Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20](O)=[O:21])[CH:16]=1)[CH3:13])(=[O:11])=[O:10].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:35]1[CH2:39][CH2:38][N:37]=[C:36]1[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH:47][CH3:48])=[CH:42][CH:41]=1.Cl>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][C:15]1[O:19][CH:18]=[C:17]([C:20]([N:47]([CH2:46][C:43]2[CH:44]=[CH:45][C:40]([C:36]3[NH:37][CH2:38][CH2:39][N:35]=3)=[CH:41][CH:42]=2)[CH3:48])=[O:21])[CH:16]=1)[CH3:13])(=[O:10])=[O:11]
Reactant: CN(Cc1cc(C(=O)O)co1)S(=O)(=O)c1ccc(Cl)cc1Cl
Reactant: CNCc1ccc(C2=NCCN2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: CN(Cc1ccc(C2=NCCN2)cc1)C(=O)c1coc(CN(C)S(=O)(=O)c2ccc(Cl)cc2Cl)c1
Reaction time: 2 h

Procedure:
5-({[(2,4-dichlorophenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (34 mg, 0.08 mmol) was dissolved in DCE (1 mL) and CDI (26 mg, 0.16 mmol) was added. The reaction was stirred for 2 h. The activated acid solution in DCE was added to a vial containing 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylmethanamine.HCl (41 mg, 0.16 mmol) and TEA (0.022 mL, 0.16 mmol). The reaction was stirred at ambient temperature for 18 h, then partitioned between saturated aqueous NaHCO3 (1 mL) and DCE (3×1 mL)). The organic layer was dried over MgSO4 and solvents were removed in vacuo. A portion of the crude was product purified using prep method A.
Reaction SMILES: [H-].[Na+].[C:3]([C:8]1[CH:22]=[CH:21][C:11]([CH2:12]P(=O)(OCC)OCC)=[CH:10][CH:9]=1)([O:5][CH2:6][CH3:7])=[O:4].[CH:23]([C:25]1[C:34]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:32]2[C:31]([CH3:40])([CH3:39])[CH2:30][CH2:29][C:28]([CH3:42])([CH3:41])[C:27]=2[CH:26]=1)=O.Cl>O1CCCC1.CS(C)=O>[CH3:39][C:31]1([CH3:40])[CH2:30][CH2:29][C:28]([CH3:41])([CH3:42])[C:27]2[CH:26]=[C:25](/[CH:23]=[CH:12]/[C:11]3[CH:10]=[CH:9][C:8]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][CH:21]=3)[C:34]([O:35][CH2:36][CH2:37][CH3:38])=[CH:33][C:32]1=2
Reactant: CCOC(=O)c1ccc(CP(=O)(OCC)OCC)cc1
Reactant: CCCOc1cc2c(cc1C=O)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C=C/c1ccc(C(=O)OCC)cc1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1.3 g of sodium hydride, 50% in mineral oil, were suspended in 20 ml of abs. dimethyl sulphoxide (DMSO) and treated dropwise at 15° C. with a solution of 8.6 g of diethyl (4-carbethoxybenzyl)-phosphonate in 25 ml of abs. DMSO. The mixture was stirred at room temperature for 1 hour and then a solution of 3.3 g of the above aldehyde in 25 ml of abs. DMSO and 10 ml of tetrahydrofuran was added dropwise thereto. After stirring at 40° C. for 2 hours the mixture was poured into ice-water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. After drying the organic phase with sodium sulphate and evaporation of the solvent the crude product was filtered over a silica gel column (eluent hexane/5% methyl tert.butyl ether). After recrystallization from hexane/ethyl acetate there were obtained 4.4 g of ethyl (E)-4-[2-(5,5,8,8-tetra-methyl-3 -propoxy-5,6,7,8 -tetrahydro-naphthalen-2-yl)vinyl]benzoate in the form of white crystals, melting point 97°-100° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)CC)C>C(Cl)Cl>[Br:20][CH2:23][CH2:24][C:25]1([OH:35])[CH2:34][CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1
Reactant: OCCC1(O)CCc2ccccc2C1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1(CCBr)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a 0° C. solution of triphenylphosphine (1.03 g, 3.93 mmol), in CH2Cl2 (15 ml) was added slowly a solution of bromine (0.192 ml, 3.74 mmol) in CH2Cl2. After 1 hour stirring at room temperature, the reaction mixture was cooled to 0° C. and treated slowly with a solution of (RS)-2-(2-hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.72 g, 3.74 mmol) in CH2Cl2 (15 ml). After 1.5 hour stirring at room temperature, the reaction mixture was again cooled to 0° C., treated slowly with triethylamine (0.52 ml, 3.74 mmol), washed successively with H2O and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel (hexane-ethylacetate 9:1) to provide (RS)-2-(2-bromo-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol (0.58 g, 61%) as a colorless oil, MS: m/e=255.1 (M).
Reaction SMILES: C([O:5][C:6](=[O:19])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][S:15][C:16](=[O:18])[CH3:17])(C)(C)C.C1([O:26]C)C=CC=CC=1>FC(F)(F)C(O)=O>[C:16]([S:15][CH2:14][CH2:13][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:5])=[O:19])=[O:26])(=[O:18])[CH3:17]
Reactant: CC(=O)SCCCN1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1-(3-Acetylthiopropanyl)-L-proline-t-butyl ester (4.7 g.) is dissolved in a mixture of anisole (34 ml.) and trifluoroacetic acid (68 ml.) and the mixture is kept at room temperature for 1 hour. The solvents are removed in vacuo and the residue is precipitated from ether-hexane several times. The residue (3.5 g.) is dissolved in acetonitrile (25 ml.) and dicyclohexylamine (2.8 ml.) is added. The crystalline salt is filtered and recrystallized from isopropanol. Yield 3.8 g. m.p. 176°-177°. The salt is reconverted to 1-(3-acetylthiopropanoyl)-L-proline as in Example 1, yield 1.25 g., m.p. 89°-90° (ethyl acetate-hexane).
Reaction SMILES: [C:1]([C:3]1[N:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)#[N:2]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH:18]([C:15]1[CH:16]=[CH:17][C:12]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:3]2[C:1]#[N:2])=[CH:13][CH:14]=1)=[O:19]
Reactant: N#Cc1cc2ccccc2n1-c1ccc(CO)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: N#Cc1cc2ccccc2n1-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
1.0 g (0.0038 mole) of 2-cyano-1-[4-(hydroxymethyl)phenyl]indole was dissolved in 150 ml tetrahydrofuran, 10.0 g of activated manganese dioxide was added, and the mixture stirred at room temperature for 16 hours. The reaction was filtered and the filtrate evaporated to an oil, which was crystallized from a mixture of methyl-t-butyl ether and hexane 1:1 to give 0.63 g (0.0026 mole) of 1-(4-formylphenyl)-2-cyanoindole as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H](C3C=CC(OC)=CC=3)C)[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[N:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][NH:18][C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH3:11])[CH:7]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Cl)cn4ncc(C)c34)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnn2cc(Cl)nc(O[C@H](C)[C@H]3CNC(=O)C3)c12
Temperature: 60 °C
Reaction time: 17 h
Yield: 101.8 %

