Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:27]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1)=[C:28]=[O:29]>ClCCl>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][NH:27][C:28]([N:17]2[CH2:18][CH2:19][CH:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH2:14][CH2:13]3)[CH2:16]2)=[O:29])=[CH:32][CH:33]=1
Reactant: Cc1ccc(CN=C=O)cc1
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(CNC(=O)N2CCC(N3CCC(c4ccccc4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (preparation #7) (0.050 g, 0.165 mmol) and triethylamine (0.092 mL, 0.66 mmol) in dichloromethane (1 mL) was added 1-isocyanatomethyl-4-methyl-benzene (0.024 g, 0.165 mmol) and the reaction mixture was stirred at ambient temperature for about 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel using 5% MeOH/EtOAc as the mobile phase to give 3-(4-phenyl-piperidin-1-yl)-pyrrolidine-1-carboxylic acid 4-methyl-benzylamide (0.042 g, 68%). RP-HPLC (Table 1, Method b) Rt 1.72 min; m/z: (M+H)+ 378.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@H:9]1[CH2:11][C@@H:10]1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CC(C)=O.O.O.[Ru](=O)=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@H:10]1[CH2:11][C@@H:9]1[C:8]([OH:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C[C@H]1C[C@@H]1C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 91.3 %

Procedure:
Sodium metaperiodate (1729 mg, 8.08 mmol) and ruthenium(IV) oxide hydrate (48.8 mg, 0.32 mmol) were added to a solution of benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (712 mg, 3.23 mmol) in acetone (11.5 mL) and water (13 mL) at 0° C., and the mixture was stirred at 0° C. for 2.5 hr. The reaction mixture was poured into water (100 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give (1S,2R)-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (690 mg, 2.95 mmol, 91%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Br:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:12]([OH:13])[N:11]=[CH:4]2
Reactant: NC(N)=O
Reactant: Nc1ccc(Br)cc1C=O
Product: Oc1ncc2cc(Br)ccc2n1
Temperature: 180 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of 2-amino-5-bromobenzaldehyde (29) (6 g, 30.0 mmol) and urea (30) (27 g, 450.0 mmol) was heated to 180° C. and stirred for 5 hours. LCMS showed the reaction was completed. The reaction mixture was cooled to room temperature, and the resulting precipitate was washed with H2O (3×500 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. 6-bromoquinazolin-2-ol (31)(6 g, 89%) was obtained as a yellow solid. MS (ES+) C8H5BrN2O requires: 224. found: 225, 227 [M+H]+.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:3][CH:2]=1.COS(OC)(=O)=O.[C-:24]#[N:25].[Na+]>C(O)(C)C>[C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=Cc2cccc[n+]2[O-])cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(C)O
Solvent: COS(=O)(=O)OC
Product: Cc1ccc(C=Cc2cccc(C#N)n2)cc1

Procedure:
In a variation to the procedure referred to in example1, 2-(2-p-tolyl-vinyl)-pyridine 1-oxide (9.8 g, 46 mmol) was reacted first with dimethylsulfate (5.8 g, 46 mmol) and then with NaCN (2.74 g, 56 mmol). After extraction and crystallization 6-(2-p-tolyl-vinyl)-pyridine-2-carbonitrile (5.8 g, 57%) was obtained as a yellow crystalline material. Mp. 137–138° C. (isopropanol), MS: m/e=220 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[Br:27][CH2:28]/[CH:29]=[CH:30]/[CH2:31]Br>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[N:10]([CH2:31][CH:30]=[CH:29][CH2:28][Br:27])[C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC/C=C/CBr
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CC=CCBr)c1ccc2c(c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 39.3 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (5 g, 17.5 mmol) in dry THF (85 mL) was cooled to −78° C. At this temperature n-BuLi (2.5M solution in hexanes, 14 mL) was added dropwise and the clear solution stirred at −78° C. for 20 min. A solution of E-1,4-dibromobut-2-ene (4.9 g, 23 mmol) in THF (42 mL) was added dropwise and the mixture slowly allowed to warm to rt. The mixture was poured on water and extracted with EA. The combined org. extracts were dried over MgSO4 and concentrated. The product was purified by FC (Hept/EA 9:1, 4:1) and obtained as a greenish oil (2.88 g, 38% yield) which was used as such in the next step despite some contaminations with starting material.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O-:11].[Na+]>CO>[CH3:10][O:11][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: C[O-]
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1ccccn1

