Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:16][CH:15]=1)[C:10](=[O:25])[CH:9]=3.Cl.[CH3:29][NH:30][CH3:31].C(B)#N.[Na]>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH2:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[N:12][N:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH:22]([N:30]([CH3:31])[CH3:29])[CH3:23])=[CH:16][CH:15]=1)[C:10](=[O:25])[CH:9]=3
Reactant: CC(=O)COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1
Reactant: CNC
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(COc1ccc(-n2nc3c(cc2=O)CCc2ccc(F)cc2-3)cc1)N(C)C

Procedure:
To a mixture of 37 g of 9-fluoro-2-[4-(2-oxopropoxy)phenyl]-5,6-dihydrobenzo[h]cinnolin-3(2H)-one, 33 g of dimethylamine hydrochloride and 700 ml of ethanol is added dropwise 200 ml of an ethanol solution of 10 g of sodium cyanoboron hydride while stirring under heating and reflux over the period of 2 hours. After the completion of the dropwise addition, the reaction is concentrated under reduced pressure. To the residue is added 200 ml of water, and then conc. hydrochloric acid is added thereto under ice-cooling. After the mixture is stirred at room temperature for 1 hour, it is rendered alkaline with potassium carbonate and extracted with ethyl acetate. After the extract is washed with water and dried over magnesium sulfate, the solvent is distilled off under reduced pressure Ethanol is added to the thus obtained oily substance and further fumaric acid is added thereto to convert into its salt. The resultant crystals are recrystallized from hydrous ethanol to give 9-fluoro-2-[4-(2-dimethylaminopropoxy)phenyl]-5,6 -dihydrobenzo[h]cinnolin-3(2H)-one.fumarate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([C:16]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@@H:20]2[F:32])=[O:17])[N:5](COCC[Si](C)(C)C)[C:6]=1[CH3:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N)CN>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([C:16]([NH:18][C@@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:21][C@@H:20]2[F:32])=[O:17])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(F)c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: NCCN
Product: Cc1[nH]c(C(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2F)c(F)c1Cl
Temperature: 50 °C
Yield: 91 %

Procedure:
tert-butyl (3S,4R)-4-{[(4-chloro-3-fluoro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidine-1-carboxylate (Intermediate 259, 80 mg, 0.16 mmol) was dissolved in anhydrous THF (6 ml), followed by the addition of tetra-butyl ammonium fluoride (1 ml, 1M in THF) and ethylene diamine (1 mmol), the mixture was then stirred at 50° C. over night. After cooling down to room temperature, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml) and brine (10 ml), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (100%˜70% hexanes/ethyl acetate) to give the desired product (55 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([C:9]([C:11]2[CH:16]=[C:15]([I:17])[C:14]([OH:18])=[C:13]([I:19])[CH:12]=2)=[O:10])=[CH:4][C:3]=1[I:20].Br[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CC(N(C)C)=O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[C:3]([I:20])=[CH:4][C:5]([C:9](=[O:10])[C:11]2[CH:12]=[C:13]([I:19])[C:14]([OH:18])=[C:15]([I:17])[CH:16]=2)=[CH:6][C:7]=1[I:8])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(c1cc(I)c(O)c(I)c1)c1cc(I)c(O)c(I)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: O=C(COc1c(I)cc(C(=O)c2cc(I)c(O)c(I)c2)cc1I)OCc1ccccc1
Yield: 2.3 %