Procedure:
(R)-4-((R)-1-(6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 5.53 (31 mg, 0.07 mmol) was dissolved in 1.5 mL of TFA and mixture was heated at 60° C. After 17 hours, reaction mixture was cooled to rt and concentrated under reduced pressure. Resulting residue was taken up in ethyl acetate and washed with sat NaHCO3 (aq). Layers were separated and aqueous was extracted with ethyl acetate. Combined organics were washed with 1:1 sat. NaHCO3 (aq)/brine, dried, filtered, and concentrated under reduced pressure to yield (R)-4-((R)-1-((6-chloro-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.54 (21 mg), which was used without further purification.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]([OH:9])[CH2:5][C:6]([OH:8])=[O:7])#[N:2].S(=O)(=O)(O)O.[C:15](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:15][O:7][C:6](=[O:8])[CH2:5][C@H:4]([OH:9])[CH2:3][C:1]#[N:2]
Reactant: O=C([O-])[O-]
Reactant: N#CC[C@@H](O)CC(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C[C@H](O)CC#N
Yield: 91 %

Procedure:
(R)-4-cyano-3-hydroxybutyric acid (1.0 mol) in methanol (500 ml) and conc. sulfuric acid (5 g) were refluxed for 5 hours. The reaction mixture was neutralized with sodium carbonate and filtered. The filtrate was concentrated in vacuo to afford (R)-4-cyano-3-hydroxybutyric acid methyl ester (130 g, 91%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9]O)[OH:8])[OH:6])[OH:4].O.[NH2:12][NH2:13]>CO>[CH:9](=[N:12][NH2:13])[C@@H:7]([C@H:5]([C@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8]
Reactant: NN
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Solvent: CO
Solvent: O
Product: NN=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reaction time: 8 h

