Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:28]([O:30]C)=[O:29])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:6]=2[CH:5]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:2]=[CH2:3].[OH-].[Na+].O>CO.O1CCCC1>[CH2:1]([C:4]1([C:28]([OH:30])=[O:29])[NH:9][C:8](=[O:10])[C:7]2[S:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:13][C:6]=2[CH:5]1[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OC)NC(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCC1(C(=O)O)NC(=O)c2sc(N3CCOCC3)cc2C1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.8 %

Procedure:
A mixture of methyl 5-allyl-4-(3,4-dichlorophenyl)-2-(morpholin-4-yl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.118 g, 0.245 mmol), methanol (2.0 mL), tetrahydrofuran (2.0 mL) and a solution of 1.0 M sodium hydroxide in water (1.50 mL, 1.50 mmol) was stirred at rt overnight. Additional methanol (2.0 mL) and 1.0 M Sodium hydroxide in water (1.50 mL, 1.50 mmol) was added. The mixture was stirred at rt for 2 days. The mixture was concentrated to remove most of volatile solvents and then acidified by 1M HCl. The precipitate was collected and dried in air to afford crude product. Final purification by HPLC afforded pure product as a white solid (43.3 mg, 23%). LCMS (FA) ES+: 467, 469. 1H NMR (400 MHz, DMSO) δ 7.45 (d, J=8.3 Hz, 1H), 7.38 (s, 1H), 7.25 (br s, 1H), 7.12 (d, J=8.2 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.74-5.63 (m, 1H), 4.99-4.89 (m, 2H), 4.18 (s, 1H), 3.68 (br s, 4H), 3.12 (br s, 4H), 2.54-2.50 (m, 2H, overlapping with DMSO peak).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:32]>>[CH2:31]([N:33]([CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: CCNCCc1ccccn1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCN(CCc1ccccn1)C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-(2-pyridin-2-yl-ethyl)-amine. MS (ESI): 491.4 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:18][C:19]1[CH:24]=[C:23]([O:25][C:2]2[C:3]([CH3:11])=[N:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Oc1ccnc(Cl)c1
Reactant: Cc1nc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Temperature: 100 °C
Yield: 54.7 %

Procedure:
A solution of Example A3 (25.59 g, 118 mmol), K2CO3 (48.9 g, 354 mmol) and 2-chloro-4-hydroxy-pyridine (30.6 g, 236 mmol) in DMF (160 mL) was sparged with Ar, heated at 100° C. overnight, then cooled to RT. The mixture was treated with water and EtOAc, the solids removed via filtration through diatomaceous earth and washed with water, EtOAc, then DCM. The aqueous filtrate was extracted with EtOAc (2×) and the organic extracts were combined with the organic filtrates, washed with water, then brine, dried over Na2SO4 and concentrated to dryness. The residue was treated with MTBE, sonicated and the resulting solid collected via filtration to afford 3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-nitropyridine (17.16 g, 55%). 1H NMR (400 MHz, DMSO-d6): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.16 (dd, J=5.7, 2.3 Hz, 1H), 2.46 (s, 3H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH2:14])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>N1C=CC=CC=1>[N:1]1[C:5]2[C:6]3[C:11]([CH2:12][CH2:13][C:4]=2[S:3][C:2]=1[NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Nc1nc2c(s1)CCc1ccccc1-2
Reactant: CCC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2c(s1)CCc1ccccc1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
Under ice-cooling, to a solution of 4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (1.50 g, 7.4 mmol) in pyridine (20 mL) was added propionyl chloride (1.03 g, 11 mmol), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3:1) to give the title compound (1.75 g, yield 91%) as a powder.
Reaction SMILES: CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[C:14]([O:17][C@H:18]1[CH2:23][CH2:22][C@H:21]2[C@H:24]3[C@H:35]([CH2:36][CH2:37][C@:19]12[CH3:20])[C@:32]1([CH2:33][OH:34])[C:27]([CH2:28][C@@H:29]([O:38][CH2:39][CH3:40])[CH2:30][CH2:31]1)=[CH:26][CH2:25]3)(=[O:16])[CH3:15].O>CC(C)=O>[C:14]([OH:17])(=[O:16])[CH3:15].[CH2:39]([O:38][C@H:29]1[CH2:30][CH2:31][C@@:32]2([CH:33]=[O:34])[C:27](=[CH:26][CH2:25][C@@H:24]3[C@@H:35]2[CH2:36][CH2:37][C@@:19]2([CH3:20])[C@H:21]3[CH2:22][CH2:23][C@@H:18]2[OH:17])[CH2:28]1)[CH3:40]
Reactant: CCO[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)O
Product: CCO[C@H]1CC[C@@]2(C=O)C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1