Procedure:
A solution of bis-(4-hydroxy-3,5-diiodophenyl)-methanone (prepared according to Example 9, 3.59 g, 5.0 mmol) and benzyl 2-bromoacetate (1.15 g, 5.0 mmol) in 20 mL DMAc was stirred with cesium carbonate (3.3 g, 10 mmol) for 14 hours. Next was added 1 M HCl, and a yellow oil formed along with a hazy white precipitate. The precipitate was isolated by filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as colorless crystals (98 mg, 2.2%). No attempt was made to isolate more product from the oil. 1H NMR (400 MHz, CDCl3): δ 8.11 (s, 2H), 8.10 (s, 2H), 7.45-7.35 (m, 5H), 6.22 (s, 1H), 5.33 (s, 2H), 4.72 (s, 2H). HPLC (40-90), 19.17 min. (EI−) calc'd for [C22H14I4O5—H] 864.7, found 864.6.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH:25]([N:28]([CH:44]([CH3:46])[CH3:45])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35](O)=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:27])[CH3:26]>C(#N)C>[CH:44]([N:28]([CH:25]([CH3:27])[CH3:26])[C:29](=[O:43])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[C:34]([C:39]#[N:40])[C:33]=1[C:41]#[N:42])([CH3:46])[CH3:45]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)N(C(=O)COc1ccc(O)c(C#N)c1C#N)C(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C(=O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1C#N)C(C)C

Procedure:
0.58 ml of ethyl diisopropylamine and 0.59 ml of trifluoromethanesulfonic anhydride were added to a solution of 900 mg of the product of Stage A in 50 ml of acetonitrile and the reaction medium was refluxed for one hour. Then, the solvent was evaporated under reduced pressure and the crude product obtained was chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (50-50) to obtain 600 mg of the expected product.
Reaction SMILES: [CH2:1]1[C:6]2=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][N:5]2[CH2:4][CH2:3][O:2]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:35]1([C@H:41]([NH2:44])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.O>[C:35]1([C@H:41]([NH:44][C:10]([C:7]2[CH:8]=[CH:9][N:5]3[CH2:4][CH2:3][O:2][CH2:1][C:6]=23)=[O:12])[CH2:42][CH3:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccn2c1COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H](NC(=O)c1ccn2c1COCC2)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a solution of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (comp. no. 8a) (5 g, 29.9 mmol) in dimethylformamide (50 ml) was added 1-hydroxybenzotriazole (4.45 g, 32.9 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.31 g, 32.9 mmol). The mixture was stirred for 1 h at 50° C., then (R)-1-phenyl-propylamine (4.45 g, 32.9 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the precipitate was filtered off, washed with a small amount of water and dried in vacuo to give 5.05 g (59%) of 3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide as a white solid. LC/MS (method 2): Rt=1.05 min; m/z=285.23 (M+H+).
Reaction SMILES: O([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[N+:19]([O-:21])=[O:20])S(C(F)(F)F)(=O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1>>[N+:19]([C:10]1[C:11]2[CH2:12][CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=[CH:18][C:9]=1[NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=1)([O-:21])=[O:20]
Reactant: COc1cccc(N)c1
Reactant: O=[N+]([O-])c1c(OS(=O)(=O)C(F)(F)F)ccc2c1CCCC2
Product: COc1cccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)c1

Procedure:
1-Nitro-5,6,7,8-tetrahydronaphthalen-2-yl triflate and m-anisidine were used in a process similar to Example 1(1) to give the titled compound.
Reaction SMILES: C([O:5][C:6]([C@:8]1([NH:30]C(OC(C)(C)C)=O)[CH2:13][C@@H:12]([S:14][C:15]2[NH:19][C:18]([CH:20]([F:22])[F:21])=[N:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:23]([O:25]C(C)(C)C)=[O:24])=[O:7])(C)(C)C.[ClH:38]>O1CCOCC1>[ClH:38].[NH2:30][C@@:8]1([C:6]([OH:7])=[O:5])[CH2:13][C@@H:12]([S:14][C:15]2[N:19]=[C:18]([CH:20]([F:21])[F:22])[NH:17][N:16]=2)[C@@H:11]2[C@H:9]1[C@H:10]2[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Sc2nnc(C(F)F)[nH]2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@]1(C(=O)O)C[C@@H](Sc2n[nH]c(C(F)F)n2)[C@H]2[C@H](C(=O)O)[C@H]21
Temperature: 50 °C
Yield: 93 %

