Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)[N:13]=1)=O)C>C1COCC1>[Br:27][C:24]1[CH:23]=[CH:22][C:21]([N:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[C:12]([CH2:10][OH:9])=[N:13]2)=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Br)cc2)c2c1CCCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1nn(-c2ccc(Br)cc2)c2c1CCCC2
Reaction time: 1 h
Yield: 70.4 %

Procedure:
Lithium aluminum hydride (1.52 g) in THF (100 ml) was treated with 1-(4-bromophenyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl ester (6.98 g) and reacted at ambient temperature for 2 hours. Additional reagent (1.52 g) was added and the reaction was continued for one hour to complete the conversion. Excess reagent was quenched, the mixture was filtered, and the filtrate was evaporated to yield crude title compound (548 g). Crystallization from acetonitrile gave pure title compound (4.32 g, m.p. 126°-127° C.). The filtrate residue contained equal proportions of title compound and the des-bromo derivative.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][O:19][CH2:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCOC3)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCOC3)c2n1
Yield: 64 %

Procedure:
A solution of N2-butyl-8-(methoxy)-9-[2-(tetrahydro-3-furanyl)ethyl]-9H-purine-2,6-diamine (181 mg) in methanol (1 mL) was treated with 4N HCl in 1,4-dioxane (0.5 mL) for 1.5 h. The reaction was evaporated and the residue treated with water then basified with saturated sodium bicarbonate solution. The resulting solid was filtered, washed with water and dried to give the title compound (111 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([NH2:11])=[CH:9][N:8]=[C:7]([NH:12][CH2:13][CH2:14][C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[N:6]=2)[CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>CC(N(C)C)=O>[CH:1]1([N:4]2[C:26]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:11][C:10]3[C:5]2=[N:6][C:7]([NH:12][CH2:13][CH2:14][C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[N:8][CH:9]=3)[CH2:3][CH2:2]1
Reactant: O=Cc1ccncc1
Reactant: Nc1cnc(NCCc2cccs2)nc1NC1CC1
Solvent: CC(=O)N(C)C
Product: c1csc(CCNc2ncc3nc(-c4ccncc4)n(C4CC4)c3n2)c1
Temperature: 140 °C
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a solution of 0.032 g (0.12 mmol, 1.0 eq.) of N4-cyclopropyl-N2-(2-(thiophen-2-yl)ethyl)pyrimidine-2,4,5-triamine (I-3) in 5 mL of DMA was added 0.05 mL (0.38 mmol, 3.2 eq.) of 4-pyridinecarboxaldehyde. The mixture was stirred at 140° C. for 16 h and the solvent was removed in vacuo. The residue was purified by flash chromatography (EtOAc) to afford 0.015 g (0.04 mmol, 35%) of 9-cyclopropyl-8-(pyridin-4-yl)-N-(2-(thiophen-2-yl)ethyl)-9H-purin-2-amine (I-4) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].N1C=CC=CC=1.C(Cl)Cl.[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>O>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:16]
Reactant: OCC(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reaction time: 0.25 h

Procedure:
Combine 2,2,2-trifluoro-ethanol (6.2 mL), pyridine (6.8 mL) and CH2Cl2 (20 mL) cooled in an ice bath. Add Tf2O (25 g) over about 45 minutes. After 15 minutes, add water, separate the layers and extract with water. The organic layer was dried over Na2SO4 and concentrated through a short path distillation apparatus (8 g, 54%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])=[CH:12][C:13]=3[CH2:14]2)=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH:9]=[CH:10][C:11]([CH2:17][CH2:18][C:19](=[O:21])[CH3:20])=[CH:12][C:13]=3[CH2:14]2)=[CH:6][CH:5]=1
Reactant: CC(=O)CCc1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2
Solvent: CO
Product: CC(=O)CCc1ccc2c(c1)Cc1cc(N)ccc1-2