Procedure:
A solution of 2.0 g of L-arabinose in 5 ml of methanol and 5 ml of hydrazine hydrate was stirred overnight and then evaporated in vacuo. A 5 ml portion of methanol was added to the residue. After standing overnight the oil solidified. The solid was collected and dried, giving 1.5 g of L-arabinose hydrazone.
Reaction SMILES: C([C:3]1[C:11]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])C.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH:14]1([CH2:13][O:12][C:11]2[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCc1c(OCC2CCCCC2)cccc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 101.9 %

Procedure:
Ethyl 3-cyclohexylmethoxy benzoic acid (1.8 g, 6.7 mmol) was dissolved in ethanol (50 ml) and THF (50 ml), wereupon NaOH (4 N, 10 ml) was added, and the solution was stirred overnight at 20° C. To the reaction mixture was added HCl (2 N, 200 ml), and the resulting solution was extracted with DCM (3×100 ml). The combined organic extracts were washed with water (100 ml), dried (MgSO4) and evaporated to give 1.6 g of the title compound. LC-MS (m/z): 236 (M+2).
Reaction SMILES: [CH3:1][S:2][C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7].C(OO)(=[O:21])C>O1CCOCC1.C(O)(=O)C>[CH3:1][S:2]([C:3]1([NH:8][C:9](=[O:18])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][NH:5][C:4]1=[O:7])=[O:21]
Reactant: CC(=O)OO
Reactant: CSC1(NC(=O)COc2ccccc2)CNC1=O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CS(=O)C1(NC(=O)COc2ccccc2)CNC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of (25) (175 mg) in dry dioxan (7 ml) was treated with a solution of peracetic acid in glacial acetic acid (0.99 ml of a 5.07% w/v solution). The mixture was stirred at room temperature for approximately 20 mins, then evaporated to dryness. The residue was evaporated once more from dry dioxan before drying thoroughly in vacuo. The residue was taken up in chloroform and chromatographed on a short column of silica gel eluting with 10% meOH/CHCl3 to give the product (26) (186 mg) a mixture of sulphoxide isomers (approximately 1:2) νmax(CHCl3) 3410, 1785, 1690, and 1490 cm-1, δppm (CDCl3) (90 MHz) 2.60 (major isomer) and 2.67 (minor isomer) (both s, together 3H), 3.79 and 4.12 (ABq, minor isomer, J8 Hz) and 3.87 and 4.01 (ABq, major isomer, J6Hz) (together 2H), 4.53 (minor isomer) and 4.60 (major isomer) both s, together 2H), 6.52 (s, 1H, exch.), 6.80 to 7.45 (m, 5H), 7.78 (s, 1H, exch.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)=[C:4]([F:21])[CH:3]=1.[H][H]>[Pt]=O.C(O)C>[NH2:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([F:21])=[C:5]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][CH2:19][F:20])[N:13]=[N:12]2)[CH:6]=1
Reactant: O=c1n(CCCF)nnn1-c1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cc(-n2nnn(CCCF)c2=O)c(F)cc1Cl
Yield: 246.6 %

Procedure:
To a 500 ml Parr hydrogenation bottle was added 0.2 g of platinum oxide, 200 ml of ethanol, then 14.0 g (0.014 mole) of 1-(4-chloro-2-fluoro-5-nitrophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one. The bottle was placed in a Parr hydrogenator and the reaction mixture hydrogenated until the theoretical amount of hydrogen was taken up. The bottle was removed from the hydrogenator and the reaction mixture filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and subjected to column chromatography on silica gel. The appropriate fractions were combined and concentrated under reduced pressure to yield 10.0 g of 1-(5-amino-4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 84°-°86° C. The reaction was repeated several times.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=3[S:15][C:16]=2[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[N:27]1([C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[OH:39])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[N:27]1([C@@H:33]2[CH2:38][CH2:37][CH2:36][CH2:35][C@H:34]2[O:39][C:4]2[CH:5]=[CH:6][C:7]([C:10]([C:12]3[C:13]4[CH:23]=[C:22]([F:24])[C:21]([O:25][CH3:26])=[CH:20][C:14]=4[S:15][C:16]=3[N:17]([CH3:19])[CH3:18])=[O:11])=[CH:8][CH:9]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCCC1
Reactant: COc1cc2sc(N(C)C)c(C(=O)c3ccc([N+](=O)[O-])cc3)c2cc1F
Product: COc1cc2sc(N(C)C)c(C(=O)c3ccc(O[C@@H]4CCCC[C@H]4N4CCCCC4)cc3)c2cc1F

