Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C(OC([N:9]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH2:45][CH2:44][N:43](C(OC(C)(C)C)=O)[CH2:42][CH2:41]2)=[CH:36][CH:35]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])=[CH:14][C:13]=1[Cl:32])=O)(C)(C)C.C(OCC)C>O1CCOCC1.C(#N)C>[ClH:32].[ClH:1].[Cl:32][C:13]1[C:12]([CH2:11][CH2:10][NH:9][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[CH:36][CH:35]=2)=[CH:17][C:16]([O:18][CH3:19])=[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[N:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)=[O:22])[CH:14]=1
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1cc(CCNCc2ccc(N3CCNCC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A 3 N HCl solution in 1,4-dioxane (0.4 mL) was slowly added to a solution of tert-butyl 4-(4-((tert-butoxycarbonyl (2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxy-phenethyl)amino)methyl)phenyl)piperazine-1-carboxylate (0.1 g) in acetonitrile (5 mL) at 0° C. The mixture was allowed to warm to room temperature and then stirring continued for one hour. Diethyl ether (25 mL) was added and after stirring continued for 15 minutes then the supernatant was decanted and the resulting solid was triturated with diethyl ether (25 mL) and dried under reduced pressure to yield a yellow solid. The solid was further triturated with methanol followed by diethyl ether and dried under reduced pressure to give the title compound (0.05 g, 60%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:32]4[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH2:29]3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:38])[CH:3]=1.[CH2:39]([S:41]([NH2:44])(=[O:43])=[O:42])[CH3:40]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([CH2:39][CH3:40])(=[O:43])=[O:42])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:32]4[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH2:29]3)[CH2:27][CH2:28]2)=[O:22])=[C:4]([CH3:38])[CH:3]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC3(CC2)COc2cccc(F)c23)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC4(CC3)COc3cccc(F)c34)cnc12
Yield: 27.3 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.025 g, 0.048 mmol) obtained in step 4 and ethanesulfonamide (0.026 g, 0.241 mmol), the title compound (0.008 g, 27%) was obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([Mg]Br)=[N:31][CH:32]=1>O1CCCC1>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([C:4]([C:6]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)[CH:7]=2)=[O:5])=[N:31][CH:32]=1
Reactant: Cc1ccc([Mg]Br)nc1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)nc1
Yield: 35.4 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 with 200 mg (0.593 mmol) of 1-(6-Methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl amide, 5.2 mL (1.30 mmol, 0.25 M in tetrahydrofuran) of 5-methyl-2-pyridylmagnesium bromide, and 2.6 mL of tetrahydrofuran. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 77.6 mg of 3-(5-Methyl-pyridine-2-carbonyl)-1-(6-methyl-pyridin-2-ylmethyl)-1H-quinolin-4-one. LC-MSD, m/z for C23H19N3O2 [M+H]: 370.15 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 0.91 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>C(Cl)Cl>[Cl:25][C:24]([Cl:27])([Cl:26])[CH2:23][O:22][C:20]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)=[O:21]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CCOC(=O)c1csc(CO)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
To a solution of ethyl 2-(hydroxymethyl)-thiazole-4-carboxylate 33 (38.4 g) and pyridine (41 mL) in 100 mL of CH2Cl2 is slowly added 2,2,2-trichloroethyl chloroformate (32 mL, 0.23 mol) at 0° C. After the resulting mixture is stirred for 30 minutes, the reaction is quenched by the addition of 10% aq NaHCO3. The organic layer is separated, and the aqueous layer is extracted with CH2Cl2. The combined organic extracts are washed with 2 N HCl, 10% aq NaHCO3, and brine, dried (Na2SO4), and concentrated. The residue is then recrystallized in ethanol (50 mL) to yield a light yellow solid (35 g). The mother liquor is concentrated and chromatographed to afford an additional amount (35 g) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29][CH2:28]1)=[O:26])[CH3:23]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:22]([O:24][C:25]([C:27]1([C:31]2[CH:36]=[CH:35][C:34]([C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:11][N:10]=[C:9]([CH3:20])[C:8]=4[NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[CH:14][CH:15]=3)=[CH:33][CH:32]=2)[CH2:28][CH2:29][CH2:30]1)=[O:26])[CH3:23]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CCC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid tert-butyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutanecarboxylic acid ethyl ester. Additionally, (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used as the catalyst in place of tetrakis(triphenylphosphine)palladium(0).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1C.ClC1C=CC(B(O)O)=CC=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: Cc1cc(N)ccc1Br
Agent: OB(O)c1ccc(Cl)cc1
Product: Nc1ccc(-c2cccc(Cl)c2Cl)cc1