Procedure:
One equivalent of Jones Reagent is added to a solution of 3β-ethoxy-5-androstene-17β,19-diol 17-acetate in acetone at 10° C. After stirring for 30 minutes the acetone layer is poured onto cold water with vigorous stirring. The precipitate which forms is filtered, washed with water and dir dried. Crystallization of this precipitate from an ether-hexane mixture yields 3β-ethoxy-17β-hydroxy-5-androsten-19-one acetate.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=1)=[N+]=[N-].C(N(CC)CC)C.[H][H]>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:9]=[N:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Nc1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
To a stirred solution of 2-Azido-5,6-diphenylpyrazine (45 mg, 0.17 mmol) in 50 mL EtOAc at room temperature was added triethylamine (100 μL) followed by Pearlman's Catalyst (50 mg). The suspension was put through a vacuum/purge cycle three times with hydrogen gas and then held under I atmosphere of hydrogen for 2 hours. The suspension was then filtered through GF/F filter paper with EtOAc and concentrated. The crude product was eluted through a Biotage 12S column with 1/1 EtOAc/hexane to give pure product, as a clear oil (25 mg, 59%)., 1H-NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.42-7.20 (m, 10H), 4.62 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([F:23])[CH:25]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Reactant: Nc1cccc(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2cccc(F)c2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (1.0 g, 3.0 mmol) and 3-fluoroaniline (0.29 mL, 3.0 mmol) in dry DCM (25 mL) is added sodium triacetoxyborohydride (953 mg, 4.49 mmol) in three portions over 1-2 minutes. The suspension is stirred at RT for 1 hour. 1N sodium hydroxide (25 mL) is added and the mixture is stirred at RT for 20 min. The mixture is then diluted with DCM (50 mL) and the DCM layer separated and washed with 1M HCl (25 mL) and brine (15 mL), dried (MgSO4), filtered and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 50 g pre-packed column and eluted with 30% EtOAc/isohexane. Product is isolated as a colourless oil which is triturated with diether ether-isohexane to afford the title compound as colourless crystals. [MH+429.24].
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[CH3:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][C:29](=[O:35])[NH:30]2.N1CCCCC1>C(O)C>[OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12](/[CH:15]=[C:28]3\[C:29](=[O:35])[NH:30][C:31]4[C:27]\3=[C:26]([CH3:25])[CH:34]=[CH:33][CH:32]=4)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Reactant: Cc1cccc2c1CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cccc2c1/C(=C/c1[nH]c3c(c1C)C(=O)N(C[C@@H](O)CN1CCOCC1)CCC3)C(=O)N2
Temperature: 45 °C
Reaction time: 16 h
Yield: 62.8 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol 1) and 4-methyl-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-5-(2-hydroxy-3-morpholinopropyl)-3-methyl-2-((4-methyl-2-oxoindolin-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 83 (35 mg, yield 63.6%) as a yellow solid.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[CH2:21](I)[CH3:22].[H-].[Na+].O>C1COCC1.CN(C=O)C>[N:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([CH2:21][CH3:22])[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](Cc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 54 %

Procedure:
To a solution of Boc-Phe(4-F)-OH (1.0 g, 3.53 mmol) in THF/DMF (6 ml/1.5 ml), ethyl iodide (2.24 ml, 20.8 mmol) and 60% sodium hydride (422 mg, 10.6 mmol) were added under cooling with ice and stirred at room temperature for 19 hours. The reaction mixture was mixed with water slowly and then with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate:methylene chloride=1:1:15), giving Boc-N-Et-Phe(4-F)-OH (P10) (593 mg, 54%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:23](F)=[O:24])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCCS)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (83.0 mg, 0.99 mmol) in 4.8 mL water was added 2-aminoethanethiol hydrochloride (60.3 mg, 0.53 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25h (112.6 mg, 0.48 mmol) in 4.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 26h as a colorless oil.
Reaction SMILES: C(C1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][C:10]3[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:18]=1)#N.[OH-:19].[Na+].[CH2:21]([OH:23])[CH3:22]>>[F:17][C:14]1[CH:15]=[CH:16][C:9]2[S:8][C:7]3[CH:18]=[C:22]([C:21]([OH:19])=[O:23])[CH:4]=[CH:5][C:6]=3[CH:12]=[CH:11][C:10]=2[CH:13]=1
Reactant: CCO
Reactant: N#Cc1ccc2c(c1)Sc1ccc(F)cc1C=C2
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)c1ccc2c(c1)Sc1ccc(F)cc1C=C2
Reaction time: 0.5 h

Procedure:
Suspend 300 mg. of the cyano compound of Step 1 in 8 ml. of 20% aqueous sodium hydroxide and 8 ml. of absolute ethanol. Reflux under nitrogen for 2 hours. Evaporate the ethanol. Acidify the suspension with 20% hydrochloric acid and separate the solids by filtration. Dissolve the residue in 20 ml. of hot methanol and add a few drops of concentrated hydrochloric acid. Evaporate the methanol, dilute with ether and evaporate again. Dilute with water, stir for 30 minutes, and filter. Wash the solids with water and dry in vacuo at 100° C. to obtain the title product (m.p., 270°-272° C.).
Reaction SMILES: COCCOC[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[NH:12][CH2:11][C:10]1[CH:9]=[C:8]([OH:7])[CH:15]=[CH:14][CH:13]=1
Reactant: COCCOCOc1cccc(CN)c1
Reactant: Clc1ccc2ccccc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: Oc1cccc(CNc2ccc3ccccc3n2)c1
Temperature: 140 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[(2-methoxyethoxy)-methoxy]-benzylamine (422 mg, 2 mmol, example 9) in DMSO (4 mL) is added 2-chloroquinoline (328 mg, 2 mmol). The resulting solution is warmed to 140° C. and stirred at this temperature for 3 h. The resulting mixture is cooled, diluted with water, then extracted with ethyl acetate. The organic extract is washed with brine, dried over MgSO4 and concentrated. The residue is taken up in methanol (10 mL) then p-toluene sulphonic acid monohydrate (190 mg, 1 mmol) is added. This mixture is warmed to 60° C. and stirred at this temperature for 2 h. The reaction mixture is then cooled, concentrated under reduced pressure and the residue purified by flash chromatography (silica, 30% ethyl acetate in dichloromethane) to give the title compound. MS (ESI) 251 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
Add 4-chloro-3-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and pyridine (1.0 g, 12.8 mmol) in DCM (10 mL), stir well and cool to 0° C. Add phenyl chloroformate (1.04 g, 6.6 mmol) at 0° C. After addition, stir the reaction at room temperature for 1 hr. TLC (EtOAc:PE=1:2) shows the reaction is complete. Wash the organic layer with 1M HCl solution (20 mL) and brine (20 mL) respectively. Dry over anhydrous Na2SO4; concentrate under reduced pressure to give the target compound (1.16 g) which is used without further purification. MS: (M+1): 316.1.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28](O)=[O:29])[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:33]1([CH:39]([NH2:42])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:33]1([CH:39]([NH:42][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:29])[CH2:40][CH3:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: CCC(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(NC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with 1-phenylpropylamine (31 mg, 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was concentrated under vacuum, the residue was suspended in water, and the solid was collected by vacuum filtration. This material was purified by preparative thin-layer-chromatography on silica eluting with a 3:1 ethyl acetate-hexanes mixture. The product containing band was collected and eluted with 5% methanol in ethyl acetate to afford 66 mg of the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH:5]=1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[S:33]([CH3:32])(=[O:35])=[O:34])[CH:5]=1
Reactant: COC(=O)c1cccc(CCCNCCCc2cccc(Cl)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CCCN(CCCc2cccc(Cl)c2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 115.5 %

Procedure:
To a solution of 3-(3-{[3-(3-chloro-phenyl)-propyl]-amino}-propyl)-benzoic acid methyl ester (50.3 mg, 0.145 mmol) and triethylamine (32.4 mg, 0.32 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (18.3 mg, 0.16 mmol) at 0° C. The reaction mixture was stirred for 24 h at room temperature and was diluted with CH2Cl2. The organic solution was washed consecutively with aqueous HCl (5.5%, 1×), H2O (1×), NaHCO3 (1×) and brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title product of Step A as an oil (71 mg). MS 424 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>C1COCC1.O>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: Cc1ccc(C(=O)c2ccc3noc(-c4cccc(Cl)c4)c3c2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)c2ccc(N)c(C(=O)c3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A mixture of intermediate 19 (0.071 mol) in THF (250 ml) was cooled on an ice bath. TiCl3 15% in water (250 ml) was added dropwise. The mixture was stirred at room temperature overnight, then poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 20.5 g (82.6%) of [2-amino-5(4-methylbenzoyl)phenyl](3-chlorophenyl)-methanone (intermediate 20).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:31][CH2:32][CH2:33][N:34]2[CH2:38][CH2:37][CH2:36][C:35]2=[O:39])[C:7]2[C:16]3[CH:15]=[C:14]([CH2:17][CH2:18][N:19]4[C:27](=[O:28])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C:20]4=[O:29])[CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:30]=1.ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:52].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:52][C:9]1[C:8]2[N:30]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:31][CH2:32][CH2:33][N:34]3[CH2:38][CH2:37][CH2:36][C:35]3=[O:39])[C:7]=2[C:16]2[CH:15]=[C:14]([CH2:17][CH2:18][N:19]3[C:20](=[O:29])[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]3=[O:28])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: COCCc1nc2cnc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccc(CCN4C(=O)c5ccccc5C4=O)cc3c2n1CCCN1CCCC1=O
Reaction time: 18 h

Procedure:
2-(2-{2-(2-Methoxyethyl)-1-[3-(2-oxo-pyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)-dione (2.1 g, 3.8 mmol) in dichloromethane (75 mL) was combined with 3-chloroperoxybenzoic acid (60% pure, 2.0 g, 7.5 mmol) and the reaction was stirred for 18 hours. Concentrated ammonium hydroxide (40 mL) was added and the mixture was vigorously stirred for an additional 10 minutes. p-Toluenesulfonyl chloride (791 mg, 4.12 mmol) was added and the mixture was stirred for an additional 1 hour. The fractions were separated and aqueous fraction was extracted with chloroform (10×35 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, and concentrated to provide 2.2 g of 2-(2-{4-amino-2-(2-methoxyethyl)-1-[3-(2-oxopyrrolidin-1-yl)propyl]-1H-imidazo[4,5-c]quinolin-8-yl}ethyl)-1H-isoindole-1,3(2H)dione as an off-white foam. MS (APCI) m/z 541 (M+H)+.