Procedure:
Add ditert-butyl(1R,2S,4R,5R,6R)-2-(tert-butoxycarbonylamino)-4-[[5-(difluoromethyl)-4H-1,2,4-triazol-3-yl]sulfanyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.356 g, 651.3 μmol) in 1,4-dioxane (1.63 mL) to a solution of hydrogen chloride (4M in dioxane). Heat the mixture to 50° C. with stirring. A solid precipitate out of solution soon after heating commenced. Cool the reaction mixture and concentrate under reduced pressure. Purify the residue by silica gel chromatography (40 g SiO2) eluting with 0-20% hydrochloric acid (0.01 M aqueous) in acetonitrile gradient over 60 minutes at 40 mL/minute flow rate. Concentrate under reduced pressure to provide the crude material as oil. Re-purify using same conditions. Concentrate under reduced pressure to give the title compound as a white solid (0.196 g, 93%). MS (m/z): 335 (M+1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[ClH:34]>CN(C=O)C.[Pd]>[NH2:1][C@H:2]([C:11]([NH:13][C@@H:14]([C:21]([NH2:23])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:7])([CH3:8])[CH3:9].[ClH:34]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C(N)=O)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)N[C@@H](C(N)=O)c1ccccc1
Yield: 99.1 %

Procedure:
12.83 g (28.2 mmoles) of Z-Asp(OtBu)-D-Phg-NH2, prepared as described in Example 1, Step 3, are dissolved in 200 ml of DMF, and 2.46 ml (28.2 mmoles) of concentrated hydrochloric acid and 2 g of palladium-on-carbon catalyst are added to the cooled solution. Gaseous hydrogen is bubbled through the resulting suspension for 2.5 hours under stirring. The catalyst is filtered off, the filtrate is evaporated, the residue is dissolved in ethanol, and the solution is decolourized. Ethanol is evaporated in vacuo, and the residue is triturated with ether. 10.0 g (99%) of H-Asp(OtBu)-D-Phg-NH2.HCl are obtained; the chromatographically uniform substance melts at 169°-170° C. Rf4 =0.15.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36].O>CN(C)C=O>[C:38]([O:37][C:35](=[O:36])[CH2:34][C:11]1([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[N:16]2[CH:17]=[CH:18][CH:19]=[C:15]2[C:14](=[O:20])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:12]1=[O:30])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(OCc1ccccc1)C1C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OCc2ccccc2)C(=O)N(Cc2ccc(Cl)c(Cl)c2)C(=O)c2cccn21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(3,4-dichlorobenzyl)-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid benzyl ester (9.4 g) in anhydrous dimethylformamide (40 ml) was added portionwise sodium hydride (63% dispersion in mineral oil, 0.7 g) under ice cooling, while a stream of nitrogen was passed over the mixture. The resulting mixture was stirred at 25° C. for 1 hour and thereto was added tert-butyl bromoacetate (4.3 g). The mixture was stirred at 25° C. for 15 hours, poured into water, and extracted with ethyl acetate. The extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using n-hexane/ethyl acetate (20:1) as the eluent. Fractions containing the title compound were pooled and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (9.2 g, 78.0%) as colorless crystals, mp 86°-88° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[C:22](C(O)=O)=[N:21][C:20]2[C:19]3[S:26][CH:27]=[CH:28][C:18]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:13]=1.CC[O:31]C(C)=O>C1(C)C=CC=CC=1>[OH:31][CH2:11][C:12]1[CH:22]=[N:21][C:20]2[C:19]3[S:26][CH:27]=[CH:28][C:18]=3[CH2:17][CH2:16][O:15][C:14]=2[CH:13]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(nc1C(=O)O)-c1sccc1CCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OCc1cnc2c(c1)OCCc1ccsc1-2
Temperature: 0 °C