Procedure:
2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Freshly prepared sodium methoxide (5 g., 0.22 mole of sodium dissolved in 150 ml. of methanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(methoxymethyl)pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Nc2ccnc3[nH]c4c(c23)CNCC4)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4cccc(F)c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.5 %

Procedure:
(3-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (15 mg, 0.05 mmol), acetic anhydride (53 μL, 0.05 mmol), and triethylamine (22 μL, 0.16 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 61 (3 mg, 15% yield) as an oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1.[Li+].[OH-].CC(O)=O>CO>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([C:11]3[C:12]4[C:19]([C:20]([OH:22])=[O:21])=[CH:18][N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:7]=[CH:8]2)=[N:3]1
Reactant: CCOC(=O)c1cn(COCC[Si](C)(C)C)c2ncnc(-c3ccc4cn(C)nc4c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Cn1cc2ccc(-c3ncnc4c3c(C(=O)O)cn4COCC[Si](C)(C)C)cc2n1
Temperature: 60 °C

Procedure:
To a solution of ethyl 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate in MeOH (2.0 mL) was added 2 M aqueous LiOH (1.1 mL) and the reaction mixture was heated at 60° C. for 17 hours. The reaction mixture was then acidified with AcOH and extracted with EtOAc (×3). The combined organic layers were then washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-methyl-2H-indazol-6-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid. No further purification was carried out. LRMS (ESI) calc'd for C21H26SiN5O3 [M+H]+: 424, found 424.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[C:13](=O)(O)[O-].[Na+]>CO.O>[NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C([O-])O
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(F)cc1N
Yield: 80.6 %

Procedure:
A stirred solution of 2-amino-4-fluorobenzoic acid (4.86 g, 31.3 mM) in anhydrous methanol (100 mL) was saturated with anhydrous hydrogen chloride and then refluxed for 4 days. During the reflux period, the reaction mixture was periodically resaturated with hydrogen chloride. After the reflux period, the reaction mixture was cooled and concentrated to leave a white solid. This material was dissolved in water and the resulting solution neutralized with aqueous sodium bicarbonate and extracted with diethyl ether. The combined extracts were dried (MgSO4), filtered and concentrated to leave (4.08 g, 80.6%) of the title compound as an off white solid, mp 66°-67° C.; MS(CI): 170 (M+H).
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][CH2:25]Br)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C(O)C>[C:4]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]1[CH2:24][CH2:25][C:1]#[N:2])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCBr)C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCC#N)C1
Temperature: 110 °C

Procedure:
To an aqueous solution (3.0 ml) of potassium cyanide (85.0 mg) was added a solution of 1,4-bis(t-butoxycarbonyl)-2-(2-bromoethyl)piperazine (393 mg) in ethanol (3.0 ml), followed by stirring under heat at 110° C. for 3 hours. After the removal of ethanol by distillation under reduced pressure, methylene chloride (100 ml) was added to the residue. The organic layer was washed with distilled water until the water phase became neutral. The resulting organic layer was washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column (silica gel 15 g, hexane:ethyl acetate=2:1), whereby the title compound (145.0 mg, 43%) was obtained as a white solid.
Reaction SMILES: C(O)(=O)C.[C-:5]#[N:6].[Na+].[CH2:8]1[N:19]2[C:20]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[N:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=32)[CH2:9]1>C(OCC)(=O)C>[C:5]([CH:15]1[C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[CH2:9][CH2:8][N:19]([C:20]=23)[C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16]1)#[N:6]
Reactant: [C-]#N
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#CC1Nc2ccccc2N2CCc3cccc1c32
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Acetic acid (30 ml) was added to a slurry consisting of sodium cyanide (10 g), 1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]-benzodiazepine (19 g) and ethyl acetate (250 ml) dropwise at room temperature. The mixture was stirred for 18 hours and thereafter diluted with ethyl acetate to 1 liter and washed with 1N sodium hydroxide (2×500 ml), water (2×600 ml) and brine (2×600 ml) The solution was dried over anhydrous magnesium sulfate and concentrated to a solid. The solid was triturated with ether (2×150 ml). Recrystallization from hot toluene (450 ml) yielded 14.8 g of crystals, m.p. 185°-186.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[N:12]=[CH:13][C:14]([F:25])=[C:15]3[C:19]([C:20](=[O:24])[C:21](O)=[O:22])=[CH:18][NH:17][C:16]=23)[CH:7]=1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:57]1([C:63]2[C:67]([N:68]3[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]3)=[CH:66][NH:65][N:64]=2)[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[F:25][C:14]1[CH:13]=[N:12][C:11]([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:10][N:9]=2)=[C:16]2[NH:17][CH:18]=[C:19]([C:20](=[O:24])[C:21](=[O:22])[N:71]3[CH2:72][CH2:73][N:68]([C:67]4[C:63]([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)=[N:64][NH:65][CH:66]=4)[CH2:69][CH2:70]3)[C:15]=12
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)O)c[nH]c23)n[nH]1
Reactant: c1ccc(-c2n[nH]cc2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5c[nH]nc5-c5ccccc5)CC4)c[nH]c23)n[nH]1
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 48.8 %

