Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]1[C:34]2[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=2[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]1=[O:45]>>[CH2:1]([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:25][C:26]([CH3:47])([CH3:46])[CH2:27][CH2:28][N:29]2[C:34]3[C:35]([O:39][CH3:40])=[CH:36][CH:37]=[CH:38][C:33]=3[C:32]([CH2:43][CH3:44])([CH2:41][CH3:42])[O:31][C:30]2=[O:45])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)N)c2c(OC)cccc21
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(OCc3ccccc3)c3c2OCC(=O)N3)c2c(OC)cccc21

Procedure:
The product is prepared analogously to Example 14a starting from 5-benzyloxy-8-(2,2-dihydroxyacetyl)-4H-benzo[1,4]oxazin-3-one and 1-(3-amino-3-methylbutyl)-4,4-diethyl-8-methoxy-1,4-dihydrobenzo[d][1,3]oxazin-2-one. The crude product is purified by column chromatography (silica gel, dichloromethane/MeOH 95:5). Yield: 70 mg (18%); HPLC-MS: Rt=16.5 min. (method A).
Reaction SMILES: CN1C=C[C:4]([C:7]([OH:9])=O)=[C:3]1[C:10]([F:13])([F:12])[F:11].[CH3:14][N:15]([CH:17]=O)[CH3:16].[CH:19]1([CH:22]2[CH2:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH2:32])[CH2:21][CH2:20]1.C(N(CC)CC)C>C(Cl)Cl>[CH:19]1([CH:22]2[CH2:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:7]([C:4]2[C:3]([C:10]([F:11])([F:12])[F:13])=[CH:16][N:15]([CH3:14])[CH:17]=2)=[O:9])[CH2:20][CH2:21]1
Reactant: CN(C)C=O
Reactant: Cn1ccc(C(=O)O)c1C(F)(F)F
Reactant: Nc1ccccc1C1CCC1C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2ccccc2C2CCC2C2CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
190 mg (1 mmol) 1-Methyl-trifluoromethyl-1H-pyrrole-3-carboxylic acid and 140 mg (1.05 mmol) oxalylic acid chloride were dissolved in 10 ml methylene chloride. The solution was stirred for 3 hours at room temperature in the presence of catalytic amounts of DMF. Then the resulting reaction mixture was slowly added to a solution consisting of 190 mg (1 mmol) 2-(2-cyclopropylcyclobutyl)phenylamine (prepared as described in Example 5), 200 mg (2 mmol) of triethylamine and 10 ml methylene chloride. After stirring for 16 hours at room temperature the solvent was distilled off and the raw material purified by flash chromatography over silica gel (eluant: hexane/methylene chloride/ethyl acetate 2:2:1). Yield: 240 mg (66% of theory) of 1-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid [2-(2-cyclopropylcyclobutyl)phenyl]amide (cis-isomer) in the form of slightly yellow crystals (mp.: 167-169° C.).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(=O)NC(=O)C2=CC=CC=C12.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)COCC1(C2C=CC=CC=2)CCC(O)C1.[F:53][C:54]([F:91])([F:90])[C:55]1[CH:56]=[C:57]([CH:83]=[C:84]([C:86]([F:89])([F:88])[F:87])[CH:85]=1)[CH2:58][O:59][CH2:60][C:61]1([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:65][CH2:64][CH:63]([N:66]2[C:74](=[O:75])[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:67]2=[O:76])[CH2:62]1>C1COCC1.C(OCC)(=O)C.O>[F:88][C:86]([F:87])([F:89])[C:84]1[CH:83]=[C:57]([CH:56]=[C:55]([C:54]([F:91])([F:90])[F:53])[CH:85]=1)[CH2:58][O:59][CH2:60][C@:61]1([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[CH2:65][CH2:64][C@H:63]([N:66]2[C:74](=[O:75])[C:73]3[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=3)[C:67]2=[O:76])[CH2:62]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C1NC(=O)c2ccccc21
Agent: OC1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@](COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tripehnylphosphine (102 mg) in THF (0.20 mL) at 0° C. was added diethyl azodicarboxylate (61 μL) and the resulting solution was stirred at 0° C. for 30 min. Phthalimide (57 mg) was added followed by 3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentanol (available from Step E of Example 1) (148 mg) in THF (0.50 mL), and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was diluted with ethyl acetate and water was added. The aqueous layer was extracted with ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by preparative TLC eluting with 20% ethyl acetate/80% hexanes to give two products as racemates: 2-((1SR,3RS)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (less polar fraction) and 2-((1RS,3RS)-3-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-3-phenylcyclopentyl)isoindoline-1,3-dione (more polar fraction).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=C[C:12]=1[OH:13])[O:9][CH:8]([C:14]([F:17])([F:16])[F:15])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]2)[CH3:2].S(Cl)([Cl:24])(=O)=O.Cl[CH2:27][Cl:28]>C(OCC)(=O)C>[Cl:24][C:4]1[C:3]([CH2:1][CH3:2])=[C:12]([OH:13])[C:27]([Cl:28])=[C:10]2[C:5]=1[CH:6]=[C:7]([C:18]([OH:20])=[O:19])[CH:8]([C:14]([F:17])([F:16])[F:15])[O:9]2
Reactant: CCc1cc2c(cc1O)OC(C(F)(F)F)C(C(=O)O)=C2
Reactant: O=S(=O)(Cl)Cl
Reactant: ClCCl
Solvent: CCOC(C)=O
Product: CCc1c(O)c(Cl)c2c(c1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 21.5 %

