Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.S([O-])([O-])(=O)=O.[Mg+2].O=[C:27]([CH3:35])[CH2:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31].C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:1][CH:27]([CH3:35])[CH2:28][P:29](=[O:34])([O:32][CH3:33])[O:30][CH3:31])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN)c2nc1OC
Reactant: COP(=O)(CC(C)=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COc1nc2cc([N+](=O)[O-])cc(CNC(C)CP(=O)(OC)OC)c2nc1OC
Reaction time: 4 h

Procedure:
200 mg (0.757 mmol) of 5-aminomethyl-7-nitro-2,3-dimethoxyquinoxaline, 547 mg (4.5 eq.) of magnesium sulfate and 163 mg (1.3 eq.) of dimethyl 2-oxopropylphosphonate are stirred at room temperature for 20 hours in 8 ml of dichloromethane. 4 ml of methanol, 0.095 ml of acetic acid and 52 mg (1.1 eq.) of sodium cyanoborohydride are then added and stirred for 4 hours. The reaction mixture is then filtered and the filtrate is extracted with water and brine. The organic phases are combined, dried over magnesium sulfate and evaporated. The title compound is obtained as a brown oil.
Reaction SMILES: [CH3:1][C@H:2]([C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:21]O>>[CH3:12][CH:10]([CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:13]([O:15][CH3:21])=[O:14])[CH3:1])=[CH:4][CH:5]=1)[CH3:11]
Reactant: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc(CC(C)C)cc1

Procedure:
S-(+)-ibuprofen (5.0 g; 0.024 mole) was shed into methanol (35 ml), concentrated sulfuric acid (1 ml) was added and the reaction mixture was heated for 3 hours at the reflux temperature of the reaction mixture. Then it was evaporated in vacuo at the temperature of 30° C. to dryness. S-(+)-ibuprofen methyl ester (5.1 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[Cl-].[CH:15](=[N+:22]([CH3:24])[CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:23][N:22]([CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([OH:13])=[O:12])[CH3:24]
Reactant: C[N+](C)=Cc1ccccc1
Reactant: O=C(O)c1cc2cc(O)ccc2[nH]1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccc(O)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-hydroxy-1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](OS(C(F)(F)F)(=O)=O)[CH:3]=1.C[C:24]1[C:25]([CH2:30][NH2:31])=[N:26][CH:27]=[CH:28][CH:29]=1>COCCOC>[NH2:1][C:2]1[CH:3]=[C:4]([NH:31][CH2:30][C:25]2[CH:24]=[CH:29][CH:28]=[CH:27][N:26]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: N#Cc1c(OS(=O)(=O)C(F)(F)F)cc(N)nc1-c1ccco1
Reactant: Cc1cccnc1CN
Solvent: COCCOC
Product: N#Cc1c(NCc2ccccn2)cc(N)nc1-c1ccco1

Procedure:
From trifluoromethanesulfonic acid 6-amino-3-cyano-2-furan-2-yl-pyridin-4-yl ester and C-(3-methyl-pyridin-2-yl)-methylamine in DME. ES-MS m/e (%): 306 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[O:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[CH2:34][NH2:35]>>[CH3:18][N:15]1[C:14]([C:19](=[O:21])[NH:35][CH2:34][C@@H:30]2[CH2:31][CH2:32][CH2:33][O:29]2)=[C:13]([NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])[CH:17]=[N:16]1
Reactant: NC[C@@H]1CCCO1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)NC[C@@H]1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (30 mg, 79 μmol; example 236, step 3) and (S)-(tetrahydrofuran-2-yl)methanamine (15 μl, 142 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (31 mg, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]([CH3:26])[CH2:16][CH2:17][NH:18]C(=O)OC(C)(C)C)=[CH:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].O.CC#N>ClCCl.FC(F)(F)C(O)=O>[NH2:18][CH2:17][CH2:16][N:15]([CH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)[N:10]=[N:11][CH:12]=1)[CH3:26]
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cnnn1-c1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN(CCN)Cc1cnnn1-c1ccc(C#N)cc1
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A solution of tert-butyl N-[2-([[1-(4-cyanophenyl)-1H-1,2,3-triazol-5-yl]methyl](methyl)amino)ethyl]carbamate (100 mg, 0.28 mmol, 1.00 equiv) in dichloromethane (4 mL) and trifluoroacetic acid (4 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under vacuum and the crude product was purified by Prep-HPLC with the following conditions (2#-Waters 2767-2(HPLC-08)): Column, XBridge Shield RP 18, 5 μm, 19*×150 mm; mobile phase, water with 50 mmol NH4HCO3 and CH3CN (10.0% CH3CN up to 28.0% in 2 min, up to 46.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254 nm to give 41.6 mg (58%) of 4-(5-(((2-aminoethyl)(methyl)amino)methyl)-1H-1,2,3-triazol-1-yl)benzonitrile as a white solid. 1H NMR (400 MHz, CD3OD) δ: 8.04-7.91 (s, 5H), 3.76 (s, 2H), 2.76 (t, J˜6.2 Hz, 2H), 2.53 (t, J˜6.2 Hz, 2H), 2.21 (s, 3H) ppm. LCMS (method H, ESI): RT=1.02 min, m/z=257.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH2:11][CH2:12][CH2:13]2)=[CH:8][CH:9]=1
Reactant: COC(=O)NC1(c2ccc([N+](=O)[O-])cc2)CCC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)NC1(c2ccc(N)cc2)CCC1
Reaction time: 8 h