Procedure:
The title compound was prepared in 51% from 2-dimethylamino-5-fluoro-6-methoxybenzo[b]thiophene-3-yl 4-nitrophenyl ketone (Example 117, Part C) and (±)-trans-2-(1-piperidyl)cyclohexanol by essentially following the procedure detailed in Example 117, Part D.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:62](=[O:70])[C:63]([O:65]C(C)(C)C)=[O:64])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]([O:48]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:47])=[C:35]([CH2:71][CH3:72])[CH:34]=1)[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@@H:16]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]C(C)(C)C)=[CH:23][CH:22]=1)[C:17]([OH:19])=[O:18])=[O:14])=[O:7])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.ClCCl>>[C:1]([NH:4][C@H:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:17]([OH:19])=[O:18])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[O:14])=[O:7])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([N:39]([C:62]([C:63]([OH:65])=[O:64])=[O:70])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]([OH:48])=[O:47])=[C:35]([CH2:71][CH3:72])[CH:34]=1)(=[O:3])[CH3:2]
Reactant: CCc1cc(CC(NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(OC(C)(C)C)cc2)C(=O)O)ccc1N(C(=O)C(=O)OC(C)(C)C)c1ccccc1C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C[C@H](NC(C)=O)C(=O)NCCCCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)O)ccc1N(C(=O)C(=O)O)c1ccccc1C(=O)O

Procedure:
(2S)-2-[(5-{[2-(acetylamino)-3-(4-{2-[(benzhydryloxy)carbonyl][tert-butoxy(oxo)acetyl]anilino}-3-ethylphenyl)propanoyl]amino}pentanoyl)amino]-3-(4-tert-butoxyphenyl)propanoic acid was treated with trifluoroacetic acid/dichloromethane (1 mL, 1:1) at ambient temperature for 3 hours, concentrated under reduced pressure and purified by HPLC eluting with 5-100% acetonitrile/aqueous 0.1% trifluoroacetic acid to provide the titled compound. MS (ESI(+)) m/e 705 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12-13.5 (bs, 2H), 9.18 (s, 1H), 8.11-7.78 (m, 4H), 7.59-6.98 (m, 7H), 6.80-6.61 (m, 3H), 4.57-4.40 (m, 1H), 4.39-4.32 (m, 1H), 3.00-2.55 (m, 6H), 2.04-2.00 (m, 2H), 1.78, 1.75 (s, s, 3H), 1.40-1.36 (m, 2H), 1.35-1.20 (m, 2H), 1.35-0.91 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[N:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: Brc1cnc(Br)cn1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2cnc(Br)cn2)COC1
Temperature: 25 °C
Yield: 48.4 %

Procedure:
2,5-Dibromopyrazine (1 g, 4.2 mmol) was dissolved in toluene (20 mL) under nitrogen and cooled to −78° C. n-Butyllithium (2.5M solution in hexanes, 1.77 mL) was added slowly with stirring and allowed to stir for a further 10 minutes upon complete addition. Oxetan-3-one (270 μL, 4.62 mmol) was added, and the reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was allowed to warm to room temperature and the solvent was removed in vacuo. The residue was taken up in DCM (50 mL) and washed with saturated aqueous sodium bicarbonate solution (40 mL). The aqueous layer was re-extracted with DCM (50 mL). The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo. The crude brown oil was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (470 mg, 45%) as a yellow solid. Method B HPLC-MS: MH+ m/z 231, RT 1.13 minutes.
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CS(C)=O.CO>[CH2:16]([O:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:15]=[CH2:14]
Reactant: OCc1ncccc1O
Reactant: C=CCBr
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CS(C)=O
Solvent: CO
Product: C=CCOc1cccnc1CO
Reaction time: 2 h