Procedure:
To a suspension of 1.5 g (5.2 mmol) of 6-ethyl-7-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid in 45 mL of anhydrous dichloromethane was added dropwise a solution of 1.0 M sulfuryl chloride (22.75 mmol, 4.4 eqv). The resulting suspension was stirred at room temperature for 12 h; the reaction turned into a clear yellow solution. The sample was concd and the residue dissolved in ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Silica chromatography with ethyl acetate:hexane:acetic acid as the eluant afforded 0.12 g (21.5%) of a white solid: 1H NMR (CDCl3/400 MHz) 7.72(s, 1H), 6.68(s, 1H), 5.79(q, J=5.6 Hz, 1H), 2.42(m, 1H), 2.11(m, 1H), 0.85(t, J=7.6 Hz, 3H). MS (ESI+) 357.0 (M+1, 100). MS(ES−) 355.0 (M−H, 100). HRMS (ES−) m/z calcd for (C13H8Cl2F3O4) M−H: 354.9746, found: 354.9724.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:23])([F:22])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:12][C:10]=1[NH2:11]>C1(C)C=CC=CC=1>[F:5][C:6]([F:22])([F:23])[CH2:7][O:8][C:9]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]([F:21])([F:19])[F:20])=[CH:12][C:10]=1[N:11]=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reaction time: 0.5 h

Procedure:
To a cooled (15°-20° C.) solution of 67.6 g. (0.684 mole) of phosgene in 250 ml. of toluene is added dropwise over one hour a solution of 49.5 g. (0.171 mole) of 2,5-bis-(2,2,2-trifluoroethoxy)aniline in 350 ml. of toluene. After addition is complete, stirring is continued for 30 minutes, then the mixture is heated to its reflux temperature and maintained at reflux for 30 minutes. The solution is evaporated to provide a liquid residue which gradually crystallizes. The solid is recrystallized from heptane to provide 2,5-bis(2,2,2-trifluoroethoxy)phenyl isocyanate as a white solid, m.p. 50°-52° C.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.Cl[Si](C)(C)C.CCN(C(C)C)C(C)C.Cl[C:23]([O:25][CH:26](Cl)[CH:27](C)C)=[O:24].[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([OH:40])=[O:39])=[CH:36][CH:37]=1>C(Cl)(Cl)Cl>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([O:40][CH2:27][CH2:26][O:25][C:23]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:24])=[O:39])=[CH:34][CH:33]=1
Reactant: NC1(C(=O)O)CC1
Reactant: Cc1ccc(C(=O)O)cc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C(=O)OCCOC(=O)NC2(C(=O)O)CC2)cc1
Yield: 14.5 %