Procedure:
To a solution of 2-(7-(5-(ethoxycarbonyl)-1H-pyrazol-3-yl)-4-fluoro-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (0.017 g, 0.049 mmol) in DMF (1.5 mL) was added TBTU (0.017 g, 0.054 mmol), diisopropylethylamine (0.15 mL), and 1-(3-phenyl-1H-pyrazol-4-yl)piperazine (0.011 g, 0.049 mmol). The mixture was stirred under N2 at rt for 14.5 h and was quenched with 10 mL of H2O. The solvent was removed under reduced pressure, and the residue was dissolved in DMF. The DMF solution was passed though a plug of celite to remove solids, and the DMF solution was purified by prep HPLC to give the title compound as a white solid (13.3 mg). LCMS: m/e 557.4 (M+H)+, ret time 1.79 min (method 1). 1H NMR (500 MHz, MeOD) δ ppm 8.44 (s, 1H) 8.31 (d, J=2.44 Hz, 1H) 7.95 (d, J=7.32 Hz, 2H) 7.63 (s, 1H) 7.56 (s, 1H) 7.46 (t, J=7.63 Hz, 2H) 7.36 (t, J=7.48 Hz, 1H) 4.46 (q, J=7.22 Hz, 2H) 3.88-3.92 (m, 2H) 3.65-3.70 (m, 2H) 3.00-3.04 (m, 2H) 2.91-2.95 (m, 2H) 1.45 (t, J=7.02 Hz, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][N:3]=[N:2]1.[C:6]([OH:10])(=[O:9])[CH:7]=[CH2:8].Cl>N1C=CC=CC=1.O>[N:1]1([CH2:8][CH2:7][C:6]([OH:10])=[O:9])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: c1nnn[nH]1
Reactant: C=CC(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)CCn1cnnn1

