1CCc2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C(C)CC2

Procedure:
10-Amino-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (5.0 g., 0.018 mole) and acetic anhydride (50 ml.) are stirred and heated on a steam bath for three hours. After cooling, the solid precipitate is separated by filtration, washed with water, dried, then recrystallized from N,N-dimethyl formamide to provide 10-acetamido-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, m.p. 277°-279° C.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].C(O[C:39]1(O[Si](C)(C)C)[CH2:41][CH2:40]1)C>CO.C(O)(=O)C>[CH:39]1([N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[C:6]2[C:7]([S:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:41][CH2:40]1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(SC)nn12
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CC3)C3CC3)c(SC)nn12
Temperature: 25 °C

Procedure:
After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (60 μL), acetic acid (298 μL) and sodium cyanoborohydride (171 mg) were added and the mixture was heated to reflux for 6 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added, extraction was performed with ethyl acetate, and the organic layer washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (74 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>CC(N(C)C)=O>[N:13]1([C:2]2[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Product: N#Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 107.8 %

Procedure:
A mixture of 5-chloro-2-nitrobenzonitrile (20.0 g) and imidazole (22.3 g) in DMA (150 ml) was heated at 140° C. for 6 hours. The mixture was evaporated and the residue was triturated with water to give 5-(1-imidazolyl)-2-nitrobenzonitrile (25.3 g); NMR Spectrum: (CD3SOCD3) 7.20 (d, 1H), 8.05 (t, 1H), 8.28 (m, 1H), 8.62 (m, 2H), 8.51 (d, 1H);
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:21][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=O)[O:26]1)[CH3:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>C(COC)OC.C1COCC1>[CH3:23][N:22]([CH2:24][CH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])[O:26]1)[CH3:21]
Reactant: CN(C)CC1OC(=O)c2ccccc21
Reactant: O=C1Cc2ccccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: C1CCOC1
Product: CN(C)CC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
To a solution of oxindole (205 mg, 1.54 mmol) in dimethoxyethane (4.0 ml) at room temperature was added 1.0M LiHMDS in THF (1.54 ml). After stirring for 10 minutes at room temperature, 3-dimethylaminomethyl-3H-isobenzofuran-1-one (235 mg, 1.23 mmol) in dimethoxyethane (0.5 ml) was added and the mixture was stirred rapidly for 1 hour. Additional 1.0M LiHMDS/THF (1.54 ml) was added. After 2 hours the reaction was quenched into 10% HCl (50 ml) and 25 ml water added. The aqueous layer was washed with EtOAc and then basified with saturated NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc. The EtOAc layer was washed with brine, dried over anhydrous Na2SO4, and rotary evaporated to provide a yellow solid. The yellow solid was chromatographed silica gel column (CHCl3 to 2.5% MeOH/CHCl3 gradient) and then recrystallized from MeOH to give 3-(3-dimethylaminomethy-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one as yellow needles (92 mg, 24%).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.NC(N)=[S:22].[OH-].[Na+].Cl>O.C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[NH:6][C:2](=[S:22])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1oc(=S)[nH]c1-c1ccc(Cl)cc1
Yield: 100 %

