Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C.Cl[C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42]>C(Cl)Cl>[Si:16]([O:15][CH2:14][C@@H:2]([NH:1][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[N+:41]([O-:43])=[O:42])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2ccccc12
Temperature: 0 °C
Reaction time: 48 h
Yield: 99.1 %

Procedure:
tert-Butyl (4S)-4-amino-5-{[tert-butyl(dimethyl)silyl]oxy}pentylcarbamate (3.76 g, 11.3 mmol) was dissolved in 100 mL of dry CH2Cl2 and the solution was cooled to 0° C. under N2. Triethylamine (3.10 mL, 22.3 mmol) and 4-chloro-3-nitroquinoline (2.36 g, 11.3 mmol) were then added and the reaction was allowed to warm to ambient temperature and stirred for 2 days. The reaction mixture was then concentrated under reduced pressure to give a yellow solid. The solid was dissolved in 200 mL of CH2Cl2 and was washed successively with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated under reduced pressure to give yellow solid. Chromatography (SiO2, 20-35% ethyl acetate/hexanes) gave tert-butyl (4S)-5-{[tert-butyl(dimethyl)silyl]oxy}-4-[(3-nitroquinolin-4-yl)amino]pentylcarbamate (5.65 g) as a yellow syrup.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:20][CH3:21])=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[CH3:22])=O)(C)(C)C.BrC[CH2:25][CH2:26][CH2:27][C:28]12[CH2:39][CH2:38][CH2:37][C:35]3[C:36]1=[C:31]([CH:32]=[CH:33][CH:34]=3)[NH:30][C:29]2=[O:40].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.Cl>[CH3:19][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[O:20][CH3:21])[CH:9]([CH3:22])[N:8]([CH2:6][CH2:25][CH2:26][CH2:27][C:28]13[CH2:39][CH2:38][CH2:37][C:35]4[C:36]1=[C:31]([CH:32]=[CH:33][CH:34]=4)[NH:30][C:29]3=[O:40])[CH2:17][CH2:16]2
Reactant: COc1cc2c(cc1OC)C(C)N(C(=O)OC(C)(C)C)CC2
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)C(C)N(CCCCC13CCCc4cccc(c41)NC3=O)CC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-t-Butoxycarbonyl-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (190 mg, 0.61 mmol) was dissolved in hydrochloric acid methanol solution (4 ml) and stirred at room temperature for 2.5 hours. The residue obtained by evaporating the solvent from the reaction solution under a reduced pressure was dissolved in anhydrous N,N-dimethylformamide (2 ml), and the solution was mixed with 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indole-2-one (190 mg, 0.61 mmol) and potassium carbonate (250 mg, 1.8 mmol) and stirred at room temperature for 14 hours. The reaction solution was mixed with ethyl acetate, washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 200 mg (0.46 mmol, 76% in yield) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10]([NH:17][S:18](Cl)(=[O:20])=[O:19])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].O>C1COCC1>[C:10]([NH:17][S:18]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)(=[O:19])=[O:20])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NS(=O)(=O)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
TEA (4.2 mL, 30 mmol) was added to a solution of indole (1.17 g, 10 mmol) in dry THF (12.0 mL) at 0° C. and stirred for 10 min. N-Boc sulfamoyl chloride (4.31 g, 20 mmol) was added, the mixture allowed to warm to RT, and stirred overnight. The reaction mixture was poured into water, and the crude product extracted into EtOAc. The organic layer was evaporated to dryness, and dried under vacuum overnight to provide N-Boc 1H-indole-3-sulfonamide (1.57 g, 53% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu](C#N)[C:15]#[N:16]>C(OCC)(=O)C>[CH3:10][O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])c(C#N)cc1C
Yield: 41.6 %

Procedure:
A mixture compound 108 (20 g, 100 mmol) and copper cyanide (11.25 g, 125 mmol) in n-methyl-pyrrolidone-2 (60 ml) was stirred for 20 h at 140-150° C. The mixture was diluted with ethyl acetate filtered and washed four times with water. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (8 g, 41%).
Reaction SMILES: [CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5]2(OCC[O:6]2)[CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[CH3:1][C:2]1([C:12]#[N:13])[CH2:11][CH2:10][C:5](=[O:6])[CH2:4][CH2:3]1
Reactant: CC1(C#N)CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C#N)CCC(=O)CC1
Yield: 62.8 %