Procedure:
Following the general procedure for the one pot synthesis, ACPC (1.02 g, 9.8 mmol) was reacted with chlorotrimethylsilane (2.48 mL, 19.7 mmol) in anhydrous chloroform in the presence of DIEA (3.64 mL, 19.7 mmol). Subsequent reaction of the intermediate with 1-chloro-2-methylpropyl chloroformate (1.6 mL, 14.8 mmol) followed by a mixture of DIEA (3.64 mL, 19.7 mmol) and p-toluic acid (2.6 g, 19.7 mmol) provided 0.436 g (14.3% yield) the title compound (21) as a white solid after aqueous work-up and mass-guided preparative HPLC purification. M.p: 177.7-182.5° C. 1H NMR (CDCl3, 400 MHz): δ=7.91 (d, 2H), 7.22 (m, 4H), 7.02 (q, 1H), 5.38 (s, 1H), 2.43 (s, 3H), 1.63 (m, 5H) 1.36 (m, 2H). MS (ESI) m/z 329.93 (M+H)+; 305.97 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16](=[O:22])[C:17](=[O:21])[C:18]=2OC)[CH2:10]1.[NH2:29][C@@H:30]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>CC#N>[CH:41]1([CH2:40][C@H:30]([NH:29][C:18]2[C:17](=[O:21])[C:16](=[O:22])[C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:10]2)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1
Reactant: COCCCOC(c1ccccc1F)C1CCCN(c2c(OC)c(=O)c2=O)C1
Reactant: CC(C)(C)OC(=O)NC[C@@H](N)CC1CCCCC1
Solvent: CC#N
Product: COCCCOC(c1ccccc1F)C1CCCN(c2c(N[C@H](CNC(=O)OC(C)(C)C)CC3CCCCC3)c(=O)c2=O)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To the crude 3-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-4-methoxycyclobut-3-ene-1,2-dione in MeCN there was added tert-butyl (S)-2-amino-3-cyclohexylpropylcarbamate (27.0 mg, 0.11 mmol), the resulting solution was stirred at rt for 10 min, filtered through HPLC filter, purified by HPLC to give tert-butyl (2S)-3-cyclohexyl-2-(2-(3-((2-fluorophenyl)(3-methoxypropoxy)methyl)piperidin-1-yl)-3,4-dioxocyclobut-1-enylamino)propylcarbamate (17.4 mg, 40%) as on oil. MS ESI+ve m/z 616 (M+1).
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20]CC)=[O:19])=[CH:12]2)C1C=CC=CC=1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1O[C:42]2[CH:44]=[C:45](Cl)[C:46](CCl)=[CH:47][C:41]=2O1>>[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][N:14]2[C:15]3[C:11](=[CH:10][CH:9]=[CH:17][CH:16]=3)[C:12]([C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:42]=3)=[C:13]2[C:18]([OH:20])=[O:19])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure of Example 1(a)-1(d), except substituting ethyl indole-2-carboxylate for ethyl 5-benzyloxyindole-2-carboxylate in step (a) and 4-benzyloxybenzyl chloride for 6-chloropiperonyl chloride in step (c), the title compound was prepared (39% overall). mp 193°-194° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:42][CH2:41][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[O:33][CH3:32])[CH2:45][CH2:44]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: COc1ccccc1N1CCN(C(=O)c2cccc(-c3cnc4c(c3)N(Cc3cc(Cl)ccc3C(F)(F)F)CCN4)c2)CC1

Procedure:
(3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(2-methoxyphenyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=621.97 (M+H+); retention time=0.95 minutes.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.[CH2:16](I)[CH2:17][CH2:18][CH3:19].Cl>CCCCCCC.O1CCCC1.C1C=CC=CC=1.C1COCC1>[CH2:16]([C:9]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C(O)C1CCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of lithium di-isopropylamide (100 mL, 2.0 M, 200 mmol) in heptane/tetrahydrofuran/benzene was diluted with 100 mL of anhydrous THF. To the LDA solution at 0° C. was added dropwise 10 g (100 mmol) of cyclobutanecarboxylic acid in 15 mL of anhydrous THF over 20 minutes under Argon. The mixture was sired at room temperature for 3 hours. To the reaction mixture was added 11.4 mL (100 mmol) of butyl iodide at 0° C. The reaction mixture was warmed to RT and stirred overnight. HCl (2N) was used to adjust the pH to 2˜3. The mixture was extracted with EtOAc (3×200 mL). The combined organic phase was washed with 100 mL of brine, dried (MgSO4) and concentrated. Thus obtained crude product was used directly for next step.
Reaction SMILES: [NH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[NH2:2].[CH:13]([O:16][C:17](Cl)=[O:18])([CH3:15])[CH3:14]>N1C=CC=CC=1>[CH:13]([O:16][C:17]([NH:2][NH:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)OC(=O)Cl
Reactant: NNc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: CC(C)OC(=O)NNc1n[nH]c2cc(Cl)ccc12
Yield: 68 %