Procedure:
A mixture of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (5.72 g), thiourea (4.57 g) and ethanol (70 ml) was stirred under reflux for 30 minutes. An aqueous solution of 2N sodium hydroxide (40 ml) was added to the reaction mixture, and stirred under reflux for an additional 30 minutes. Water was added to the reaction mixture, which was then neutralized with 6N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 3-[4-(4-chlorophenyl)-2-thioxo-4-oxazolin-5-yl]propionic acid (5.41 g, yield: 96%). This was recrystallized from ethanol to give colorless needles. mp 196-197° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28]([NH:30][C@H:31]([C@H:39]1[O:41][CH2:40]1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CO.O>[OH:41][C@H:39]([C@@H:31]([NH:30][C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:40][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CC(C)(C)OC(=O)NNCc1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 58.7 g (197 mmol) of N1 -(tert-butoxycarbonyl)-N2 -(4-biphenylylmethyl)hydrazine and 51.8 g (197 mmol) of N-(tert-butoxycarbonyl)-2(S)-amino-1-phenyl-3(R)-3,4-epoxybutane (=(2R,3S)-1-[3-Boc-amino-2-phenylethyl]-oxirane) in 700 ml of absolute methanol is heated to reflux temperature during 16 h. The mixture is then cooled to 0° C. and diluted with 1.5 l of water. The solid is filtered and dried at 70° C. for 6 h to give the title compound:
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C=O)C>[CH:22]1([CH:14]([C:11]2[CH:10]=[CH:9][C:8]([CH3:7])=[CH:13][CH:12]=2)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Reactant: BrC1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
33.5 g (0.3 mol) of potassium tert-butylate are initially introduced into 100 ml of anhydrous DMF at 0° C., and 51.6 g (0.25 mol) of tert-butyl 4-methylphenyl-acetate in 250 ml of anhydrous DMF are added dropwise. The mixture is stirred at 0° C. for 30 minutes, 32.2 ml (0.3 mol) of cyclopentyl bromide in 150 ml of anhydrous DMF are added dropwise at 5-15° C. and the mixture is stirred at 25° C. for 20 hours. After concentration, the residue is partitioned between water and diethyl ether and the ether phase is dried over sodium sulphate and concentrated. The product crystallizes out.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:15]>C([O-])(C([O-])=O)=O.C([O-])(C([O-])=O)=O.O=[Ti+2].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][OH:12])(=[O:9])[O:4][CH2:5][CH2:6][OH:15])[CH3:2]
Reactant: OCCO
Reactant: CCCCOP(=O)(CC)CCO
Agent: O=[Ti+2]
Agent: O=C([O-])C(=O)[O-]
Agent: [K+]
Product: CCP(=O)(CCO)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To 388 g (2 mol) of butyl ethyl(2-hydroxyethyl)phosphinate (produced as in Example 5) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyloxalate, followed by stirring at 200° C. for 2 h. Volatiles are distilled off by gradual evacuation to leave 315 g (96% of theory) of 2-hydroxyethyl ethyl-(2-hydroxyethyl)phosphinate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][OH:19])[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2].N1C=CC=CC=1.[N+:30]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([N+:42]([O-:44])=[O:43])[CH:41]=1)[C:36](Cl)=[O:37])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:23])[C:8]2[CH:9]=[C:10]([F:22])[C:11]([F:21])=[C:12]3[O:17][CH2:16][CH:15]([CH2:18][O:19][C:36](=[O:37])[C:35]4[CH:34]=[C:33]([N+:30]([O-:32])=[O:31])[CH:41]=[C:40]([N+:42]([O-:44])=[O:43])[CH:39]=4)[N:14]([CH:20]=1)[C:13]=23)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2CO
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)OCC2COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 75.2 %