Procedure:
To 400 ml of methanol were added 5.62 grams of 4-(7-nitro-2-fluorenyl)-butan-2-one and 280 mg of platinic oxide (monohydrate) and subjected to catalytic reduction at ordinary pressure. The catalyst was removed by filtration and methanol was removed by evaporation in vacuo. To the residue was added small amount of methanol and the crystals separated out were collected by filtration to give 4-(7-amino-2-fluorenyl)-butan-2-one, m.p. 116°-117° C.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].B(F)(F)F.CCOCC.[C:18](O)(=[O:22])[CH:19]([CH3:21])[CH3:20].CC([O-])=O.[Na+]>>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:18](=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)C(=O)O
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Resorcinol (1 eq) was taken up in BF3.OEt2 (6 eq) and isobutyric acid (1 eq) added. The solution was heated for 1.5 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted in to EtOAc. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-phenyl)-2-methyl-propan-1-one as a red oil which was used without additional purification
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)OCC
Temperature: 125 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with piperidine (0.426 g, 0.5 mL, 5 mmol) and acetic acid (0.3 g, 0.3 mL, 5 mmol). To this, toluene (25 mL) was added, followed by 4-hydroxybenzaldehyde (2 g, 16.4 mmol) and diethyl malonate (3.15 g, 19.7 mmol). The RM was heated at 125° C., by fitted with a dean-stark's apparatus for 5 h. After 5 h, the RM was concentrated; water (50 mL) was added and extracted with ethyl acetate (50 mL×2)). The organic layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid. (2 g, yield: 46.2%); MS (ESI, 120 eV): m/z=263.1 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.58 (s, 1H), 7.36-7.38 (d, 2H), 6.81-6.84 (d, 2H), 4.17-4.32 (m, 4H), 4.06-4.14 (q, 1H), 1.21-1.26 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:15]1([S:21]([N:24]2[C:32]3[C:27](=[N:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[CH:26]=[C:25]2[CH2:34]Br)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([CH2:34][C:25]2[N:24]([S:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:23])=[O:22])[C:32]3[C:27](=[N:28][C:29]([Cl:33])=[CH:30][CH:31]=3)[CH:26]=2)[C:9]1=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)n1c(CBr)cc2nc(Cl)ccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2cc3nc(Cl)ccc3n2S(=O)(=O)c2ccccc2)C1=O

Procedure:
The title compound is prepared from (2-oxopyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester as described in EXAMPLE 1, Part H using 1-benzenesulfonyl-2-bromomethyl-5-chloro-1H-pyrrolo[3,2-b]pyridine in place of 7-bromomethyl-1-chloro-isoquinoline. The crude product is purified by column chromatography eluting with a gradient of 15% EtOAc/hexanes to 50% EtOAc/hexanes to give the title compound as a beige solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[CH:10]=[C:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CO.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CC(O)=O>[CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cc(=O)c2ccc(S(C)(=O)=O)cc2o1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C1CCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
A mixture of ethyl 7-(methylsulfonyl)-4-oxo-4H-chromene-2-carboxylate (1.3 g, 4.4 mmol), palladium on carbon (10%, 0.44 g), MeOH (45 ml) and AcOH (5 ml) was hydrogenated at 40 Psi for 64 h at 60° C. Filtration through Celite (EtOAc) and evaporation followed by filtration through a plug of Al2O3 (EtOAc/ACN) gave the title compound. Yield: 0.6 g. MS m/z (rel. intensity, 70 eV) 307 (64), 302 (91), 286 (14), 285 (M+1, bp), 211 (18).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)[Cl:42]>Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH2:37]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:23]([C:34](=[O:36])[CH3:35])[CH:22]=1)[CH2:38][CH2:39][CH3:40]
Reactant: ClCCl
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(C(C)=O)c1
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-[5-(3-acetyl-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.17 mmol) in DCM (2.0 mL), 4.0 M HCl in dioxane (2.0 mL) was added and stirring continued for 30 min. Solvent evaporated, resulting solid was washed with ether, dried to provide 1-{5-[3-butyl-6-(piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenyl}-ethanone dihydrochloride salt (60 mg).
Reaction SMILES: C1(O)C=CC=CC=1.Cl[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[CH:11][N:10]=1.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+]>[I-].[K+].C(OCC)(=O)C>[N+:15]([C:14]1[C:9]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Oc1ccccc1
Product: CCOC(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
To phenol (22.92 g) were added 2-chloro-3-nitropyridine (13.22 g) and potassium iodide (0.42 g), and the mixture was stirred at 100° C. for 10 min. Ethyl 4-aminobenzoate (13.2 g) were added, and the mixture was stirred at 100° C.-150° C. for 6 hr. The reaction mixture was poured into ice water, and 4N aqueous sodium hydroxide solution (63 mL) and ethyl acetate (100 mL) were added. The precipitated solid was collected by filtration, and recrystallized from ethanol to give ethyl 4-(3-nitropyridin-2-ylamino)benzoate (15.48 g). Then, to a solution of ethanol (186 mL) and water (46 mL) were added ammonium chloride (1.12 g) and iron (8.1 g), the mixture was stirred at 60° C.-70° C., and the obtained ethyl 4-(3-nitropyridin-2-ylamino)benzoate (10.67 g) was added. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, and the solvent was evaporated to give ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g). To the obtained ethyl 4-(3-aminopyridin-2-ylamino)benzoate (8.77 g) was added triethyl orthoformate (87 mL), and the mixture was stirred with heating under reflux for 4 hr. The solvent was evaporated from the reaction mixture, and toluene (35 mL) and a small amount of p-toluenesulfonic acid hydrate were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was evaporated from the organic layer, and to the residue were added ethylether and hexane, and the precipitated solid was collected by filtration to give the title compound (7.926 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=[O:6].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=S)[C:21]=1[C:29]([F:32])([F:31])[F:30].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5]([C:4]2[CH:15]=[CH:16][C:17]3[NH:18][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[C:21]=4[C:29]([F:32])([F:30])[F:31])=[N:1][C:2]=3[CH:3]=2)=[O:6])=[CH:13][CH:12]=1
Reactant: Nc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N
Reactant: FC(F)(F)c1c(Cl)cccc1N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1ccc2[nH]c(Nc3cccc(Cl)c3C(F)(F)F)nc2c1