Procedure:
To a solution of 1.00 M of diisobutylaluminum hydride in toluene (4.02 mL) at 0° C. was added 3-methylcarboxy-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (0.420 g, 1.61 mmol) in toluene (17.8 mL, 167 mmol). The reaction mixture was stirred at 0° C. 2 h. The reaction is diluted with EtOAc then quenched with 1M HCl. The organic layer was dried Na2SO4, concentrated to give 3-hydroxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in triethylamine (0.336 mL, 2.41 mmol) and N,N-dimethylformamide (10.5 mL, 136 mmol). Tert-butyldimethylsilyl chloride (0.291 g, 1.93 mmol) was added. The reaction was stirred at room temperature 20 min. The reaction was diluted with EtOAc then wash with water and brine, dried and concentrated to give 3-tert-butyldimethylsilyloxymethyl-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine which was dissolved in DCM/Acetic acid at 0° C. N-Bromosuccinimide (315 mg, 1.77 mmol) was added. The reaction was stirred overnight at room temperature. The reaction was concentrated and purified by flash chromatography (EtOAc/Hex) (eluted 10%) to give 3-tert-butyldimethylsilyloxymethyl-9-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine (61.3% yield). MS: (ESI+) 426.1
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][OH:21])[CH2:18][CH2:19]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Reaction time: 1 h

Procedure:
A mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methanol (0.080 g, 0.26 mmol) (Example 2, Step 1) and 10% palladium on carbon (0.03 g) in methanol (3 mL) was hydrogenated under balloon pressure of H2 at room temperature for 1 h. The mixture was filtered. The filtrate was concentrated, diluted with dichloromethane, then dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 10% MeOH in dichloromethane) to give the desired product (41 mg, 57%). LCMS calculated for C14H20N3OS (M+H)+: m/z=278.1. Found: 278.1.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[O:35])=[CH:30][CH:29]=1>>[CH:1]1([CH:7]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:35])=[CH:32][CH:33]=2)[C:9]2[C:10]([CH2:24][O:25][CH3:26])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 10.5 %

Procedure:
Using cyclohexyl{3-(methoxymethyl)-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (1.2 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.94 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.19 g, 10%) was obtained as a white solid.
Reaction SMILES: [C:1]1([C:7](=[O:16])[CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19]I>C1COCC1>[CH3:9][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([CH3:19])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:16]
Reactant: CI
Reactant: CC(C(=O)c1ccccc1)c1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of compound 3 (3.0 g, 14.2 mmol) in THF (10 mL) is added to a suspension of sodium hydride (60%, 0.63 g, 15.6 mmol) in THF (60 mL) at 0° C. The reaction mixture is kept at the same temperature for 2 hours and methyl iodide (0.93 mL, 14.9 mmol) is added at 0° C. The reaction mixture is allowed to warm up to room temperature overnight and then quenched with water. The mixture is separated and the aqueous phase is extracted with ethyl acetate (2×40 mL). The extracts are combined, washed with brine, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 50:1 to 4:1) to give 4 (2.2 g, 69%) as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18](OC)=[O:19])[CH:12]=[C:11]2[CH3:22]>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH2:18][OH:19])[CH:12]=[C:11]2[CH3:22]
Reactant: COC(=O)c1cc(C)c2cc(Br)ccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CO)nc2ccc(Br)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere at 0C, 1.50 mL (1.50 mmol) of a lithium aluminum hydride solution (1M in THF) was slowly added to a solution of 0.65 g (2.32 mmol) of methyl 6-bromo-4-methylquinoline-2-carboxylate in 30 mL of THF and the mixture was stirred for 30 minutes at 0° C. A further 0.25 mL of lithium aluminum hydride solution (1M in THF) was added and the mixture was stirred for 20 minutes at 0° C. The reaction mixture was combined with a few drops of EtOAc, worked up using the Fieser-Fieser method, and the precipitate was filtered off and washed with EtOAc. The filtrate was evaporated down in vacuo. Yield: 0.25 g (43% of theoretical); C11H10BrNO (M=252.107); calc.: molpeak (M+H)+: 252/254 (Br); found: molpeak (M+H)+: 252/254 (Br); Rf value: 0.25 (silica gel, PE/EtOAc 3:2).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(Cl)(Cl)=O.Cl.[CH2:20](OCC)[CH3:21]>C(O)C>[CH3:1][C:2]1[C:3]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: CCOCC
Reactant: Cc1cc2c(cc1C(=O)O)OCCO2
Agent: Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2c(cc1C)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (1.72 g, 8.8 mmol) in ethanol (100 mL) was cooled to 0° C. and stirred for 1 h prior to dropwise addition of thionyl chloride (3.9 mL, 53.2 mmol) over 1 h. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath, and heated to 70° C. overnight. The mixture was then cooled to room temperature and 2 N hydrochloric acid (50 mL) added slowly followed by diethyl ether (50 mL). The aqueous layer was extracted twice with diethyl ether (50 mL), the combined organic layers washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure to afford ethyl 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.7 g, 89%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.70 (s, 1H), 4.30 (q, J=7.0, 7.5 Hz, 2H), 4.26 (m, 4H), 2.49 (s, 3H), 1.36 (t, J=7.0, 7.5 Hz, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=2)(=[O:31])=[O:30])=[O:27])[CH2:22][CH2:21]1.Cl>CS(C)=O>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:20]1[CH2:25][CH2:24][CH:23]([C:26]([NH:28][S:29]([C:32]2[CH:33]=[C:34]([C:42]([F:43])([F:44])[F:45])[CH:35]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:37]=2)(=[O:30])=[O:31])=[O:27])[CH2:22][CH2:21]1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCN(c2ccccc2[N+](=O)[O-])CC1
Reaction time: 18 h