Procedure:
Analogously to Example 1, 0.05 mol of 3-hydrazino-6-chloro-indazole and 0.05 mol of chlorocarbonic acid isopropyl ester in 30 ml of pyridine at 0° - 5° C, followed by 3 hours at room temperature, give 3-isopropoxycarbonylhydrazino-6-chloroindazole (melting point 184° - 185° C after recrystallisation from isopropanol: yield, 68% of theory).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:19])[CH:13]=[N:12]2.C(N(CC)CC)C.[C:27](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:28]>C(Cl)Cl>[N:19]([C:14]1[CH:13]=[N:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([CH3:8])[CH:10]=2)[N:15]=1)=[C:27]=[S:28]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Cc1ccc2nc(N)cnc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N=C=S)cnc2c1
Yield: 38 %

Procedure:
A mixture of 6-methylquinoxalin-2-amine 2,2,2-trifluoroacetate (546 mg, 2 mmol), triethylamine (243 mg, 2.400 mmol), and 1,1′-thiocarbonyldipyridin-2(1H)-one (557 mg, 2.40 mmol) was stirred in 5 mL DCM for 4 h. The reaction was directly eluted on a 120 g silica gel cartridge with 0 to 25% EtOAc in hexane, 25 min, at 35 mL/min to afford 2-isothiocyanato-6-methylquinoxaline (153 mg, 0.760 mmol, 38% yield).
Reaction SMILES: [OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[C:3]([F:6])([F:5])[F:4].Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][C:2]([C:14]1[S:15][CH:16]=[CH:17][N:18]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:8]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: Oc1cccc(C(O)(c2nccs2)C(F)(F)F)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cccc(OCc2ccc3ccccc3n2)c1)(c1nccs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.1 %

Procedure:
A mixture of 2-[1-hydroxy-1-(3-hydroxyphenyl)-2,2,2-trifluoroethyl]thiazole (0.33 g), 2-chloromethylquinoline hydrochloride (0.22 g), potassium carbonate (0.5 g) and dimethylformamide (5 ml) was stirred at ambient temperature for 24 hours. The mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with chloroform/ethyl acetate (9/1 v/v) to give 2-[1-hydroxy-1-[3-(quinol-2-ylmethoxy)phenyl]-2,2,2-trifluoroethyl]thiazole (0.15 g, 30%), m.p. 177° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:10])=[CH:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].C(N(C(C)C)CC)(C)C.[CH3:20][Si:21]([CH3:28])([CH3:27])[CH2:22][CH2:23][O:24][CH2:25]Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:6]([CH:5]=[CH:4][C:3]=1[O:10][CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:28])([CH3:27])[CH3:20])[CH:7]=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ccc(O)c(Cl)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCOc1ccc(C=O)cc1Cl
Reaction time: 8 h

Procedure:
5 g (31.93 mmol) of 5-chloro-4-hydroxybenzaldehyde are dissolved in 300 ml of methylene chloride and 6.7 ml (38.3 mmol) of N,N-diisopropyl-N-ethylamine and 5.9 ml (33.52 mmol) of 2-trimethylsilylethoxymethyl chloride (SEMCl) are added to this at 0° C. The mixture is allowed to return to room temperature and stirred overnight. Water is then added and the mixture is extracted with methylene chloride. The organic phase is dried and the solvent is evaporated off. The product of the title is obtained, which is purified by chromatography on a silica gel column, eluting with a 95/5 and then 9/1 heptane/ethyl acetate mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([F:40])=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37](O)=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]([C:6]2[C:11]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[CH:15][C:16]([F:40])=[C:17]([C:22]5[N:26]([CH:27]6[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]6)[C:25]6[CH:33]=[CH:34][C:35]([C:37]([N:47]7[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]7)=[O:38])=[CH:36][C:24]=6[N:23]=5)[CH:18]=4)[N:13]=3)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1cc3ccc(-c4ccccc4-c4ccc(Cl)cc4)nc3cc1F)n2C1CCCCC1
Reactant: OC1CCNCC1
Product: O=C(c1ccc2c(c1)nc(-c1cc3ccc(-c4ccccc4-c4ccc(Cl)cc4)nc3cc1F)n2C1CCCCC1)N1CCC(O)CC1

Procedure:
The title compound was synthesized from Compound 408 and 4-hydroxypiperidine using standard HBTU activation.
Reaction SMILES: [OH-].[NH4+:2].C1(=O)OC(=O)C=C1.[C:10]([OH:17])(=[O:16])/[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14].N>O>[NH2:2][C@H:11]([C:10]([OH:17])=[O:16])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [NH4+]
Agent: N
Agent: O=C1C=CC(=O)O1
Agent: [OH-]
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
In a 250 ml reagent bottle, an amount of 69 ml (0.11 mole) of a 10% solution of concentrated ammonium hydroxide (15.9 M) was slowly added with smooth stirring to 9.8 g (0.1 mole) of maleic anhydride in 18 ml (1 mole) of water at 60° C. The bottle was capped and the solution allowed to react for 2 hours. The anhydride converted to maleic acid in the presence of the water, and the ammonia added across the double bond of maleic acid to form aspartic acid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[CH2:14]([O:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O)[CH3:15]>>[CH2:14]([O:16][C:17]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]1[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:17](=[O:16])[CH:24]([F:25])[CH2:23]1)[CH3:15]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: CCOc1c(F)cccc1C=O
Product: CCOc1c(F)cccc1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 2-ethoxy-3-fluorobenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 415.87 g/mol.
Reaction SMILES: CC(C)=O.[SH:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>C(Cl)Cl>[Cl:21][CH2:20][CH2:19][S:5][N:6]1[NH:10][N:9]=[CH:8][N:7]1[CH3:11]
Reactant: CN1C=NNN1S
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN1C=NNN1SCCCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an acetone (50 ml) solution containing 2-mercapto-1-methyltetrazole (4.0 g) and anhydrous potassium carbonate (20 g) was added 1-bromo-2-chloroethane (5.0 ml) under ice-cooling. The mixture was stirred for 90 minutes at room temperature, to which was added methylene chloride (50 ml). The mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure to afford 2-(chloroethylthio)-1-methyltetrazole (6.0 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:9]=2)[S:6][CH:7]=1.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31].O1CCOCC1>C(#N)C>[ClH:1].[CH:20]1([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:8]([C:5]3[S:6][CH:7]=[C:3]([CH2:2][N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[N:4]=3)=[CH:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CNCCOC
Reactant: COc1cccc2c(-c3nc(CCl)cs3)cn(CC3CCCCC3)c12
Solvent: CC#N
Solvent: C1COCCO1
Product: COCCN(C)Cc1csc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)n1
Product: Cl

Procedure:
A mixture of 3-[4-(chloromethyl)thiazol-2-yl]-1-(cyclohexyl)methyl-7-methoxy-1H-indole (100 mg, 0.27 mmol), (2-methoxyethyl)methylamine (119 mg, 1.33 mmol), 1,4-dioxane (2 ml), and acetonitrile (1 ml) was subjected to microwave irradiation for 10 min at 160° C. The reaction mixture was concentrated in vacuo and the obtained reside was mixed with aqueous sodium hydroxide (1M; 50 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was purified by column chromatography eluting with ethyl acetate to give the free base of the title compound as an oil. Hydrochloride salt formation was achieved by the addition of hydrogen chloride (1M solution in diethyl ether; 3 ml) to a solution of the free base in diethyl ether (15 ml). The mixture was concentrated in vacuo to afford the title compound as a 1:1 hydrochloride salt (95.1 mg). 1H NMR (400 MHz, CD3OD) δ 1.00-1.30 (5H, m), 1.55-1.94 (6H, m), 3.00 (3H, s), 3.32-3.66 (5H, m), 3.80 (2H, t, J 5.0), 3.97 (3H, s), 4.29 (2H, d, J 7.2), 4.52 (2H, s), 6.81 (1H, d, J 8.0), 7.16 (1H, dd, J 8.0, 8.0), 7.62 (1H, s), 7.80 (1H, d, J 8.0), 7.85 (1H, s).