Procedure:
A suspension of Pd/C (10%) (120 mg) and methyl 1-(4-nitrophenyl)cyclobutylcarbamate (A118) (404 mg, 1.61 mmol) in MeOH (17.0 mL) was vigorously stirred overnight under a hydrogen atmosphere. The resulting mixture was filtered through Celite then the filtrate concentrated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-75% EtOAc in cyclohexane) to give the title compound A119 (237 mg, 67%); 1H NMR (300 MHz, CDCl3); δ 7.21 (d, J=8.3 Hz, 2H), 6.63 (d, J=8.5 Hz, 2H), 5.57 (brs, 1H), 3.66 (s, 2H), 3.58 (s, 3H), 2.48 (m, 4H), 2.02 (m, 1H), 1.80 (m, 1H). LCMS-B: rt 2.35 min; m/z 221.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[NH2:18][C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:21]=2[CH2:20][C@H:19]([NH:18][C:15](=[O:17])[C:12]2[CH:11]=[CH:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)=[CH:14][CH:13]=2)[CH2:28][CH2:27]3)[CH2:30][CH2:31]1
Reactant: CCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(C(=O)N[C@@H]3CCc4cccc(N5CCN(C)CC5)c4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4′-Ethyl-4-biphenylcarboxylic acid (1.0 g, 4.4 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 1 h. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (130 mg, 0.53 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (120 mg, 0.48 mmol) and triethylamine (99 μL, 0.72 mmol) in methylene chloride (20 mL) . After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with water. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:4) as the eluent. Yield: 140 mg (53%) of the title compound as white crystals: mp 234-235° C.; [α]21D −73° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (10, M+)
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[N:5][CH:4]=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1.C(Cl)Cl>C(=O)([O-])[O-].[Na+].[Na+].O>[Cl:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][N:12]([C:18]([CH:15]3[CH2:17][CH2:16]3)=[O:19])[CH2:13][CH2:14]2)[CH:6]=[N:5][CH:4]=1
Reactant: Clc1cncc(N2CCNCC2)n1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(C1CC1)N1CCN(c2cncc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
To a stirred suspension of 4.70 g (20.0 mmol) of 6-chloro-2-(1-piperazinyl)-pyrazine hydrochloride in 75 ml saturated aqueous sodium carbonate cooled in an ice bath is added 3 ml (33 mmol) of cyclopropanecarboxylic acid chloride. The mixture is stirred 45 minutes at ice bath temperature and then treated with 5 ml methylene chloride and warmed to room temperature during 30 minutes. Additional acid chloride (3 ml, 33 mmol) is added and stirring is continued 30 minutes longer. The mixture is diluted with water and extracted with chloroform to give 5 g crude 6-chloro-2-(4-cyclopropanecarbonyl-1-piperazinyl)-pyrazine which crystallizes, mp 69°-71° C. (100%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:44]=[CH:43][C:39]3=NO[N:42]=[C:38]3[CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[NH2:8][C:6]1[N:7]=[CH:2][C:39]2[C:38](=[CH:37][CH:36]=[C:44]([C:2]3[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]4[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=4[N:7]=3)[CH:43]=2)[N:42]=1
Reactant: CC1(C)OB(c2ccc3nonc3c2)OC1(C)C
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4nc(N)ncc4c3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reaction time: 8 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.180 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,1,3-benzoxadiazole (57.7 mg, 0.235 mmol), DMSO (2 mL), sodium carbonate (0.271 mL, 0.541 mmol), and bis(triphenylphosphine)palladium(II) chloride (12.67 mg, 0.018 mmol), wherein the reaction time was 8 h. The final product was collected as 28 mg (31%). LCMS E-S (M+H)=497.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.8 Hz, 6H), 2.12 (s, 3H), 2.26 (s, 3H), 4.41 (d, J=5.0 Hz, 2H) 5.30 (quin, J=6.6 Hz, 1H), 5.89 (s, 1H), 7.16 (br. s., 2H), 7.56 (d, J=9.1 Hz, 1H), 7.78 (s, 1H) 8.60 (dd, J=8.8, 2.0 Hz, 1H), 8.69 (d, J=1.8 Hz, 1H), 8.76 (t, J=4.9 Hz, 1H), 9.28 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][CH:18]([NH2:30])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1>CS(C)=O>[CH3:17][CH:18]([N:30]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1
Reactant: COc1ccc(CC(C)N)cc1OC
Reactant: CCCCOc1ccccc1C(=O)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCOC(=NC(C)Cc1ccc(OC)c(OC)c1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.0 g of 2-n-butoxyphenylglyoxal hydrate (crude oil) are dissolved in 9 ml of dimethylsulfoxide, and 2.8 g of α-methyl-3,4-dimethoxyphenethylamine are added thereto. The mixture is stirred at room temperature for 30 minutes, whereby a solution of α-(α-methyl-3,4-dimethoxyphenylethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1-O-benzyl-3-O-t-butyldimethylsilylglycerol (1.63 g) was added to pyridine (6 ml), and the mixture was cooled to 5° C., and mesyl chloride (0.5 ml) was added dropwise thereto, and the resultant mixture was stirred overnight at room temperature. Upon confirming the completion of the reaction, the reaction liquid was cooled to 5° C., water (0.5 ml) was added thereto and the mixture stirred at the same temperature for 30 minutes.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]12[CH2:11][O:10][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][Si](C)(C)C)=[CH:14][CH:13]=3)([O:8][CH2:9]1)[O:6][CH2:5]2.CC(C)(C)CC12CO[C:32](C3C=CC(I)=CC=3)(OC1)[O:31][CH2:30]2.C[Si](C#C)(C)C>>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]12[CH2:11][O:10][C:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:30][O:31][CH3:32])=[CH:14][CH:13]=3)([O:8][CH2:9]1)[O:6][CH2:5]2
Reactant: CC(C)(C)CC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Reactant: CC(C)(C)CC12COC(c3ccc(I)cc3)(OC1)OC2
Agent: C#C[Si](C)(C)C
Product: COCCCc1ccc(C23OCC(CC(C)(C)C)(CO2)CO3)cc1

