Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:22]([O-:24])=[O:23])[C:7]2[CH2:8][CH2:9][N:10]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:11](=[O:14])[C:12]=2[CH:13]=1)([O-])=O.[H][H].[CH3:27]O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:22]([O:24][CH3:27])=[O:23])[C:7]2[CH2:8][CH2:9][N:10]([CH:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[C:11](=[O:14])[C:12]=2[CH:13]=1
Reactant: CO
Reactant: [H][H]
Reactant: CCCC(CCC)N1CCc2c(C(=O)[O-])cc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Product: CCCC(CCC)N1CCc2c(C(=O)OC)cc(N)cc2C1=O

Procedure:
8.6 g of 7-nitro-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate, 10 cm3 of methanol and 28 mg of 10% (dry basis) palladium-on-carbon are stirred under 2 bar of hydrogen in an autoclave for 2 h 20 min at a temperature of 25° C. The catalyst is filtered through a Celite 545 pellet and washed with 2 lots of 100 cm3 of methanol. The filtrate is then concentrated under reduced pressure (5 kPa). 7.7 g of methyl 7-amino-1-oxo-2-(1-propylbutyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate are obtained in the form of a light green powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C@@H:13]([CH2:24][O:25][Si](C(C)(C)C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(O)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18])[C@@H:13]([CH2:24][OH:25])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
(3R,4R)-1-Benzyloxycarbonyl-3-(tert-butyldimethylsilyl)oxymethyl-4-(tert-butyldimethylsilyl)oxypyrrolidine (5.46 g) was dissolved in tetrahydrofuran (23 mL). While this solution was chilled in an ice water bath, water (23 mL) and acetic acid (68 mL) were sequentially added and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluant: hexane: ethyl acetate=4:1->1:1) to give (3R,4R)-1-benzyloxycarbonyl-3-hydroxymethyl-4-(tert-butyldimethylsilyloxy)pyrrolidine as a colorless oil (2.74 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=2)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A solution of 4-chloro-3-nitrobenzoyl chloride (1.00 g, 4.99 mmol) in dry methylene chloride (20 mL) under a nitrogen atmosphere was treated with 2-amino-5-chloropyridine (643 mg, 4.99 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.00 mmol), and the resulting mixture stirred at room temperature for 18 hours. The solvent was removed by rotary evaporation in vacuo, the residue taken up in ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL). The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 5% ethyl acetate/methylene chloride afforded the title compound as a dark yellow solid (660 mg, 42%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[CH3:19][O:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23]>>[CH3:19][O:20][C:21](=[O:28])[C@@H:22]([NH:23][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and L-leucine methyl ester hydrochloride (1:1) (CAN 7517-19-3) as starting materials, LC-MS (UV peak area/ESI) 100%, 361.2120 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]([CH2:17][CH2:18][CH3:19])([C:14]([O-:16])=[O:15])C([O-])=O)=[CH:4][CH:3]=1.[CH3:21][C:22](C)=O.[OH-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:20])[CH2:9][CH:10]([CH2:17][CH2:18][CH3:19])[C:14]([O:16][CH2:21][CH3:22])=[O:15])=[CH:6][CH:7]=1
Reactant: CCCC(CC(=O)c1ccc(Br)cc1)(C(=O)[O-])C(=O)[O-]
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(CC(=O)c1ccc(Br)cc1)C(=O)OCC
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 20 %