Procedure:
4.5 g of tetrazole are stirred for 8 hours at 90° with 4.5 ml of acrylic acid and 15 drops of pyridine. After cooling, 150 ml of water are added to the reaction mixture and the whole is acidified with HCl (concentrated) and concentrated under reduced pressure in a rotary evaporator. The crystalline residue is digested three times with methyl ethyl ketone and the combined organic phases are dried over sodium sulphate. After concentration by evaporation, the crystalline residue is stirred with isopropanol/ether and filtered off.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[CH2:28]([O:35][C:36]1[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=1[NH2:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:38][C:37]1[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=1[O:35][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(CNc1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
6.38 g of sodium triacetoxyborohydride (30.1 mmol) was added to a solution of 4.68 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (25.0 mmol), 5.0 g of 2-benzyloxyaniline (25.0 mmol) and 1.44 ml of acetic acid (25.0 mmol) in methylene chloride (250 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 8.50 g of the title compound (yield: 91%).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH:9]=[CH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[O:25]1[CH:9]([CH2:8][CH:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: c1ccc(C(CC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 96.2 g. of 4,4-diphenyl-1-butene dissolved in 400 ml. of chloroform was added dropwise over one hour to a cold (0° C) suspension of 110.0 g. of m-chloroperbenzoic acid in 700 ml. of chloroform. The reaction mixture was warmed to about 25° C. and stirred for four hours. The reaction mixture was then washed with aqueous 2N sodium hydroxide solution, with water, and dried. Evaporation of the solvent under reduced pressure provided 158.3 g. of a yellow oil as the crude product. The oil was distilled to afford 1,2-epoxy-4,4-diphenyl-butane. B.P. 124°-126° C at 0.03 torr.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[C:24]([CH3:30])[C:23]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:34]2[CH2:35][CH2:36][N:31]([C:23]3[C:24]([CH3:30])=[C:25]([CH3:29])[CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:32][CH2:33]2)=[O:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Reactant: COc1nc(C)c(C)nc1NC(=O)Oc1ccccc1
Product: COc1nc(C)c(C)nc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 65.5 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)carbamate and 1-(2,3,5,6,-tetramethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[N:19](COCC[Si](C)(C)C)[C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12.C(OCC)(=O)C.Cl>CO>[N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]3[CH:33]=[CH:32][C:13]([O:14][C:15]4[NH:19][C:18]5[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=5[N:16]=4)=[CH:12][CH:11]=3)[C:5]=12
Reactant: C[Si](C)(C)CCOCn1c(Oc2ccc(-c3cccn4ccnc34)cc2)nc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc2[nH]c(Oc3ccc(-c4cccn5ccnc45)cc3)nc2c1
Yield: 76.6 %

Procedure:
A mixture of 2-[4-(imidazo[1,2-a]pyridin-8-yl)phenoxy]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (0.53 g), 4 M hydrogen chloride-ethyl acetate solution (20 ml) and methanol (4 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to give the title compound (0.29 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[Li].[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[OH:27][CH2:26][C@@H:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1)=[O:16]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [Li]
Product: O=C(c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)N1CCC[C@H]1CO

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B′ from 4′-trifluoromethyl-biphenyl-4-carboxylic acid, lithium salt using (S)-2-pyrrolidine methanol as the amine. MS (ES+) 350.2
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]#[CH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH2:15][CH3:16]>CN(C)C=O.CCOCC>[C:1]([N:8]([CH2:9][C:10]#[CH:11])[CH2:15][CH3:16])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CCI
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CCN(CC)C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Di-tert-butyl dicarbonate (42.8 g, 196 mmol) in dichloromethane (100 mL) was added dropwise to a solution of propargylamine (11.02 g, 200 mmol) in dichloromethane (200 mL) at room temperature with magnetic stirring. After 2 h, the reaction mixture was washed with aqueous 1N hydrochloric acid (300 mL) and saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layers were washed with dichloromethane (300 mL). The dichloromethane solutions were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40S, EtOAc-hexanes V/V 1:9 as solvent) to give crude N-Boc-propargylamine. (32.32 g). The crude N-Boc-propargylamine (3.1 g, 20 mmol) was dissolved in dry dimethylformamide (20 mL) with magnetic stirring and cooled in an ice-water bath. Sodium hydride (0.61 g, 24 mmol) was added in small portions. After stirring for 15 min., iodoethane (3.74 g, 24 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 3 h. then diluted with ether and extracted with water and saturated brine. The aqueous layers were back washed with ether and the ether layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (Biotage 40M, ethyl acetate-hexanes as solvent to give N-Boc-N-ethylpropargylamine. (Yield 3.19 g, 87%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4](=[CH:5][C:6]([F:24])=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[F:24])[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:11]([C:12]1[N:16]=[N:15][NH:14][N:13]=1)=[C:10]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Fc1cc2nc(Cl)c(-c3nnn[nH]3)c(-c3ccccc3)c2cc1Cl
Reactant: C1CCNCC1
Product: Fc1cc2nc(N3CCCCC3)c(-c3nn[nH]n3)c(-c3ccccc3)c2cc1Cl

Procedure:
The title compound was prepared in analogy to example 102 step C from 2,6-dichloro-7-fluoro-4-phenyl-3-(1H-tetrazol-5-yl)-quinoline and piperidine. Off-white solid. MS (ESI): 409.5 (M+H)+.