Procedure:
Using methodology described in Example 1, 4-(2,2-dimethylpropyl)-1-[4-(2-trimethylsilylethynyl)phenyl]-2,6,7-trioxabicyclo[2,2,2]octane was prepared from 4-(2,2-dimethyl-propyl)-1-(4-iodophenyl)-2,6,7-trioxabicyclo[2,2,2]octane and trimethylsilylacetylene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]3[CH2:16][CH2:17][CH2:18][C@@H:12]3[CH2:11]2)=[CH:6][C:5]=1[O:19][CH:20]([CH3:22])[CH3:21])([O-])=O.O.NN>C(O)C.[Pd]>[CH2:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([O:19][CH:20]([CH3:22])[CH3:21])[CH:6]=2)[CH2:15][CH2:14][N:13]2[CH2:16][CH2:17][CH2:18][C@H:12]12
Reactant: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(N2CCN3CCC[C@@H]3C2)ccc1N
Temperature: 80 °C
Yield: 98.8 %

Procedure:
A mixture of 1.38 g of (8aR)-2-[4-nitro-3-(propan-2-yloxy)phenyl]octahydropyrrolo[1,2-a]pyrazine, 2.72 g of hydrazine hydrate and 240 mg of 10% palladium-on-carbon (240 mg, 5 mol %) in 30 ml of ethanol is heated at 80° C. (bath) for 1 h 30. The mixture is filtered on Clarcel and the filtrate is concentrated under vacuum, so as to obtain 1.23 g of 4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-2-(propan-2-yloxy)aniline in the form of a purple oil.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.C(Cl)[Cl:18]>Cl.O1CCOCC1>[ClH:18].[ClH:18].[CH3:1][N:2]([CH3:16])[C@@H:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1
Reactant: CN(C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)[C@@H]1CCCNC1
Reaction time: 4 h

Procedure:
1,1-Dimethylethyl (3R)-3-(dimethylamino)-1-piperidinecarboxylate (5.0 g crude, 21.12 assumed mmol) was dissolved and stirred in a mixture of CH2Cl2 (10 mL) and 4M HCl in dioxane (21 mL, 4 eqv.) A white precipitate formed. The reaction appeared to stall at approximately 70% completion, and therefore another 21 mL of 4M HCl in dioxane was added to the reaction mixture. After 4 h at room temperature, the solvent was evaporated, providing (3R)—N,N-dimethyl-3-piperidinamine, dihydrochloride as a white solid (3.5 g, 89% for two steps).
Reaction SMILES: [C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](O)C>>[C:1]1([N:7]2[C:13]3[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=3[N:11]([CH3:21])[C:10](=[O:19])[CH2:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCO
Product: CN1C(=O)CC(=O)N(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Starting from 1-phenyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine (obtained according to the example XI) and from a methyl halide, and operating according to the example X, there is obtained 1-phenyl 5-methyl 8-chloro 1,2,4,5-tetrahydro 2,4-dioxo 3H-1,5-benzodiazepine, melting at 166°-168° C after recristallisation in 50% ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18]C.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:7]2[S:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18]
Reactant: COc1ccc2c(-c3ccccc3F)csc2c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c(-c3ccccc3F)csc2c1Cl
Temperature: 190 °C
Yield: 98.4 %