Procedure:
To a sodium methoxide, methanol mixture made from 1.43 g (62 mmole) sodium metal and 100 ml methanol was added 5.9 g (31 mmole) 3-hydroxy-2-hydroxymethylpyridine and the methanol removed in vacuo. The resulting residue was dissolved in 80 ml dimethylsulfoxide (DMSO) and 3.0 ml (34.7 mmole) allyl bromide in 20 ml DMSO was added over 20 minutes at room temperature. The mixture was stirred for two hours, the DMSO distilled in vacuo and the reside partitioned between chloroform/water. The aqueous phase was adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to give 3.48 g (68%) of the desired ether.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1([CH:36]=O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH2:1]([C:8]1[N:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Nc1cccc(-c2c(Cc3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1cccc2c(-c3cccc(NCc4cccc5ccccc45)c3)c(Cc3ccccc3)nnc12

Procedure:
The title compound was prepared from [3-(3-benzyl-8-chlorocinnolin-4-yl)phenyl]amine and naphthalene-1-carbaldehyde according to the procedure of Step 5 Example 6. MS (ES) m/z 486.1.
Reaction SMILES: C([N:11]([C:28]1[CH:29]=[C:30]([C:33](Cl)=[O:34])[S:31][CH:32]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(OCC1C=CC=CC=1)=O.[CH2:36]([N:38](CC)[CH2:39][CH3:40])[CH3:37].N1CCCC1>CCOCC>[CH2:12]([NH:11][C:28]1[CH:29]=[C:30]([C:33]([N:38]2[CH2:39][CH2:40][CH2:37][CH2:36]2)=[O:34])[S:31][CH:32]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1csc(C(=O)Cl)c1
Solvent: C1CCNC1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1csc(C(=O)N2CCCC2)c1

Procedure:
A warm solution of 1.0 g. of 4-[N-(carbobenzyloxy)-N-hexadecylamino]-2-thiophenecarbonyl chloride and 1.3 g. of triethylamine in 100 ml. of ether is added to 1.2 g. of pyrrolidine. A precipitate forms; the mixture is stirred under reflux for 1 hour, filtered, and extracted with hot ether. The extract is evaporated and a solution of the resulting residue in 100 ml. of tetrahydrofuran is shaken under 50 psi of hydrogen in the presence of 0.6 g. of 10% palladium on carbon. The mixture is filtered and the filtrate evaporated. The residue is crystallized from acetic acid to yield the product as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=N[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38](C1C=CC(C(Cl)=O)=CC=1)(C)(C)[CH3:39]>>[C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[C:38]([CH3:39])[CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3C)cc2C1=O
Yield: 82 %

Procedure:
The compound of example 467 was prepared analogous to the compound of example 403 by reaction of the compound of example 466 with 4-(t-butyl)benzoyl chloride.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)[OH:22])C1C=CC=CC=1.[CH:29]([O-:31])=O.[NH4+]>CO.[Pd]>[CH2:11]([O:13][N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:10](=[C:29]=[O:31])[C@H:9]1[CH:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=1)[OH:22])[CH:10]=[CH2:9]
Reactant: Cn1cc(C(O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2Cc2ccccc2)cn1
Reactant: O=C[O-]
Agent: [Pd]
Agent: [NH4+]
Solvent: CO
Product: C=CCON1C[C@H](O[Si](C)(C)C(C)(C)C)C(=C=O)[C@H]1C(O)c1cnn(C)c1
Reaction time: 0.5 h
Yield: 193 %

Procedure:
To a solution of (2S,4R)-1-{1-benzyl-4-(t-butyl-dimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methyl-4-pyrazolyl)methanol (70 g) in methanol (700 ml) was added ammonium formate (44 g) and 10% Pd-C (wet, 20 g). The mixture was refluxed for 40 minutes, then cooled. After filtration of Pd-C, the solvent was evaporated. To the residue was added chloroform (500 ml) and precipitated excess ammonium formate was filtered off with celite. The filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran-water (1:1, 1 l) and a solution of allyl chloroformate (22.3 ml) in tetrahydrofuran (60 ml) was added thereto, while adjusting pH to 8.5~10 with 4N-sodium hydroxide solution at 0°~5° C. The mixture was stirred for 30 minutes at the same temperature. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (×2). The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 1-{(2S,4R)-1-allyloxy-carbonyl-4-(t-butyldimethylsilyloxy) pyrrolidin-2-yl}-1-(1-methylpyrazol-4-yl) methanol (66.2 g).