Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[N:9]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[S:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH2:10][CH:8]1[NH:9][C:3](=[NH:17])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: [Cl-]
Reactant: COC1=NC(Cc2cccs2)CCCC1
Reactant: [NH4+]
Solvent: CO
Product: Cl
Product: N=C1CCCCC(Cc2cccs2)N1

Procedure:
The title product of Example 55 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
3,4-Dichlorobenzyl bromide (35.20 g, 150 mmol) was added to a solution of N-(tert-butoxycarbonyl)piperazine (24.84 g, 130 mmol) and triethylamine (20.91 ml, 150 mmol) in chloroform (100 ml) over 30 min. After 1 h, the reaction mixture was diluted with ethyl acetate and the product was precipitated out as the hydrochloride salt by adding 1N aqueous hydrogen chloride solution. The solid product was filtered, washed with water and then resuspended in ethyl acetate. Two equivalents of 1N aqueous sodium hydroxide solution was added and the free amine was extracted into ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to provide 1-(tert-butoxycarbonyl)-4-(3,4-dichlorobenzyl)piperazine (45 g).
Reaction SMILES: [Br:1][CH:2](O)[CH3:3].N1C=CC=CC=1.[N+:11]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)([O-:13])=[O:12].CC[O:25]CC>>[Br:1][CH2:2][CH2:3][O:19][C:18](=[O:25])[C:17]1[CH:21]=[CH:22][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=1
Reactant: CC(O)Br
Reactant: CCOCC
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Product: O=C(OCCBr)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, bromoethanol (29 mmols) was dissolved in 25 mL ether. Pyridine (34 mmols) was added to the solution, followed by a solution of 4-nitrobenzoyl chloride (27 mmols) in 35 mL ether. The reaction was stirred overnight, and a white precipitate was formed. Ether (50 mL) was added, and the reaction mixture was then washed with aqueous KHSO4, aqueous NaHCO3, and water. The ether layer was then dried over Na2SO4, filtered, and concentrated to give 6.3 g of 4-nitrobenzoic acid 2-bromo-ethyl ester. Material was used in coupling reactions without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2c(c1)NC(=O)C2(C)C
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 82.1 %

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-3-methyl-1,3-dihydro-indol-2-one (679 mg, 3.83 mmol) in THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by dropwise addition of 2.5M n-BuLi (3.06 mL, 7.66 mmol). The mixture is stirred for 15 min then warmed to −25° C. Add dropwise iodomethane (275 μL, 4.40 mmol) and let stir for 30 min. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. The organic layer is washed with sat NH4Cl soin, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 35% ethyl acetate/hexanes) to give 601 mg of title compound as a white crystalline solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.O.O.O.C([O-])(=O)C.[Na+].[Br:17]Br.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([Br:17])=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: Cc1cnc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cnc(N)c(Br)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To acetic acid (1500 ml.), 2-amino-5-methylpyrazine (1 mole) and 326.5 g. sodium acetate trihydrate are slowly added 1.1 mole bromine in 180 ml. acetic acid at 2° C. in the absence of light. The mixture is stirred about 15 hours at 20° C., stripped of acetic acid in vacuo, poured into ice, made alkaline with sodium hydroxide, filtered, the residue extracted with ether, the extract stripped and the 2-amino-3-bromo-5-methylpyrazine crystallized from a suitable solvent.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:13])=O.CN(C)C=O>ClCCl>[S:1]1[CH2:6][CH2:5][CH:4]([C:7]([Cl:13])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCSCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCSCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To an ice cold solution of 1.36 g (9.32 mmol) tetrahydro-thiopyran-4-carboxylic acid in 25 mL of dichloromethane (DCM) was added dropwise 1.1 mL (12.6 mmol) of oxalyl chloride, and the resulting mixture was stirred at 0° C. for 2 h. Then 2 μL of dimethylformamide (DMF cat) was added, and the reaction mixture was stirred at rt for 2 h, and concentrated to give 1.43 g (93%) of desired tetrahydro-thiopyran-4-carbonyl chloride as a brown oil as indicated by 1H NMR. The product was used without any further purification in the next step toward the preparation of 6-(4-Benzyloxy-phenyl)-7-(tetrahydro-thiopyran-4-yl)-3-(1H-tetrazol-5-yl)-pyrazolo[1,5-a]pyrimidine (below, entry 375).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11]C)[CH2:6][NH2:7].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1.Br>CC(=O)CC>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH2:6][NH:7][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15]
Reactant: COc1ccc(CN)cc1OC
Reactant: O=S1(=O)CCCO1
Agent: Br
Solvent: CCC(C)=O
Product: O=S(=O)(O)CCCNCc1ccc(O)c(O)c1
Temperature: 25 °C