Procedure:
Prepared analogously to example 106a from 3,4-diamino-N-(4-bromo-phenyl)-benzamide, 1-chloro-3-isothiocyanato-2-trifluoromethyl-benzene and DCC in DMF.
Reaction SMILES: O[C@:2]1([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=C(C3C=CC=CC=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8].COC(OC)(OC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>C(Cl)Cl>[C:34]1([C:44]2[N:13]=[C:9]([C@:2]34[O:8][C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7]4)[O:10][C:11]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O[C@H]1CCCC[C@]1(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: COC(C)(OC)OC
Solvent: ClCCl
Product: c1ccc(-c2nc([C@@]34CCCC[C@@H]3O4)oc2-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 38251.2 %

Procedure:
To a solution of (1R,2S)-1,2-dihydroxy-1-(4,5-diphenyl-oxazol-2-yl)cyclohexane (18 g) in CH2Cl2 (200 ml) were added orthoacetic acid trimethyl ester (9.7 ml) and p-toluenesulfonic acid (20 mg) at room temperature under N2. After being stirred for 30 minutes, the solvent was evaporated in vacuo. The residue was diluted with CH2Cl2 (200 ml) and acetylbromide (5.8 ml) was added to the solution at 0° C. under N2. After being stirred for 2 hours at room temperature, the solvent was evaporated in vacuo, the residue was diluted with MeOH (200 ml), and K2CO3 (12 g) was added to the solution at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyl-oxazol-2-yl)-1,2-epoxycyclohexane (14.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:7]=1.C(N(C(C)C)CC)(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:7]=1)[NH:8][CH2:9][CH2:10][CH2:11][O:12][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(Br)cc1NCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCCNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-((5-bromo-2-nitrophenyl)amino)propan-1-ol (6.73 g, 24.45 mmol) was dissolved in dry dichloromethane (50 mL), and diisopropylethyl amine (6.41 mL, 36.7 mmol) and tert-butyldimethylsilyl chloride (4.42 g, 29.3 mmol) were added. This mixture was stirred at room temperature for 3 h. The organic layer was washed with water, then saturated aqueous ammonium chloride, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give crude 5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-2-nitroaniline as an orange oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.F[C:14](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.C=O>C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH2:14])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Product: C=C1CCc2ccc(Br)cc2C1=O
Temperature: 25 °C
Yield: 40.4 %

Procedure:
A solution of 7-bromo-3,4-dihydronaphthalen-1(2H)-one (2.00 g, 8.89 mmol) in THF (50 mL) was added to a mixture of N-methylanilinium trifluoroacetate (2.95 g, 13.3 mmol) and paraformaldehyde (1.20 g, 40.0 mmol) at rt. The resulting mixture was heated at reflux for 6 hours. The oil bath was removed and the mixture was allowed to cool to rt. Diethyl ether was added to the reaction mixture, which induced the separation of a red gum. The ethereal solution was decanted from the red gum into a separatory funnel and washed with half-saturated sodium bicarbonate solution. The red gum was triturated with diethyl ether, and the resulting ethereal solution was then used to extract the washing water. The combined organic layers were dried over magnesium sulfate. Filtration and concentration of the organic layer afforded a heavy red oil. The oil was purified using silica gel column chromatography (20:1 hexanes/EtOAc) to afford 7-bromo-2-methylene-3,4-dihydronaphthalen-1(2H)-one (0.850 g, 3.59 mmol, 40% yield) as a thick viscous yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.23 (d, J=2.0 Hz, 1H), 7.60 (dd, J=8.2, 2.1 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.26 (q, J=1.3 Hz, 1H), 5.50 (q, J=1.7 Hz, 1H), 3.01-2.91 (m, 2H), 2.91-2.82 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO.CCOC(C)=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=2)[CH:10]=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)n1ncc2cc(N)ccc21
Reaction time: 8 h
Yield: 95 %