Procedure:
One gram of (±)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (I) and 500 mg of pyridine were suspended in 100 ml of anhydrous tetrahydrofuran (THF), and 1.6 g of 3,5-dinitrobenzoyl chloride was added thereto, followed by refluxing at 90° C. The suspension was once dissolved, and a colorless precipitate was then formed. The reaction was continued for 1.5 hours. After cooling, the precipitate was collected by filtration, washed with methanol and diethyl ether and dried to obtain 1.2 g of (±)-9,10-difluoro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (II) as a colorless powder having a melting point of 240°-242° C. NMR (CDCl3 /5% DMSO-d6) δ(ppm); 1,30 (3H, t, J=7.0 Hz, --CH2CH3), 4.26 (2H, q, J=7.0 Hz, --CH2CH3), 4.4-4.5 (5H, m), 7.76 (1H, dd, J=11.0 Hz, 7.0 Hz, C8 -H), 8.8 (1H, s, C5 -H), 9.0 (2H, d, J=3.0 Hz, aromatic ring proton) and 9.2 (1H, t, J=3.0 Hz, aromatic ring proton).
Reaction SMILES: C(N(CC)CC)C.C(O[C@H:12]1[NH:15][C:14](=[O:16])[C@@H:13]1[C@H:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:18][O:19][SiH:20]([CH3:22])[CH3:21])(=O)C.[N+:27](=[C:29]([C:36](=[O:38])[CH3:37])[C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N-:28].FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[C:23]([C@@H:17]([C@H:13]1[C@@H:12]([CH2:37][C:36](=[O:38])[C:29]([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])=[N+:27]=[N-:28])[NH:15][C:14]1=[O:16])[CH2:18][O:19][SiH:20]([CH3:21])[CH3:22])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)C(=[N+]=[N-])C(=O)C[C@H]1NC(=O)[C@H]1[C@@H](CO[SiH](C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
7.2 ml (52 mmol - 2.6 equivalents) of triethylamine are added to a solution, which has been cooled to 0° C., of 5.75 g (20 mmol) of (3R,4R)-4-acetoxy-3-[(1R)-1-tert.-butyldimethylsilyloxyethyl]azetidin-2-one [S. Oida et al. Chem. Pharm. Bull. 29 2899 (1981); M. Shiozaki et al. Tetrahedron 39 2399 (1983)] and 4.37 g (26 mmol - 1.3 equivalents) of allyl 2-diazo-3-oxobutanoate in 190 ml of anhydrous dichloromethane, and then 9.3 ml (48 mmol - 2.4 equivalents) of trimethylsilyl trifluoromethanesulphonate are added dropwise. The cooling bath was removed, and the mixture was stirred at room temperature for 1 h, 1.55 ml (8 mmol - 0.4 equivalent) of trimethylsilyl trifluoromethanesulphonate were added, and the mixture was stirred for a further 0.5 h at room temperature. The reaction solution was then poured into a mixture of cold, saturated NaHCO 3 solution and ethyl acetate, and extraction with ethyl acetate was carried out, and the combined organic extracts were washed with saturated NaCl solution and dried over MgSO4. The solvent was evaporated in vacuo, and the residue was filtered through 150 g of silica gel (toluene:ethyl acetate 4:1). 6.4 g (81%) of the title compound were obtained as pale crystals, melting point: 66° C., Rf: 0.33 (toluene:ethyl acetate 7:3) [α]D20 =59.2° (c 0.969, CHCl3).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:16][CH:17]=2)=[O:11])[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH2:30][CH3:31]>C(OCC)(=O)C.O1CCCC1.[Cl-].[Zn+2].[Cl-]>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH2:30][CH3:31])[N:2]=3)[CH2:8][CH2:7]2)[C:10]([C:12]2[CH:17]=[N:16][C:15]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)=[N:14][CH:13]=2)=[O:11])[CH2:25][CH2:24]1
Reactant: N#CN1CCC(N(C(=O)c2cnc(-n3ccnc3)nc2)C2CC2)CC1
Reactant: CCCC(=N)NO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1noc(N2CCC(N(C(=O)c3cnc(-n4ccnc4)nc3)C3CC3)CC2)n1
Reaction time: 24 h

Procedure:
To 2-imidazol-1-yl-pyrimidine-5-carboxylic acid (1-cyano-piperidin-4-yl)-cyclopropyl-amide (50 mg, Intermediate 33) and N-hydroxy-butyramidine (30 mg) in ethyl acetate (12 mL) and tetrahydrofuran is added zinc chloride (0.64 mL, 0.7 M in tetrahydrofuran) and the mixture is stirred for two weeks. Again zinc chloride solution and N-hydroxy-butyramidine are added and stirring is continued at room temperature for 24 h. The solvents are removed in vacuo, ethanol (15 mL) and concentrated HCl solution (0.5 mL) are added and the mixture is stirred for 3 h under reflux. After removal of the solvent the residue is purified by HPLC (MeOH, H2O, ammonia) to yield the desired product. LC (method 3): tR=1.51 min; Mass spectrum (ESI+): m/z=423 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:17])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([Cl:17])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(F)(F)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C(F)(F)c1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 2,2-difluoro-2-(4-fluorophenyl)acetic acid (1.33 g, 7.0 mmol) in DCM (50 mL) was added oxalyl chloride (0.640 mL, 7.5 mmol) and a catalytic amount of DMF. After stirring for 3 h, the mixture was concentrated under reduced pressure to afford 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride. To a solution of 2-aminobenzamide (0.857 g, 6.3 mmol) and TEA (1.04 mL, 0.0075 mol) in DCE (100 mL) at rt was added 2,2-difluoro-2-(4-fluorophenyl)acetyl chloride from above in DCE (100 mL) and the reaction mixture was stirred overnight. After adding EtOAc (200 mL) the mixture was washed with 1 N HCl, sat. NaHCO3 and brine. The organic solution was concentrated to yield an off-white solid (0.989 mg, 51%). 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 1H), 7.27 (m, 2H), 7.54 (m, 1H), 7.74 (m, 2H), 7.92 (m, 2H), 8.44 (d, 2H), 13.37 (s, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N(CCO)CCO>C1COCC1>[Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O=C(CCCl)c1ccccc1
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: O[C@@H](CCCl)c1ccccc1
Reaction time: 7 h