Procedure:
To a solution of 3,4-dimethoxybenzylamine (2.2 mL, 15.0 mmol) in 2-butanone (20 mL) was added 1,3-propane sultone (1.98 g, 15.8 mmol). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×25 mL) and dried in vacuo. The crude product was suspended in 75% Acetone/MeOH (75 mL). The suspension was stirred at reflux for 30 sec.; the solid material was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo. The solid (1.94 g, 6.7 mmol) was dissolved hydrobromic acid (48%, 27 mL). The solution was stirred at 100° C. for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in water (20 mL). The aqueous phase was washed with CH2Cl2 (3×20 mL), and evaporated under educed pressure. The solid residue was suspended in hot MeOH (75 mL). The suspension was stirred at reflux for 30 sec.; the solid was collected by filtration, washed with 50% MeOH/acetone, and dried in vacuo. This allowed the isolation of compound S, 1.22 g (70%).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)=[CH:10][CH:9]=1.CO.[OH-].[K+]>O1CCCC1.O>[C:36]([O:35][C:33]([NH:32][CH:4]([CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[C:16]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:15]=2)=[CH:10][CH:9]=1)[C:3]([OH:40])=[O:2])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CSCc1ccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert-Butoxy carbonylamino-3-[4-(4,6-diphenylpyrimidin-2-yl)-benzylsulfanyl]-propionic acid methyl ester, 0.18 g (0.32 mmol) in 10 mL of tetrahydrofuran and 5 mL of methanol was added 1.62 mL of 1.0M aq. KOH. The solution was stirred for 1 h at room temperature. The solution was diluted with 10 mL of water and acidified to pH 1-2. The aqueous was extracted with 3×30 mL portions of diethyl ether. The organic layers were combined, washed with sat. aq. NaHCO3, sat. aq. NaCl, dried (MgSO4). The solution was concentrated to the desired product in 0.10 g (57%) as an off-white solid. MP 250° C. decomp, Rf 0.09 (100% Ethyl Acetate); 1H NMR (DMSO-d6) 8.57 (d, 2H, J=9.3), 8.52-8.46 b (m, 5H), 7.60-7.58 (m, 6H), 7.51 (d, 2H, J=9.3), 4.11 (m, 1H), 3.86 (s, 3H), 2.81 (dd, 1H, J=14.8, 5.0 Hz), 2.67 (dd, 1H, J=15.3, 10.3), 1.39 (s, 9H). LCMS m/z calcd for C31H31N3O4S: 541.2 found 542.6(M+1)
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)OC.[CH3:23][C:24]1[N:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=1.[C:32](=O)([O-])[O-].[K+].[K+].C1COCC1>C(OCC)(=O)C>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8](=[O:22])[CH2:7][CH:32]=[CH:30][C:27]1[CH:26]=[N:25][C:24]([CH3:23])=[N:29][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COP(=O)(CC(=O)CCCCCOCc1ccccc1)OC
Reactant: O=C([O-])[O-]
Reactant: Cc1ncc(C=O)cn1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C=CCC(=O)CCCCCOCc2ccccc2)cn1
Temperature: 60 °C
Yield: 94.6 %

Procedure:
A mixture of 11-2 (4.4 g, 13.8 mmol), 2-methyl-pyrimidine-5-carbaldehyde (1.5 g, 12.5 mmol; for preparation, see J. Heterocyclic Chem., 28, 1281 (1991)) potassium carbonate (3.1 g, 25 mmol) and THF (200 mL) was heated at 60° C. for 3 hours. Following cooling, the mixture was diluted with ethyl acetate, washed with sat. NaHCO3 and brine, and dried over magnesium sulfate. Evaporation of the solvents gave 4.0 g (100%) of 11-3 as a white solid.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([C:19]3[CH2:23][CH2:22][CH2:21][CH:20]=3)=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:24]C(OC(Cl)C)=O>C1(C)C=CC=CC=1>[ClH:24].[C:19]1([C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:23][CH2:22][CH2:21][CH:20]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: C1=C(c2cnc3c(n2)OCCN(Cc2ccccc2)C3)CCC1
Solvent: Cc1ccccc1
Product: C1=C(c2cnc3c(n2)OCCNC3)CCC1
Product: Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
To a solution of 8-benzyl-3-(cyclopent-1-en-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (99 mg) in toluene (1 mL) was added 1-chloroethyl chloroformate (0.038 mL), and the mixture was stirred at 90° C. for 4 hr. 1-Chloroethyl chloroformate (0.038 mL) was further added, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and concentrated. To the obtained residue was added methanol (1 mL), and the mixture was stirred at 60° C. for 0.5 hr. The reaction mixture was cooled to room temperature, and concentrated. The concentrate was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient; 10→100% ethyl acetate/hexane). To a solution of the obtained oil in methanol (1 mL) was added 1 N hydrochloric acid (0.18 ml), and the mixture was concentrated under reduced pressure. The obtained crude crystals were purified by recrystallization (ethanol-diisopropyl ether) to give the title compound (41.1 mg, 50%) as colorless crystals.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].Br[C:6]1[CH:7]=[CH:8][C:9]([O:26][CH2:27][CH3:28])=[C:10]([C:12]2[NH:13][C:14](=O)[C:15]3[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=3[N:17]=2)[CH:11]=1>>[CH2:27]([O:26][C:9]1[CH:8]=[CH:7][C:6](/[CH:3]=[CH:2]/[C:1]#[N:4])=[CH:11][C:10]=1[C:12]1[NH:13][CH2:14][C:15]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:16]=2[N:17]=1)[CH3:28]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: C=CC#N
Product: CCCc1nn(C)c2c1N=C(c1cc(/C=C/C#N)ccc1OCC)NC2