Procedure:
To a 200 mL flask was added crude 2-[2-(4-bromophenyl)-2-oxoethyl]-2-propylmalonate (7.62 g, 19.2 mmol), acetone (21 mL), and ethanol (19 mL), followed by addition of 1 N aqueous sodium hydroxide solution (19.1 mL). The reaction mixture was heated to 55° C. for 3 h. The clear, orange-red reaction mixture was then concentrated under reduced pressure and the residue was redissolved in dimethoxyethane (30 mL). The mixture was heated to 80° C. for 3 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (100 mL) and water (100 mL), and stirred for 15 minutes until almost all color was extracted into the organic layer. The layers were separated and the aqueous layer extracted with additional ethyl acetate (75 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (75 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford an orange oil. The crude product was purified by flash chromatography (10:1 hexane:ethyl acetate) to afford ethyl 2-[2-(4-bromophenyl)-2-oxoethyl]pentanoate (1.33 g, 20%). LC-MS ret. time 3.60 min, m/z 326.05 (MH+); 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3H), 1.25 (t, 3H), 1.29–1.43 (m, 2H), 1.57–1.73 (m, 2H), 2.90–3.08 (m, 2H), 3.34–3.47 (m, 2H), 4.15 (q, 2H), 7.59 (d, 4H), 7.82 (d, 2H).
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:12]([O-])(O)=O.[OH2:16]>>[NH2:12][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:16])[CH:8]=[CH:7]2
Reactant: Cc1cccc2ccccc12
Reactant: O
Reactant: O=[N+]([O-])O
Product: Nc1cccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To 1-methylnaphthalene (8.0 g, 56 mmol) in round bottom flask at 0° C. was added nitric acid (26 mL) dropwise. (NOTE: A slow addition of nitric acid is most important to avoid the formation of the other regioisomers). After the reaction mixture was stirred for an additional 15 min at 0° C., it was poured into 65 mL of H2O. The aqueous solution was extracted with benzene twice and the combined benzene solution was washed with 10% NaOH solution, dried with Na2SO4, and concentrated. Silica gel chromatography (EtOAc:Hexanes=5:95) gave product still containing a few percentage of the other regioisomer. It was recrystallized with EtOAc/Hexanes to give 9.0 g (43%) of 1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[NH2:12][CH2:13][C:14]1([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:12][CH2:13][C:14]1([N:20]2[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6]
Reactant: CN1CCN(C2(CN)CCCCC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: CN1CCN(C2(CNC(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 49.3 %

Procedure:
A solution of 3,4-Dichlorobenzoylchloride (1.05 g.,) in benzene (10 ml) was added dropwise over 40 mins. to a stirred solution of 1-[1-(Aminomethyl)cyclohexyl]-4-methyl piperazine (1.06 g.,) in benzene (15 ml). The mixture was heated under reflux for 1 hr. on a steambath and the solution was evaporated. The solid residue was dissolved in ethanol, acidified with ethereal HCl and evaporated to give a white solid. This solid was suspended in water made alkaline with 5NNaOH and extracted with chloroform (x2). The combined chloroform extracts were dried (anhyd.Na 2 SO4) and evaporated. The solid residue was dissolved in hot petroleum ether (80°-100°) decolourised with charcoal and crystallised from petroleum ether (80°-100° ) to give 1-[1-(3,4 Dichlorobenzamido methyl) cyclohexyl] -4-methyl piperazine (0.95 g; 49%) m.p. 143° -146°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH2:17])[N:16]=[C:10]2[CH:9]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=[C:10]2[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2cc(Oc3cccc([N+](=O)[O-])c3)ccn2n1)C1CC1
Yield: 95.6 %

Procedure:
In the same manner as in Example 18-2 and using 7-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine (112 mg, 0.413 mmol), cyclopropanecarbonyl chloride (135 μL, 0.496 mmol) and N,N-dimethylacetamide (5 mL) as starting materials, the title compound (134 mg, 96%) was obtained as a white solid.
Reaction SMILES: [CH3:1][CH2:2]C.[N+]([O-])(O)=O.[C:8]([OH:11])(=[O:10])[CH3:9]>>[C:8]([OH:11])(=[O:10])[CH2:9][CH3:1].[C:8]([OH:11])(=[O:10])[CH2:9][CH2:1][CH3:2]
Reactant: CC(=O)O
Reactant: CCC
Solvent: O=[N+]([O-])O
Product: CCC(=O)O
Product: CCCC(=O)O

Procedure:
Examples 1-6 are generated using ASPEN computer-aided process simulation software. Propane, nitric acid, and organic acid(s) react in a reactor to produce a product stream comprising nitroalkanes (nitromethane, 1-nitropropane, 2-nitropropane, 2,2-dinitropropane, nitroethane) and oxidation byproducts (acetic acid, propionic acid, butyric acid). The product stream also contains off-gases, such as nitrous oxide, nitric oxide, carbon dioxide, carbon monoxide, unconverted propane and water.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][CH:14]([CH2:44][CH3:45])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12>C(OCC)(=O)C>[OH:13][CH:14]([CH2:44][CH3:45])[CH2:15][N:16]1[C:21](=[O:22])[C:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:28][CH:29]=2)=[C:19]([CH2:38][CH2:39][CH3:40])[N:18]2[N:41]=[CH:42][N:43]=[C:17]12
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)CC)c2ncnn12
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(O)CC)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogen carbonate (1.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[4-(2-hydroxybutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.28 g, 54%).
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].[CH3:28][N:29]([CH3:31])[NH2:30].CN1CCCC1=O>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([NH:30][N:29]([CH3:31])[CH3:28])[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CN(C)N
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C)Nc1ccc2c(ccc3n4c(ccc5cc(C(C)(C)C)ccc54)c[n+]23)c1