Procedure:
0.13 g of DIEA and 0.07 g of 1-fluoro-2-nitrobenzene are added to a solution of 0.22 g N-(piperidine-4-carbonyl)-3,5-bis-trifluoromethyl-benzenesulfonamide in the form of a hydrochloride in 4 ml of DMSO. The mixture obtained is stirred for ca. 18 h at 80°, solvent is evaporated and the evaporation residue is subjected to flash chromatography on silica gel (eluent: EtAc). N-[1-(2-Nitro-phenyl)-piperidine-4-carbonyl]-3,5-bis-trifluoromethyl-benzenesulfonamide is obtained.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].ClCCl.[S:12](=O)(=[O:15])([OH:14])[OH:13].C(C(CCCC)C([O-])=O)C.[K+:27]>C(OCC)(=O)C>[K+:27].[OH:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[S:12]([O-:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Oc1ccc(O)cc1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])c1cc(O)ccc1O
Temperature: 12.5 °C
Reaction time: 0.21 h
Yield: 77.9 %

Procedure:
Hydroquinone (10 g, 0.09 mol) and dichloromethane (30 mL), was taken in a round bottom flask, after cooling the flask to about 10-15° C., sulfuric acid (36 N, 8.9 g) was added dropwise at the same temperature and stirring continued further for about 10-15 min. Temperature was slowly raised to 30-40° C. then stirred for 1-2 h. The to reaction mass was then cooled to 25-35° C. and ethyl acetate (100 mL) added to dissolve the solid formed. A solution of potassium 2-ethylhexanoate (18.2 g, 0.099 mol) in ethyl acetate (100 mL) was added slowly. The reaction was further stirred for an hour. The precipitated crude solid was filtered, washed with ethyl acetate to give 16 g of 2,5-dihydroxybenzenesulfonic acid potassium salt.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@H:3]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:2]1.C1C(=O)N([Cl:21])C(=O)C1>C(#N)C.C(Cl)Cl>[Cl:21][C:12]1[C:7]([O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[N:8][C:9]([NH2:13])=[N:10][CH:11]=1
Reactant: Nc1nccc(O[C@H]2CCOC2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CC#N
Product: Nc1ncc(Cl)c(O[C@H]2CCOC2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of (S)-4-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-amine (intermediate 62, 100 mg, 0.552 mmol) in acetonitrile (4 ml) was treated with NCS (100 mg, 0.749 mmol) and stirred at 25° C. for 24 h. Then, the mixture was heated at 80° C. for 3 h. The resulting solution was cooled to room temperature, diluted with DCM and washed with NaOH (1 M in water) and brine. The org layer was dried over Na2SO4, filtered and concentrated. The crude was purified by normal phase chromatography (12 g gold silica gel cartridge, heptanes/EtOAc 100:0 to 8:92) to give the title compound as a white solid. (UPLC-MS 3) tR 0.64 min; ESI-MS 216.1 [M+H]+.