Procedure:
The title compound was prepared from acrylonitrile and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one following the procedure of Example 19 and was obtained as off-white crystals (33%). Found C,65.99; H,5.52; N,19.07. C20H21N5O2 requires C,66.10; H,5.82; N,19.27%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:46]([N+:50]1[N:54]=[C:53]([CH3:55])[S:52][C:51]=1[CH3:56])[CH2:47][CH2:48][CH3:49]>>[CH2:46]([N:50]1[N:54]=[C:53]([CH3:55])[S:52]/[C:51]/1=[CH:56]\[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:47][CH2:48][CH3:49]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,4-dichlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.92 (m, 3 H) 1.25-1.35 (m, 2 H) 1.67-1.77 (m, 2 H) 2.50 (s, 3 H) 4.14 (t, 2 H) 6.21 (s, 1 H) 7.45-7.50 (m, 1 H) 7.56 (d, 1 H) 7.63-7.65 (m, 1 H); MS (ESI) m/z 343 (M+H)+.
Reaction SMILES: O.[ClH:2].Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:17]>CN(C)C=O>[ClH:2].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[C:9]1[CH:10]=[C:11]([NH:12][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: CCOc1ccc(N=C=O)cc1
Reactant: Nc1cccc(C2=NCCN2)c1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(NC(=O)Nc2cccc(C3=NCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 3-(4,5-dihydro-1H-imidazol-2-yl)aniline dihydrochloride monohydrate (stored with 4 A molecular sieves, 48 mg, 0.19 mmol) and 4-ethoxyphenyl isocyanate (33 mg, 0.20 mmol) in dimethylformamide (2 ml) was stirred at room temperature overnight. After removal of the solvent, water (2 ml) was added and the resulting precipitate was collected (18 mg, 64% yield) by filtration. 1H NMR (600 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.12 (br s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.52 (t, 1H, 8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.35 (d, 2H, J=7.2 Hz), 6.86 (d, 2H, J=7.2 Hz), 3.98 (s, 4H). MS: m/z Calcd 324.4 Found MH+ 325.5
Reaction SMILES: [NH:1]([C:35](OC(C)(C)C)=[O:36])[C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:43](C(O)=O)[CH3:44].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[C@@H:43]([C:35]([NH:1][C@H:2]([C:13]([NH:15][C@H:16]([C:24]([NH:26][CH2:27][C:28]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:29])=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)=[O:36])[CH3:44]
Reactant: Cc1ccc(CSC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(CSC[C@H](NC(=O)[C@@H](C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)NCC(=O)NCC(=O)O)cc1

Procedure:
Using 300 mg Boc-Cys(MBzl)-Phe-Gly-Gly-OH, 104 mg Boc-D-Ala-OH, 110 mg HONB and 120 mg DCC, the desired product was obtained in the same manner as in Example 1-(XXI).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:30]([O:32][CH3:33])=[O:31]>>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:30]([O:32][CH3:33])=[O:31])[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: COC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)OC)C3)cc1