Procedure:
A mixture of 9.5 g of 7-chloro-3-(2-fluorophenyl)-6-methoxybenzo[b]thiophene and 80 g of pyridine hydrochloride is heated at 190° C. for 7 hours, with stirring. Water (500 ml) is added to the cooled reaction mixture and the resulting suspension is extracted with ether (3 times). The combined etheral extracts are cooled with dilute hydrochloric acid, dried over anhydrous magnesium sulfate and evaporated to afford 8.9 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)benzo[b]thiophene.
Reaction SMILES: C([C@@H](N[C@H](C(N1CCC[C@H]1C(O)=O)=O)CCCCN)CCC1C=CC=CC=1)(O)=O.C(=O)(O)[O-].[Na+].[C:35]([C@@H:38]([NH:47][C@H:48]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:64])[CH2:55][NH:56]C(OC(C)(C)C)=O)[CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([OH:37])=[O:36]>O.C(#N)C.FC(F)(F)C(O)=O>[C:35]([C@@H:38]([NH:47][C@H:48]([C:65]([N:67]1[CH2:74][CH2:73][CH2:72][C@H:68]1[C:69]([OH:71])=[O:70])=[O:66])[CH2:49][CH2:50][CH2:51][CH2:52][NH:53][C:54](=[O:64])[CH2:55][NH2:56])[CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)([OH:37])=[O:36]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)NCCCC[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.5 %

Procedure:
A solution of 405 mg (1.0 mmol) of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-L-lysyl]-L-proline and 252 gm (3.0 mmol) of sodium bicarbonate in 3 ml of water was treated with a solution of 272 mg (1.0 mmol) of N-t-butoxycarbonyl-glycine N-hydroxysuccinimide ester in 2 ml acetonitrile. The resulting clear solution was stirred at room temperature for 11/2 hours, concentrated in vacuo to 3/4 volume and acidified by dropwise addition of 2.5 N HCl. The resulting mixture was shaken with a small amount of ethyl acetate and the ethyl acetate/water layer decanted off a white, insoluble gum. The insoluble gum was flushed in vacuo with methanol and pumped out on an oil pump to provide 395 mg of crude product contaminated with a small amount of starting material. LH-20 Chromatograph (2.5×240 cm, methanol system) yield 305.6 mg of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -(N-tert-butoxycarbonylglycyl)-L-lysyl]-L-proline. 305 mg (0.54 mmol) of the above intermediate was then dissolved in 8 ml trifluoroacetic acid (drying tube) and stirred at room temperature for 20 minutes. The reaction mixture was concentrated in vacuo, flushed 2x with ethyl ether and pumped out on an oil pump. The residual dry, white foam was dissolved in 8 ml of water and put on a column of 8 ml of Dowex 50W-X2(H+) resin. After aqueous washes, the product was eluted with water containing 2% pyridine, which after freeze-drying, provided 265 mg of N-[N2 -(1(S)-carboxy-3-phenylpropyl)-N6 -glycyl-L-lysyl]-L-proline that was single spot by tlc (ethyl acetate/pryridine/acetic acid/water (10:5:1:3) system) and had an excellent nmr in deuteromethanol (aromatic singlet at 7.2 ppm and the glycyl methylene at 3.7 ppm).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:10]1([C:16]#[CH:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S([O-])([O-])(=O)=O.[Cu+2].O.CC(C)=O>[C:10]1([C:16]2[N:3]=[N:2][N:1]([C:4]3[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=3)[CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=Nc1ccncc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(-c2cn(-c3ccncc3)nn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Approximately equimolar amounts of 4-azidopyridine and phenylacetylene (4.12 ml, 41.8 mmol) were added into a 250 mL round-bottom flask with 50 mL mixture of water/acetone. Copper (II) sulfate and sodium L-ascorbate were added to this solution and the reaction was stirred at room temperature for 24 hours. The solution was filtered and concentrated. Ethyl acetate (200 ml) was added to the concentrated solution. The organic layer was washed twice with 25 mL water, dried with MgSO4, filtered, concentrated and dried in vacuo, producing 4-(4-phenyl-1H-1,2,3-triazol-1-yl)pyridine.