Procedure:
A mixture of 1.46 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo-[1,2-a:3,4-a']diquinolin-15-ium iodide, 1.64 ml. of 1,1-dimethylhydrazine and 25 ml. of N-methyl-2-pyrrolidinone is heated at reflux for 15 hours, then cooled and diluted with 300 ml. of ethyl acetate. The precipitate is collected and stirred with 1% aqueous triethylamine hydroiodide. The solid is collected, washed with water and dissolved in 150 ml. of hot methanol. The methanol solution is treated with activated charcoal, filtered, evaporated to a volume of about 25 ml. and cooled. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(2,2-dimethylhydrazino)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with cold methanol and dried; m.p. 347°-350° C., after two crystallizations from 2-propanol/ethanol.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[N:30](C(OC(C)(C)C)=O)[CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1.CCO>CO>[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[S:26][N:25]=[C:24]([CH2:27][CH3:28])[CH:23]=3)[C:19]3[C:29](=[O:39])[NH:30][CH2:31][C:18]=3[C:17]=2[F:40])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: CCc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCO
Product: CCc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3N)c(F)c3c2C(=O)NC3)sn1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
To a stirred solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-(3-ethylisothiazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (53 mg, 0.092 mmol) in MeOH (10 mL) was added 4N HCl/dioxane (10.0 mL, 40.0 mmol). The mixture was heated to 60° C. for 1 hour and then concentrated in vacuo. The residue was triturated with EtOAc and filtered. The filter cake was washed with EtOAc to give a yellow solid, which was suspended into EtOH. The mixture was stirred at 80° C. for 30 minutes and then cooled to room temperature. The resulting precipitate was collected by filtration and washed with EtOH to give a hydrochloride salt of the title compound as an off-white solid (26.8 mg, 70%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (t, J=7.57 Hz, 3H), 1.74-1.83 (m, 1H), 2.07-2.20 (m, 1H), 2.81 (q, J=7.60 Hz, 2H), 3.57-3.67 (m, 1H), 3.73-3.84 (m, 2H), 3.96-4.09 (m, 2H), 4.28-4.36 (m, 1H), 4.43-4.53 (m, 2H), 7.46 (d, J=5.37 Hz, 1H), 8.05 (br s, 3H), 8.68 (s, 1H), 8.80 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C17H20FN5O2S, 378. found, 378.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[N:7]=1.[C:20]1([O:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C.O1CCCC1>[C:20]1([O:26][C:27](=[O:28])[NH:2][C:3]2[S:4][CH:5]=[C:6]([CH2:8][N:9]([CH3:19])[C:10]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[O:11])[N:7]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1noc(C)c1C(=O)N(C)Cc1csc(N)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1noc(C)c1C(=O)N(C)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 22.9 %

Procedure:
N-((2-aminothiazol-4-yl)methyl)-N,3,5-trimethylisoxazole-4-carboxamide hydrochloride (6.16 g, 20.34 mmol) was dissolved in pyridine (35 mL) and DMAP (150 mg, 5 mol %) was added. The solution was cooled to 0° C. and a solution of phenylchloroformate (2.55 mL, 3.18 g, 20.34 mmol) in tetrahydrofuran (35 mL) was added dropwise. The mixture was stirred overnight at room temperature and the volatiles were evaporated in vacuo. The residue was taken up in water/EtOAc. The organic phase was dried over MgSO4 and the volatiles were evaporated under reduced pressure. The material was crystallized from EtOAc/i-Pr2O to afford (4-{[methyl(3,5-dimethylisoxazole-4-carbonyl)-amino]-methyl}-thiazol-2-yl) carbamic acid phenyl ester (1.80 g) as a tan-colored solid (purity ˜85%). 1H NMR (CDCl3): δ 9.85 (bs, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.20 (m, 2H), 6.80 (b, 1H), 4.75 (bs, 1H), 4.45 (bs, 1H), 3.00 (bs, 3H), 2.36 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].SC1SC2C=CC(C#N)=CC=2N=1.[Cl:23][C:24]1[S:25]C2C=CC(Cl)=CC=2N=1>>[Cl:23][C:24]1[S:25][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: Clc1ccc2sc(Cl)nc2c1
Agent: N#Cc1ccc2sc(S)nc2c1
Product: N#Cc1ccc2sc(Cl)nc2c1
Temperature: 95 °C

Procedure:
The title compound was prepared from 3-amino-4-chlorobenzonitrile via 2-mercapto-1,3-benzothiazole-5-carbonitrile as described for 2,5-dichloro-1,3-benzothiazole except that in the first step the reaction mixture was heated to 95° C. for 10 h.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=[C:40]([NH:42][C@H:43]4[CH2:48]CCN[CH2:44]4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.N(CCC)=C=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:40]([NH:42][CH:43]([CH3:48])[CH3:44])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCCN=C=O
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by isocyanatopropane (0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 439.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-:22])=[O:21])[N:11]=[C:8]2[S:9][CH:10]=1)=O)C.[OH-:23].[Na+].C1[CH2:29][O:28]CC1.O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[N:11]=[C:8]2[N:7]([CH:13]=1)[C:6]([CH2:4][C:29]([OH:28])=[O:23])=[CH:10][S:9]2)([O-:22])=[O:21]
Reactant: CCOC(=O)c1csc2nc(-c3ccccc3[N+](=O)[O-])cn12
Reactant: [OH-]
Reactant: C1CCOC1
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1csc2nc(-c3ccccc3[N+](=O)[O-])cn12
Temperature: 50 °C
Yield: 99 %

Procedure:
6-(2-Nitro-phenyl)-imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (466 mg, 1.47 mmol) in 2:1 THF/Water was combined with 4 eq of NaOH (234 mg). The reaction mixture was heated to 50° C. for 3 hours. The reaction mixture was concentrated to dryness, the residue dissolved in water (20 ml), washed with CH2Cl2, and the aqueous layer was adjusted to pH=3 with 4N HCl. The solids were collected by filtration, washed with water and air dried to obtain the acid product was a brown solid (442 mg, 99% yield) (MS, M++H=304.0)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.ClCCCOC1C=CC(C2(C#N)CCCCC2)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][NH:52][CH2:51]1>CN1C(=O)CCC1>[CH3:48][O:49][C@H:50]1[CH2:54][CH2:53][N:52]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:51]1
Reactant: CO[C@H]1CCNC1
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Agent: N#CC1(c2ccc(OCCCCl)cc2)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CO[C@H]1CCN(CCCOc2ccc(C3(C#N)CCCCC3)cc2)C1
Temperature: 160 °C
Yield: 41 %

Procedure:
A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (200 mg, 0.72 mmol), N,N-diisopropylethylamine (251 μL, 1.44 mmol) and (S)-3-methoxy-pyrrolidine (198 mg, 1.96 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds. The reaction mixture was quenched with water (10 mL) and extracted with dichloromethane (2×10 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 95:5:0.5. to give the product as a clear oil (102 mg, 41%). 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.96-3.88 (m, 1H), 3.28 (s, 3H), 2.86-2.52 (m, 6H), 2.18-1.96 (m, 5H), 1.88-1.66 (m, 8H), 1.38-1.16 (m, 1H); LCMS (APCI+) 343 (M+H)+.
Reaction SMILES: COC1C=C(C([C:20]2[C:29]3[C:24](=[CH:25][C:26](OC)=[C:27](OC)[CH:28]=3)[CH:23]=[CH:22][N:21]=2)CC(OCC)OCC)C=CC=1OC.C(O)=O.Cl>CN(C)C=O>[N:21].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][N:21]=1
Reactant: CCOC(CC(c1ccc(OC)c(OC)c1)c1nccc2cc(OC)c(OC)cc12)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=CO
Product: [N]
Product: c1ccc2cnccc2c1
Yield: 362.9 %

Procedure:
7 g (0.0154 mole) of 1-[1-(3,4-dimethoxy-phenyl)-3,3-diethoxy-propyl]-6,7-dimethoxy-isoquinoline, prepared as described in example 7A, are refluxed at 160° C. for 16 hours in a mixture of 9 ml of dimethylformamide, 1.3 ml of 85% formic acid and 0.5 ml concentrated hydrochloric acid. After the reaction mixture has been concentrated under reduced pressure, it is made alkaline and extracted with benzene. 4 g of the title product are obtained, equivalent to a yield of 71.5%. m.p. 170° C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[Br:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[Br:25][C:26]1[CH:27]=[C:28]([N:32]2[C:2]3[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=3)[C:4]([C:6]3[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=3[OH:13])=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Br)c1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cccc(Br)c3)c3cc(O)ccc23)c(O)c1
Yield: 8.1 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.123 g, 0.5 mmol), sodium acetate (0.041 g, 0.5 mmol) and 3-bromophenylhydrazine hydrochloride (0.112 g, 0.5 mmol) to give 0.016 g of product as a tan solid.