Procedure:
Method as example 34 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and methyl chloroformate as starting materials.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][CH:12]1[CH2:16][O:15][CH2:14][CH:13]1[O:17][CH2:18][CH2:19][CH2:20][OH:21].CCN(CC)CC.P([O-])([O-])([O-])=O>C(Cl)Cl>[I:11][CH:12]1[CH2:16][O:15][CH2:14][CH:13]1[O:17][CH2:18][CH2:19][CH:20]=[O:21]
Reactant: OCCCOC1COCC1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCOC1COCC1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Oxalyl chloride (580 mg, 392 μL, 4.6 mmol) was diluted in CH2Cl2 (12 mL) under argon and the solution was cooled to −78° C. Dry DMSO (715 mg, 650 μL, 9.15 mmol) in CH2Cl2 (3 mL) was added to the cold solution dropwise and the mixture was stirred for 30 min. A solution of alcohol 23 (500 mg, 1.83 mmol) in CH2Cl2 (4 mL) was then added slowly, and the mixture was kept stirring for an additional hour at −78° C. Et3N (1.3 g, 1.8 mL, 12.8 mmol) was then introduced, the white suspension was stirred at −78° C. for 20 min and slowly warmed to rt. A 0.5 M phosphate buffer solution pH 5.5 (20 mL) was added, the two phases were separated and the resulting aqueous phase was extracted with Et2O (4×). The combined organic phase was dried (MgSO4), filtered, and evaporated. The residue was purified by flash column chromatography using hexanes/EtOAc (6:1 to 4:1) to yield the desired aldehyde 24 (433 mg, 86%) as a light yellow oil. TLC: Rf=0.76 (hexanes/EtOAc=1:1); 1H NMR (CDCl3, 300 MHz) δ 9.77 (t, J=1.3 Hz, 1H), 4.35 (m, 1H), 4.30-4.19 (m, 3H), 4.04 (dd, J=2.3, 9.8 Hz, 1H), 3.92 (ddd, J=5.3, 6.7, 9.5 Hz, 1H), 3.77 (dd, J=1.7, 10.1 Hz, 1H), 3.75 (ddd, J=5.2, 6.2, 9.5 Hz, 1H), 2.69 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 200.1, 88.3, 76.1, 71.8, 63.1, 43.7, 23.3.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(O)(=O)C.[CH2:9]([O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)CCC>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[NH:22][N:3]=[N:2][N:1]=2)=[CH:23][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: c1ccc(COc2ccc(-c3nnn[nH]3)cc2)cc1
Yield: 85 %

Procedure:
6.6×10-2 mol of sodium azide and 6.6×10-2 mol of acetic acid were added to a solution of 5×10-2 mol of 4-benzyloxy benzonitrile (VIII) in 20 ml butanol. The reaction medium was then reflux-heated for 4 hours. 1 g sodium azide, 2 g acetic acid and 10 ml butanol were added and the reaction medium was again reflux-heated for 2 days. After concentration by evaporation of the solvent, the residue was dissolved in 20 ml of 10% aqueous NaOH. After filtration, the aqueous phase was extracted with ether. The alkaline solution was acidified with 2 N HCl to obtain the expected compound, which was isolated with an 85% yield (M.P.=228° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:18](=O)([O-])[O-:19].[K+].[K+].C(Br)[CH:25]=[CH2:26]>C(#N)C>[CH3:18][O:19][CH2:25][CH2:26][N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]=2[CH3:1])[CH2:13][CH2:14]1
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Reactant: O=C([O-])[O-]
Reactant: C=CCBr
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methylsulfonyl)phenyl]piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01) and allylbromide (0.01 g). MS m/z (rel. intensity, 70 eV) 311 (M+, 2), 267 (17), 266 (bp), 129 (8), 70 (10).
Reaction SMILES: [N+:1]1([O-:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Si]([C:13]#[N:14])(C)(C)C.CN(C)C(Cl)=O.O>C(Cl)Cl>[C:13]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][N+:1]=1[O-:8])#[N:14]
Reactant: C[Si](C)(C)C#N
Reactant: Cc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc[n+]([O-])c(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 4-picoline-N-oxide (20 g) in CH2Cl2 (360 mL) was added TMSCN (26.5 mL), stirred 5 minutes, added dimethyl carbamyl chloride (16.6 mL) was added slowly dropwise. The mixture was stirred at RT overnight, poured onto 400 mL H2O, and 40 g NaCO3. Separation of layers and evaporation of CH2Cl2 gave 17.25 g of 2-Cyano-4-methylpyridine-N-oxide, recrystallized from hexane, m.p. 95°-98° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][NH:16][C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:36][C:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CNC(=O)Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(Cc3ccccc3)s2)CC1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A mixture of 1-t-butyloxycarbonyl-4-(2-phenylacetamido)acetylpiperidine (595 mg, 1.653 mmol) from Step E and Lawesson's reagent (607 mg, 1.66 mmol) in 5 mL of toluene was heated to 120° C. for 3.5 h. After cooling, 3:1 mixture of ethyl acetate and methylene chloride and saturated sodium bicarbonate solution were added and the mixture was stirred for 0.5 h. The organic phase was separated and washed with brine. Solvent removal gave a crude product which was purified on silica gel using 2:3 mixture of ethyl acetate-hexane as solvent to give 330 mg of the desired product.