Procedure:
Alternatively the compound could be obtained by heating 14.2 g of 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carbonitrile in 190 mL of 80% acetic acid under reflux until conversion was complete. The mixture was cooled and poured onto 1.2 L of cold, saturated sodium bicarbonate solution. 600 mL of brine were added and the mixture was extracted several times with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over magnesium sulphate and evaporated. The residue was taken up in water and acetonitrile and lyophilized to give 6.75 g of the desired product, that could be directly used in further conversions.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl.C(#N)C>[CH3:13][O:12][C:6]1[CH:5]=[N:4][C:3]2[C:2]([NH2:1])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Nc1cccc2[nH]c(=O)cnc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: COc1cnc2c(N)cccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a suspension of 5-aminoquinoxalin-2(1H)-one (440 mg, 2.73 mmol) in methanol (1 mL), DCM (8 mL) and acetonitrile (8 mL), at 0° C., was added TEA (1.14 mL, 8.19 mmol), followed by (trimethylsilyl)diazomethane (2 mL, 4.10 mmol; 2.0M in hexanes). The reaction mixture was allowed to warm to RT and stirred for additional 3 hours. The suspension was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with 10%-50% ethyl acetate in hexane, to provide the title compound (167 mg, 0.953 mmol) as a light-yellow powder. LC/MS (ESI+) m/z=176 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1)[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[C:5]([F:18])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3ccccc3o2)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(-c2nc3ccccc3o2)c(F)c1

Procedure:
A mixture of 26 gm. 2-(4-ethyl-2-fluorophenyl) benzoxazole, 19.76 gm. of N-bromosuccinimide and 50 mg. of dibenzoyl peroxide in 150 cc. of carbon tetrachloride is refluxed until the N-bromosuccinimide is consumed. The reaction mixture is filtered and the filtrate concentrated to give a 2-[4-(1-bromoethyl)-2-fluorophenyl]benzoxazole, m.p., 103°-104° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][C:8](=[O:32])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])=[CH:20][CH:19]=1)[CH3:6].[C:33]([O-])([O-])([O-])[O:34][CH2:35][CH3:36]>>[C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]2[C:10]3[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:32])=[CH:14][CH:13]=[CH:12][C:11]=3[N:15]=[C:33]2[O:34][CH2:35][CH3:36])=[CH:19][CH:20]=1)#[N:31]
Reactant: CCOC([O-])([O-])[O-]
Reactant: CCOC(=O)c1cccc(N)c1NCc1ccc(-c2ccccc2C#N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2nc(OCC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Acetic acid (0.2 g) was added to a solution of ethyl-3-amino-2-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate (1.0 g) in ethyl orthocarbonate (5 ml). The mixture was stirred at 80° C. for one hour. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate. The solution was washed with an aqueous solution of sodium hydrogen carbonate and water. The solvent was evaporated to give crystals. Recrystallization from ethyl acetate-benzene afforded colorless crystals (0.79 g, 69%), m.p. 131°-132° C.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]([CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([NH:21][CH2:22][CH:23]([OH:32])[C:24]2[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=2)[CH3:20])=[CH:14][CH:13]=1)=[O:9].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:8]([CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH:19]([N:21]2[C:3](=[O:4])[CH2:2][O:32][CH:23]([C:24]3[N:25]=[C:26]([CH:29]([CH3:31])[CH3:30])[S:27][CH:28]=3)[CH2:22]2)[CH3:20])=[CH:16][CH:17]=1)([O:7][CH3:6])=[O:9]
Reactant: COC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(C)C)n2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(CC(C)N2CC(c3csc(C(C)C)n3)OCC2=O)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
0.60 ml (7.89 mmol) of chloroacetyl chloride is added dropwise to a stirred solution of 3.10 g (7.89 mmol) of N-[2-(4-methoxycarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-isopropyl-thiazol-4-yl)-ethanamine and 1.10 ml (7.89 mmol) of triethylamine in 20 ml of chloroform at 25° C. internal temperature. After the mixture has stood overnight at 20° C., it is concentrated in vacuo, and the resudue is dissolved in 30 ml of anhydrous dimethyl formamide. To this is added 0.888 g (15.78 mmol) of a 55% dispersion of sodium hydride in oil, during which brief foaming is observed. The mixture is stirred at 20° C. for 3 hours, concentrated in vacuo, and the residue is partitioned between water and ether. The ether solution is dried, filtered and concentrated in vacuo, and the oily residue is purified on silica gel (toluene/acetone =4:1).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27][CH2:28][CH2:29]Br>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH3:29])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2Cl)c1OC
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 104 %

Procedure:
Sodium hydride (50%, 920 mg), ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetate (6 g) and n-propyl bromide (3.2 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valerate (7 g).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[C:10](=[O:23])[C:9](=O)[CH2:8]2)[CH:2]=1.[CH3:26][C:27]([NH2:39])([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1)[CH3:28].N#N>C1(C)C=CC=CC=1>[CH3:28][C:27]([NH:39][C:9]1[C:10](=[O:23])[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=2)[CH:7]([C:3]2[CH:2]=[C:1]([CH3:25])[CH:6]=[CH:5][CH:4]=2)[CH:8]=1)([C:29]1[CH:30]=[N:31][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:33][CH:34]=1)[CH3:26]
Reactant: CC(C)(N)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cccc(C2CC(=O)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Agent: N#N
Solvent: Cc1ccccc1
Product: Cc1cccc(C2C=C(NC(C)(C)c3ccc(C(F)(F)F)nc3)C(=O)N2c2ccc(OC(F)(F)F)cc2)c1
Temperature: 80 °C
Yield: 40.1 %

Procedure:
Charge toluene (20 mL) to a flask containing (±)-5-m-tolyl-1-(4-trifluoromethoxy-phenyl)-pyrrolidine-2,3-dione (4.13 g; 11.82 mmol). Add 1-methyl-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine (4.83 g, 23.65 mmol) to the above solution in an atmosphere of N2. Heat the reaction mixture to 80° C. for 24 hours. Cool to ambient temperature and evaporate in vacuo. Dissolve in MeOH (90 mL) and pass through an SCX-2 ion exchange resin cartridge. Evaporate the MeOH wash to give the crude product. Purify on an SCX-2 ion exchange resin cartridge (eluent with methanol) and then by chromatography on a silica gel column eluting with iso-hexane/ethyl acetate (80:20) to afford the titled compound (2.54 g, 58%). MS (m/z): 536.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:33]([C@:27]1([C:30]([N:12]2[CH2:11][CH2:10][N:9]([C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:15])[F:16])[N:8]=3)[CH2:14][CH2:13]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCN(c3cccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1-[6-(trifluoromethyl)pyridin-2-yl]piperazine (249 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.10 mmol), triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (524 mg, 1.18 mmol). After being stirred overnight, the reaction was quenched with saturated sodium NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20% EA/hex to 40% EA/hexanes) provided 310 mg of the desired product. MS calculated for C24H36F3N4O3: (M+H) 485.3; found 485.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.C(Cl)Cl>[NH2:20][C:17]1[C:16]([C:21]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:29])=[N:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)Nc3ccccn3)n2)CC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncc(N2CCNCC2)nc1C(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
Tert-butyl-4-[5-amino-6-(2-pyridylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate (5.43 g, 13.59 mmol) was suspended in DCM (50 mL) and stirred at 0° C. during addition of TFA (10 ml). The reaction mixture was warmed to RT over 2 hours but analysis showed little deprotection. The reaction was treated with a further 30 ml of TFA and stirred at RT for 15 minutes. The mixture was concentrated under reduced pressure to give a dark red oil which was dissolved in MeOH/DCM and azeotroped with toluene to give an intense orange solid which was filtered, washed with ether and dried under high vacuum (5.41 g, 73% Yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[CH:6][N+:7]=1[O-].P(Cl)(Cl)([Cl:24])=O.O>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)=[C:6]([Cl:24])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)n1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2Cl)ccc1=O
Temperature: -30 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
3-Amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide (8 g) was dissolved in DMF (80 ml). The solution was cooled to −30° C. To the cooled solution was added phosphoryl chloride (12.7 g) dropwise at −30˜−40° C. After addition of phosphoryl chloride, the temperature of the reaction mixture was raised to −10˜−5° C. The mixture was stirred at −10˜−5° C. for 1 hour. To the reaction mixture was added water (400 ml). The suspension was stirred at 30-35° C. for 15 hours. The pH of the suspension was adjusted to 4.5. The suspension was cooled to 0-5° C. and stirred at the same temperature for 2 hours. The precipitate was collected by filtration and washed with water, and dried in vacuo at 40-50° C., to give 3-amino-5-chloro-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide (7.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[C:5]2[C:6](=[O:15])[C:7]3[C:8](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9](=[O:14])[C:10]=2[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: C=CC=C
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A 1 liter glass pressure reactor is charged with 600 parts of toluene and 122 parts of technical 5-nitro-1,4-naphthoquinone (100%) as ca. 93% product. The reactor is blanketed with nitrogen and 57.6 parts of butadiene are introduced under pressure. The mixture is then heated in the closed system to 80° C. and stirred for 4 hours at this temperature. The pressure falls from a maximum of 3.5 to 4 bar to ca. 3 bar at the conclusion of the reaction. The mixture is cooled, the pressure in the reactor removed over a cooling trap, and excess butadiene is distilled at 400 mbar from the autoclave into the cooling trap. At a distillation temperature of 80° C., a total amount of 336 parts of butadiene/toluene is present in the cooling trap, with a butadiene content of ca. 6%. Then the residual toluene is removed with steam, such that at the conclusion of the steam distillation the suspension of 1-nitro-5,8,11,12-tetrahydroanthraquinone in 750 parts of water is free from toluene. The suspension is then run at 10° C. into a mixture of 160 parts of 50% aqueous sodium hydroxide and 50% aqueous potassium hydroxide. Further processing as described in Example 11 gives 138 parts of pure (99%) 1-nitroanthraquinone, i.e. 90% of theory, based on 5-nitro-1,4-naphthoquinone.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[NH2:36][CH2:37][CH2:38][OH:39]>>[OH:39][CH2:38][CH2:37][NH:36][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1
Reactant: NCCO
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Product: Cc1nc(-c2ccccc2)c(C(=O)N2CC(NCCO)CCC2CNC(=O)c2cccc3cccnc23)s1

Procedure:
N-((5-(2-Hydroxyethylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and 2-aminoethanol. (ESI) 530 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Br:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11]>C(#N)C>[Br-:8].[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N+:6]=1[CH2:9][C:10](=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1csc(C)n1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Cc1csc(C)[n+]1CC(=O)c1ccccc1
Product: [Br-]
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
2,4-Dimethylthiazole (0.5 g, 4.41 mmole), 2-bromo-1-phenyl-1-ethanone (0.879 g, 4.41 mmole), and acetonitrile (0.25 mL) were heated in an oil bath at 105 C. for 1.5 hr. Product precipitation began within 10 min. After cooling, acetonitrile (5 mL) and ether (4 mL) were added and the mixture stood at room temp. overnight. Filtration and washing with 30% ether/acetonitrile gave 1.2 g crude product which was recrystalized from methanol/acetonitrile/ether to afford 0.97 g of the title compound, mp 235-237 C (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH:36]([NH2:40])([CH2:38][CH3:39])[CH3:37].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH:36]([NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34])([CH2:38][CH3:39])[CH3:37]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCC(C)N
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(C)NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, sec-butylamine (25 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 12 mg (yield 18%) of the title compound.
Reaction SMILES: C([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20]([CH:21]4[CH2:23][CH2:22]4)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC([Cl:30])=O.CO>C1(C)C=CC=CC=1>[ClH:30].[CH:21]1([C:20]2[C:13]3[CH2:12][CH2:11][C@@:10]4([CH3:24])[C@H:15]([CH2:16][NH:8][CH2:9]4)[C:14]=3[CH:17]=[CH:18][CH:19]=2)[CH2:23][CH2:22]1
Reactant: C[C@]12CCc3c(C4CC4)cccc3[C@H]1CN(Cc1ccccc1)C2
Reactant: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C[C@]12CCc3c(C4CC4)cccc3[C@H]1CNC2
Product: Cl
Temperature: 160 °C
Yield: 9.3 %

Procedure:
cis-2-Benzyl-6-cyclopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.359 mmol, 75 mg) was dissolved in toluene (1 ml). ACE-Cl (1.654 mmol, 182 μl) was added and the reaction mixture; was heated in a microwave reactor at 160° C. for 15 minutes. MeOH (1 ml) was added and the mixture was again heated in a microwave reactor at 160° C. for 5 minutes. The resulting mixture was passed through an SCX cartridge and the resulting filtrate was concentrated in vacuo to give a crude residue that was purified by preparative-HPLC. To the pure fractions was added HCl in ether (1 ml) and the resulting solution was concentrated in vacuo to afford cis-6-cyclopropyl-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (8.8 mg), m/z: 228.2 [M+H]+.