Procedure:
Palladium on carbon (780 mg) was placed under an inert atmosphere and suspended in EtOH (15 mL). A solution of give 5-nitroindazole-1-carboxylic acid tert-butyl ester (7.78 g, 29.5) in EtOH (100 mL) and EtOAc (100 mL) was added. The reaction mixture was placed under H2 atmosphere (1 Atm pressure) and stirred overnight. The resulting mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to get a greenish foamy solid. The crude product was dissolved in CH2Cl2 and purified by Biotage Flash 40M (gradient from 30% to 50% EtOAc/hex) to give the title compound (6.55 g, 95%) as a white solid: TLC (50% EtOAc/hex), Rf=0.41; ES-LCMS (rel abundance) m/z 234 (MH+, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6](=O)[CH:7](Br)[CH2:8][CH3:9])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[S:20])=[CH:17][CH:16]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:21]=[C:19]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:23][CH:22]=2)[S:20][C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCOC(=O)CC(=O)C(Br)CC
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: CCOC(=O)Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CC
Temperature: 25 °C
Yield: 70.6 %

Procedure:
4-Bromo-3-oxo-hexanoic acid ethyl ester (4.68 g, 20.98 mmol) is dissolved into denatured ethanol (100 mL) and para-trifluoromethyl thiobenzamide (4.31 g, 21 mmol) is added in one portion. The reaction is purged of air and flushed with nitrogen then heated to reflux. The reaction is monitored by TLC and HPLC and when complete, the reaction is allowed to cool to room temperature. The solvent is removed and the reaction is diluted with ethyl acetate (200 mL), followed by washes with saturated sodium bicarbonate solution, water, and brine. The ethyl acetate solution is dried over anhydrous sodium sulfate, then concentrated and further purified using flash column chromatography (10% EtOAc/Hexanes) to yield pure [5-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (5.09 g, 14.82 mmol) or 71% yield.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].N1CCCCC1>C1C=CC=CC=1.O>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A mixture of 19.6 mL (166.4 mmol) of p-tolualdehyde, 23.8 mL (158.8 mmol) of diethyl malonate, 0.5 mL of piperidine and 50 mL of benzene was heated at reflux for 18 h using a Dean-Stark water separator. The mixture was allowed to cool to room temperature, benzene was added and it was washed with water (2×), 1N HCl (2×) and NaHCO3. The aqueous phase was extracted with ethyl acetate, the organic phase was dried and the solvent was removed, to yield 41.2 g of the desired product (yield: 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([CH:18]=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:20][CH2:19][N:11]2[C:12]3[C:17]([C:18]([C:23]([Cl:22])=[O:25])=[C:10]2[CH2:9]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCn2c(cc3ccccc32)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCn2c(c(C(=O)Cl)c3ccccc32)C1
Reaction time: 2 h

Procedure:
A solution of (6,7,8,9-tetrahydro-pyrido[1,2-a]indol-8-yl)-carbamic acid tert-butyl ester (400 mg, 1.40 mmol) in dry THF (5 mL) was cooled to 0° C. Triphosgene (208 mg, 0.7 mmol) dissolved in dry THF (3 mL) and triethylamine (194 μL, 1.40 mmole) were added. A precipitation was formed. The reaction was allowed to reach room temperature and after 2 h the mixture was evaporated and the crude product was used in the next step. APCI-MS m/z: 345 [MH+] (analysis performed on a sample quenched with methanol, thus the mass corresponds to the methylester).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12]O.C([O-])=O.[Na+]>C(O)=O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])#[N:12]
Reactant: NO
Reactant: Cc1cccc(C=O)c1O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C#N)c1O
Yield: 82.5 %

Procedure:
A solution of 2-hydroxy-3-methylbenzaldehyde (18.6 g), hydroxylamine hydrochloride (14.2 g) and sodium formate (19.2 g) in formic acid (200 mL) was heated at reflux for 18 h, then cooled and partitioned between DEE/water. The organic layer was washed with water, saturated aqueous sodium bicarbonate and brine, then dried over sodium sulfate and concentrated in vacuo to afford a solid. Recrystallization from diethyl ether/petroleum ether afforded the title compound as colorless crystals (15.0 g).