Procedure:
A solution of 3-chloropropiophenone (8.93 g, 50 mmol in 25 ml THF) was added to (-) diisopinocampheylchloroborane (Ipc2BCl, 18.0 g, 56 mmole, in 25 ml THF at -24° C.). The reaction was complete within 7 hours after which all volatiles were removed under reduced pressure. The residue was dissolved in ether, and diethanolamine (2 equivalents) was added. The resulting suspension was stirred for two hours and filtered. The solid residue was washed with ether and the combined wasings and filtrate were concentrated. Distillation furnished [S]-(-)-3-chloro-1-phenyl-1-propanol. Yield: 6.1 g, 72%; mp 56°-57° C.; [α]D23 25.25, c=7.05, CHCl3 ; 97% ee.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].COC(=O)C[CH:11]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:22]=[CH:21]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:37][O:38]C(=O)C=CC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C=C2>O1CCCC1>[C:30]1([S:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([CH:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:37][OH:38])=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)(=[O:29])=[O:28])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)CC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: COC(=O)C=Cc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(C(CO)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of lithium aluminum hydride (1.0 M in THF, 5.9 mL) was added dropwise to a solution of the above obtained mixture 10/1: 3-(1-benzenesulfonyl-1H-indol-5-yl)-3-phenyl-propionic acid methyl ester and 3-(1-benzenesulfonyl-1H-indol-5-yl)-acrylic acid methyl ester CCLXVI (1.654 g, 3.935 mmol) in tetrahydrofuran (30 mL) at 0° C. After stirring for 1 hour the reaction was quenched by slow addition, at 0° C., of Rochelle salt and water. The resulting mixture was diluted with ethyl acetate and stirred at room temperature overnight. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography to afford 1.06 g (69% yield) of 2-(1-benzenesulfonyl-1H-indol-5-yl)-2-phenyl-ethanol CCLXVII.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([CH3:8])[CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH3:18])[CH2:16][CH3:17]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH:7]([CH3:8])[CH2:6][NH:5][CH2:4][C:3]1([CH3:18])[CH2:16][CH3:17]
Reactant: [H][H]
Reactant: CCC1(C)CN(Cc2ccccc2)CC(C)C1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(C)CNCC(C)C1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.4 g) and 4-amino-1-benzyl-3,5-dimethyl-3-ethylpiperidine (2.2 g, 8.9 mmol) in methanol (15 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 10 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,5-dimethyl-3-ethylpiperidine as a semi solid. Yield 1.1 g (79%), C9H20N2, m/z 157(M+1).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10][C:11]([N:13]1[CH:17]=[CH:16]N=C1)=[S:12].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](CCN)=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:16][CH2:17][NH:13][C:11]([NH:10][C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[S:12])=[CH:21][CH:20]=1
Reactant: NCCc1ccc(Cl)cc1
Reactant: S=C(Nc1nc2ccccc2[nH]1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: S=C(NCCc1ccc(Cl)cc1)Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of 1-[(2-benzimidazolyl)thiocarbamoyl]imidazole (! .22 g, 5.0 mmol) and 2-(4-chlorophenyl)ethylamine (0.79 g, 5.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90 ° C. for 2 h. The reaction was cooled to room temperature, poured into ethyl acetate, washed with water, 1N aqueous HCl, water, saturated sodium bicarbonate, and brine. The organic layer was concentrated and the resultant solid was crystallized from EtOAc to provide 1.31 g (79%) of the titled product as a white solid: