Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[C:9]2[S:19][CH:18]=[CH:17][C:10]=2[N:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)=[O:7].O=S(Cl)Cl.CCN(CC)CC.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:14]([C:12]1[N:13]=[C:8]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:9]2[S:19][CH:18]=[CH:17][C:10]=2[N:11]=1)=[O:16]
Reactant: CN(C)CCN
Reactant: O=C(O)c1nc(C(=O)c2cccs2)c2sccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C)CCNC(=O)c1nc(C(=O)c2cccs2)c2sccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A mixture of 4-(2-thienylcarbonyl)thieno[3,2-d]pyrimidine-2-carboxylic acid ( 290 mg, 1.0 mmol) and SOCl2 (4 mL) was refluxed for 30 min, concentrated in vacuo, and treated with CH2Cl2 (10 mL), Et3N (208 μL, 1.5 mmol) and N,N-dimethylethylenediamine (120 μL, 1.1 mmol). The reaction mixture was stirred at room temperature for 1 h, poured into sat. NaHCO3, extracted with EtOAc (2×10 mL), dried (MgSO4), concentrated in vacuo then triturated with EtOAc and filtered to give the title compound (234 mg, 65%) as a cream solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCOCC1.O>[OH:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH2:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(CBr)cc1
Reactant: Oc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(CSc2ccc(O)cc2)cc1
Reaction time: 24 h
Yield: 62 %

Procedure:
A solution of 4-bromomethylbenzaldehyde (0.3 g, 1.5 mmol) and 4-hydroxythiophenol (0.2 g, 1.5 mmol) in 1,4-dioxane (10 mL) was degassed and treated with triethylamine (0.44 mL, 3.11 mmol). After stirring for 1 day the mixture was diluted with water (20 mL) and extracted with ethyl acetate (2-fold 20 mL). The combined organic extracts were washed with brine and dried (sodium sulphate) and the solvent removed in vacuo. The crude material was purified by flash column chromatography on silica gel eluting with heptane:ethyl acetate (9:1 changing to 0:1, by volume) to give the title compound as a solid, 62% yield, 220 mg.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH2:6])=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1>C1COCC1>[F:17][C:18]1[CH:23]=[C:22]([N:24]2[C:33]3[C:28](=[CH:29][C:30]([S:34]([NH:6][C:3]4[CH:4]=[CH:5][O:1][N:2]=4)(=[O:36])=[O:35])=[CH:31][CH:32]=3)[CH:27]=[CH:26][C:25]2=[O:38])[C:21]([O:39][CH3:40])=[CH:20][C:19]=1[C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=1
Reactant: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
A RBF was charged with isoxazol-3-amine (0.016 g, 0.191 mmol) and THF (1.6 mL), and the vessel was cooled to −78° C. for 15 minutes. Lithium bis(trimethylsilyl)amide (1.0 M in THF) (0.208 ml, 0.208 mmol) was then added dropwise over 1 minute. The reaction was stirred for 10 minutes, and then a solution of 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (0.080 g, 0.173 mmol) in THF (1.6 mL) was added dropwise. The bath was removed, and the resulting mixture was stirred for 45 minutes. The reaction was diluted with saturated ammonium chloride (aq.) solution (30 mL), and was washed with ethyl acetate (20 mL×3). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated. The resulting material was purified via MPLC (ISCO, 40 g), eluting with 0 to 100% ethyl acetate in heptanes. The solid was dried under reduced pressure to provide 1-(2,3′-difluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.012 g, 0.024 mmol, 13.60% yield) as a mixture of atropisomers. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (d, J=1.76 Hz, 1 H) 8.15 (d, J=2.05 Hz, 1 H) 7.97 (br. s., 1 H) 7.74-7.84 (m, 2 H) 7.43-7.53 (m, 1 H) 7.37-7.42 (m, 1 H) 7.33 (d, J=9.98 Hz, 1 H) 7.11-7.18 (m, 2 H) 7.09 (d, J=9.49 Hz, 1 H) 6.86 (dd, J=14.67, 9.29 Hz, 2 H) 6.61 (d, J=1.76 Hz, 1 H) 3.72-3.81 (m, 3 H). m/z (ESI) 510.0 (M+H)+.
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[SH:18].[F:19][C:20]([F:26])([F:25])[C:21](=[O:24])[CH2:22][CH3:23]>C1COCC1>[F:19][C:20]([F:26])([F:25])[C:21]([C:17]1[S:13][C:14]([SH:18])=[N:15][CH:16]=1)([OH:24])[CH2:22][CH3:23]
Reactant: Sc1nccs1
Reactant: CCC(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC(O)(c1cnc(S)s1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
iPr2NH (2.0 g, 19.9 mmol) was dissolved in THF (23 mL) and cooled to −78° C. n-Butyllithium (2.5M, 8.0 mL, 19.9 mmol) was added dropwise, followed by thiazole-2-thiol (0.9 g, 7.9 mmol) in THF (5 mL). After 10 minutes, trifluoro-2-butanone (0.5 g, 4.0 mmol) was added and the reaction was stirred at −78° C. for 6 hours. The reaction was warmed to room temperature and quenched with 5% aqueous NH4Cl (20 mL). The aqueous layer was acidified and extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (50% EtOAc in hexanes) to give the desired product, 10b.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C1C[CH2:18][N:17]2[C:12](=[N:13][CH2:14][CH2:15][CH2:16]2)CC1.CN(C)CCCN>>[CH3:12][N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][NH:13][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)n1
Reactant: C1CCC2=NCCCN2CC1
Agent: CN(C)CCCN
Product: CN(C)CCCNc1nccc(N)n1
Temperature: 220 °C
Yield: 56.6 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (300 mg, 2.316 mmol), DBU (419 μl, 2.78 mmol) and N,N-dimethyl-1,3-propanediamine (437 μl, 3.47 mmol) was heated to 220° C. via a microwave reactor for 30 min. The reaction mixture was purified by RP-HPLC to yield N2-[3-(dimethylamino) propyl]-2,4-pyrimidinediamine (256 mg, 1.311 mmol, 57% yield). MS (ES+) m/z 196.2 (MH+).
Reaction SMILES: COC1C=CC(C[N:10](CC2C=CC(OC)=CC=2)[S:11]([CH2:14][CH2:15][CH:16]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:13])=[O:12])=CC=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:10][S:11]([CH2:14][CH2:15][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[F:30])[C:17]([O:19][CH3:20])=[O:18])(=[O:12])=[O:13]
Reactant: COC(=O)C(CCS(=O)(=O)N(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1)c1ccc([N+](=O)[O-])cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(CCS(N)(=O)=O)c1ccc([N+](=O)[O-])cc1F
Reaction time: 48 h
Yield: 86.1 %

Procedure:
Methyl .alpha.-[2-[[bis[(4-methoxyphenyl)methyl]amino]sulfonyl]ethyl]-2-fluoro-4-nitrobenzeneacetate (41.6 g, 74.3 mmol) is dissolved in methylene chloride (200 ml) and trifluoroacetic acid (50 ml). The solution is stirred for 2 days then the solvents evaporated. The residue is dissolved in ethyl acetate (750 ml) and washed with sodium bicarbonate solution (200 ml) and brine (100 ml). After drying (MgSO4), filtration and evaporation the title compound is obtained as a solid (20.5 g, 86%) mp 99-101°.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH:12]([C:18]2[CH:27]=[C:26]3[C:21]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][N:25]3[CH3:28])=[CH:20][CH:19]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[CH3:28][N:25]1[C:26]2[C:21](=[CH:20][CH:19]=[C:18]([CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][O:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH:27]=2)[C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24]1
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)N(C)CCC2(C)C
Temperature: 40 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
A solution of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid methyl ester (1.1 g, 2.6 mmole) in 14 mL of a 1:1 THF/methanol mixture was treated with a solution of 0.44 g of lithium hydroxide monohydrate in 5 mL of water and stirred at 40° C. for 6 hours. The mixture was diluted with 20 mL of water and the pH was adjusted to 2.0 with 2N HCl solution. The mixture was extracted with three 20 mL portions of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil. The product was purified by preparative tlc (SiO2, 25% ethyl acetate in hexanes) to yield 0.875 g of 4-[2-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-heptyloxy]-benzoic acid as a pale yellow oil. MS (EI): (M++1): 410.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)O1>>[CH3:15][C:13]1([CH3:16])[CH2:14][CH:9]([NH:8][C:4]2[N:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=3)[CH:7]=[CH:6][N:5]=2)[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC1(C)CC(Nc2nccc(-c3ccc(S(N)(=O)=O)cc3)n2)CC(C)(C)N1

Procedure:
The title compound was prepared from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide according to Method C (Example 178). Yield: 443 mg (86%).
Reaction SMILES: [C:1]1([CH2:6][SH:7])[S:5][CH:4]=[CH:3][CH:2]=1.C(N1C(=O)C2=CC=C[CH:20]=[C:13]2[C:12]1=[S:21])CC>>[CH2:12]([S:21][S:7][CH2:6][C:1]1[S:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][CH3:20]
Reactant: CCCN1C(=O)c2ccccc2C1=S
Reactant: SCc1cccs1
Product: CCCSSCc1cccs1

Procedure:
Starting from thenylmercaptan and N-propylthiophthalimide there is obtained propyl-thenyl-disulphide. IR (liq.): bands inter alia at 2990, 1455, 1220, 1030, 850, 700 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)[CH3:15])=[O:12].O[Li:30].O>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[C:11]([NH:13][C@H:14]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([O-:22])=[O:21])=[CH:24][CH:25]=1)[CH3:15])=[O:12].[Li+:30]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2cccc(C)c2)cc1
Reactant: [Li]O
Solvent: O
Product: Cc1cccc(CN2CCC[C@@H]2C(=O)N[C@@H](C)c2ccc(C(=O)[O-])cc2)c1
Product: [Li+]

Procedure:
The title compound (E16) (24 mg) was prepared according to the general procedure for esters hydrolysis starting from methyl 4-((S)-1-((R)-1-(3-methylbenzyl)pyrrolidine-2-carboxamido)ethyl)benzoate (D33) (29 mg). (LiOH H2O: 1.5 eq; reaction time: 24 hrs)
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12].O.COC(CC1C(Cl)=C(N)C=CC=1C(OC)=O)=O>C(#N)C>[CH3:9][O:10][C:11]([CH2:13][C:14]1[CH:23]=[C:22]([NH2:24])[C:21]([Cl:1])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)Cc1cc(N)ccc1C(=O)OC
Reactant: O=C1CCC(=O)N1Cl
Agent: COC(=O)Cc1c(C(=O)OC)ccc(N)c1Cl
Solvent: O
Solvent: CC#N
Product: COC(=O)Cc1cc(N)c(Cl)cc1C(=O)OC
Temperature: 25 °C

Procedure:
N-Chlorosuccinimide (1.0 g, 7.3 mmol) was added to a solution of methyl 2-methoxycarbonylmethyl-4-aminobenzoate (1.5 g, 6.6 mmol) in acetonitrile (10 mL). The mixture was stirred while heating under reflux for 1 hour. After the reaction solution was cooled to room temperature, water was added thereto and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Then, the resulting solid was washed with ethyl acetate to give a 0.9:1 mixture of the title compound and methyl 2-methoxycarbonylmethyl-4-amino-3-chlorobenzoate (1.5 g, 88%).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[C:29]1(=O)[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:8]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Reactant: O=C1CCC(=O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)CCC1=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
0.36 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate, prepared as described in Example 2(A)(i), was dissolved in 10 ml of dichloromethane and 0.17 g of succinic anhydride and 0.17 g of triethylamine were added. After stirring at room temperature for 2 hours, 0.2 g of hydroxybenzotriazole and 0.2 g of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 18 hours and then filtered in order to remove dicyclohexylurea. The filtrate was washed twice with 15 ml of saturated sodium hydrogen carbonate solution each time. After drying over anhydrous sodium sulfate the solvent was removed by evaporation to give a colorless gum. This gum was purified by flash chromatography on silica gel using ethyl acetate/methanol (8:1) for the elution. There was obtained 0.23 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl](succinimidomethyl)phosphinic acid methyl ester in the form of a white foam.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[C:14]1([NH:28][C:29](=[O:31])[CH3:30])[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[N+:24]([O-])=O)[C:15]1=[O:27].Cl>C(O)C.O.[Fe]>[CH3:33][N:2]([CH3:1])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[C:14]1([NH:28][C:29](=[O:31])[CH3:30])[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[NH2:24])[C:15]1=[O:27]
Reactant: CC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)N(C)C)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)N(C)C)C(=O)c2cccc(N)c2C1=O
Yield: 53.1 %

Procedure:
2-(2-acetamido-4-nitro-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)-5-isopropylphenyl dimethylcarbamate (0.20 g, 0.4 mmol) was dissolved in anhydrous ethanol (10 ml) and water (1 ml). This solution was added with iron (0.18 g, 3.2 mmol) and conc. HCl (0.03 ml). The reaction mixture was heated for 2 hrs under reflux. After filtrating and washing with MeOH, the remainder was concentrated in a vacuum and purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (90 mg, 50%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][C:20](=[O:23])[CH2:21][SH:22].CCN(CC)CC.O>CS(C)=O>[CH3:18][O:19][C:20]([C:21]1[S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:23]
Reactant: COC(=O)CS
Reactant: O=Cc1ccc(OCc2ccccc2)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 80 °C
Yield: 95.8 %

Procedure:
To a solution of 4-benzyloxy-2-fluoro-benzaldehyde (1.3 g, 5.6 mmol) in DMSO (55 mL) was added mercapto-acetic acid methyl ester (1.2 mL, 11.3 mmol) and Et3N (2.4 mL, 1.7 g, 16.8 mmol) and the reaction mixture was heated (80° C., 12 h). The reaction mixture was cooled (rt), treated with H2O (100 mL) and filtered. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-30%) to provide the title compound as yellow solid (1.6 g, 96%). MS (ESI): mass calcd. for C17H14O3S, 298.1; m/z found, 299.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.98 (s, 1H), 7.75 (d, J=8.8, 1H), 7.53-7.30 (m, 6H), 7.10 (dd, J=8.8, 2.3, 1H), 5.14 (s, 2H), 3.92 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.CC([O-])=O.[Na+].[Br:17]Br>CC(O)=O>[Br:17][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4](=[O:9])[NH:5][CH:6]=1
Reactant: BrBr
Reactant: O=c1[nH]cccc1C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(trifluoromethyl)pyridin-2(1H)-one (25.0 g, 0.15 mol) in AcOH (300 mL) were added NaOAc (15.1 g, 0.18 mol) and dropwise Br2 (8.6 mL, 0.17 mol). Then the mixture was stirred at 80° C. overnight, concentrated, diluted with sat aq. NaHCO3 and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by CC (PE/EA=7/2) to give compound P45a (29.7 g, 80%) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.Cl.[CH2:12]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.ClCCl>[CH2:12]([O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:39]=[CH:38][C:34]([C:35]([O:1][N:2]4[C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[N:4]=[N:3]4)=[O:36])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[CH:23][CH:24]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCOc1ccc(N2CCN(c3ccc(C(=O)On4nnc5ccccc54)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.8 %

Procedure:
To a solution of 1-hydroxybenzotriazole (5.35 g) and 4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoic acid hydrochloride (15 g) in the mixture of triethylamine (9.64 ml) and dichloromethane (450 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (12.6 g) and stirred for 4 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[4-[4-(4-hexyloxyphenyl)piperazin-1-yl]benzoyloxy]benzotriazole (16.78 g).
Reaction SMILES: [N:1]([C:4]1[C:12]([CH3:13])=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)=C=S.[CH2:14]([NH2:17])[CH2:15][NH2:16].[C:18]1(C)C=CC=CC=1>>[CH3:13][C:12]1[C:4]([NH:1][N:16]2[CH2:15][CH2:14][N:17]=[CH:18]2)=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2
Reactant: Cc1c(N=C=S)ccc2cc[nH]c12
Reactant: Cc1ccccc1
Reactant: NCCN
Product: Cc1c(NN2C=NCC2)ccc2cc[nH]c12

Procedure:
A solution of 6-isothiocyanato-7-methylindole (0.85 g, 4.52 mmol) in 25 mL of toluene is added to a solution of ethylenediamine (1.06 mL, 15.8 mmol) in 50 mL of toluene. The milky white mixture is stirred for 30 minutes as the desired product precipitates. The reaction is filtered to yield 1.1 g of 6-[-N'-(2-aminoethyl)thioureido]-7-methylindole as a flaky white solid (99% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)=[CH:2]1.Cl.[F:17][C:18]([F:30])([F:29])[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=1)[NH2:20].C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([NH:20][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][N:22]=3)[C:18]([F:29])([F:17])[F:30])=[O:15])=[CH:10][CH:11]=2)=[CH:2]1
Reactant: O=C(O)Cc1ccc(-c2ccsc2)cc1
Reactant: COc1ccc(C(N)C(F)(F)F)nc1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc([C@H](NC(=O)Cc2ccc(-c3ccsc3)cc2)C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.04 g (0.18 mmol) [4-(3-thienyl)phenyl]acetic acid in 0.75 mL DMF was added 0.06 g (0.2 mmol) 2,2,2-trifluoro-1-(5-methoxypyridin-2-yl)ethanamine hydrochloride, 0-1 mL (0.6 mmol) triethylamine, 0.03 g (0.2 mmol) HOAt, and 0.05 g (0.2 mmol) EDC and the mixture stirred for 1 hour at room temperature. Purification (no workup) by preparative reverse phase HPLC (linear gradient 5 to 95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 SunFire 19×150 mm) afforded 2-[4-(3-thienyl)phenyl]-N-[(1S)-2,2,2-trifluoro-1-(5-methoxypyridin-2-yl)ethyl]acetamide high resolution mass spec calc for C20H17F3N2O2S 407.1036, found 407.1043. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, 1H, J=2.84 Hz); 7.58 (d, 2H, J=8.33 Hz); 7.46 (t, 1H, J=2.10); 7.39 (d, 2H, J=2.10 Hz); 7.30 (m, 3H); 7.22 (dd, 1H, J=2.93 and 8.60 Hz); 5.73 (dq, 1H, J=7.14 and 7.14 Hz); 3.86 (s, 3); 3.70 (s, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1>O1CCCC1>[ClH:1].[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=2)=[O:17])[CH3:20]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1Nc1ccc(C(=O)O)cc1
Product: Cl
Temperature: 25 °C
Yield: 61.1 %

Procedure:
A mixture of ethyl 4-chloro-7-(trifluoromethyl)-3-quinoline-carboxylate (3.04 g) and 4-aminobenzoic acid (1.37 g) in tetrahydrofuran (53 ml) was stirred under reflux for 10 hours and cooled to room temperature. The precipitates were collected and washed with tetrahydrofuran to give 4-[[3-ethoxycarbonyl-7-(trifluoromethyl)-4-quinolyl]amino]benzoic acid hydrochloride (2.69 g) as yellow powder.
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][OH:18]>>[OH:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: NCCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 3-aminopropanol to produce [2-(3-hydroxypropyl)amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(3-hydroxypropyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 3-(3,5-dioxomorpholino)propyl methanesulfonate and (d) reacting the mesylate with 4-[bis(2-bromo-p-tolyl)methyl]piperidine.