Procedure:
The title compound was prepared as described in Example 76, STEP B, substituting 4-iodoaniline and 2,3-dichlorophenylboronic acid for 4-bromo-3-methylaniline and 4-chlorophenylboronic acid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][OH:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl.O>[CH3:31][S:32]([O:11][CH2:10][C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:12]\[C:13]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH3:22])=[O:23])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28A (300 mg, 0.85 mmol) in CH2Cl2 (10 mL) containing triethylamine (257 mg, 2.54 mmol) was treated with methanesulfonyl chloride (145 mg, 1.27 mmol) at 0° C. The mixture was stirred for 30 min at 0° C., diluted with water and extracted with CH2Cl2 (2×). The combined organic layers were dried over MgSO4, filtered and concentrated to afford the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][CH2:9][O:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:13]>C(#N)C>[O:13]=[C:12]1[CH2:11][O:10][CH2:9][CH2:8][N:14]1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1
Reactant: CCOC(=O)Cc1ccc(NC(=O)COCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
43.4 g (133 mmol) of caesium carbonate are added to a solution of 26.6 g (88.8 mmol) of ethyl {4-[2-(2-chloroethoxy)acetylamino]phenyl}acetate in 100 ml of acetonitrile, and the mixture is stirred at room temperature for 18 hours. The reaction mixture is filtered, and the filtrate is evaporated, giving ethyl [4-(3-oxomorpholin-4-yl)phenyl]acetate as a yellowish oil; ESI 264.
Reaction SMILES: ClC1C(CO)=CC=C(Cl)N=1.[Br:11][CH2:12][C:13]1[C:14]([Cl:21])=[N:15][C:16]([Cl:20])=[C:17](F)[CH:18]=1>>[Br:11][CH2:12][C:13]1[C:14]([Cl:21])=[N:15][C:16]([Cl:20])=[CH:17][CH:18]=1
Reactant: Fc1cc(CBr)c(Cl)nc1Cl
Agent: OCc1ccc(Cl)nc1Cl
Product: Clc1ccc(CBr)c(Cl)n1
Yield: 80 %

Procedure:
Compound 13B (0.88 g, 80%) was prepared from 13A (0.82 g, 4.6 mmol) using a procedure similar to the synthesis of 1B. HPLC Rt=2.44 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[NH:15][C@@H:14]([C@@H:16]([OH:18])[CH3:17])[CH2:13][O:12][CH2:11]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].N1C=CC=CC=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>ClCCl.O>[CH3:17][C@H:16]1[C@H:14]2[CH2:13][O:12][CH2:11][C@@H:10]([C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[N:15]2[C:26](=[O:27])[C:25](=[O:29])[O:18]1
Reactant: C[C@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1cc(F)c(F)c(F)c1
Reaction time: 1 h

Procedure:
To a solution consisting of (S)-1-[(3R,5R)-5-(3,4,5-trifluorophenyl)morpholine-3-yl]ethanol (1.18 g) and pyridine (5 mL) in dichloromethane (20 mL) was dropwise added oxalyl chloride (1.18 mL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 1 hour. The reaction solution was diluted with water, and the organic layer was partitioned. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), to thereby obtain the titled compound (912 mg). The physical properties of the compound were as follows. ESI-MS; m/z 316 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.54 (d, J=7.2 Hz, 3H), 3.50 (dd, J=11.6, 11.6 Hz, 1H), 3.68 (dd, J=12.4, 8.0 Hz, 1H), 4.06 (dd, J=11.6, 4.4 Hz, 1H), 4.18 (dd, J=12.4, 4.8 Hz, 1H), 4.49 (ddd, J=12.0, 4.4, 4.0 Hz, 1H), 4.64-4.70 (m, 1H), 4.78 (dd, J=8.4, 5.2 Hz, 1H), 7.01 (dd, J=8.0, 6.4 Hz, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](Cl)(=O)C>CO>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Bromo-2-methylbenzoic acid (2.00 g, 9.30 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days and was then concentrated in vacuo. This gave 1.96 g (92%) of the title compound as a light brown oil. 1H NMR (400 MHz, CD2Cl2) 2.61 (s, 3H), 3.90 (s, 3H), 7.38-7.42 (m, 2H), 7.78 (d, 1H).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[C:30]([CH3:38])[C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:30]([CH3:38])=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=O)C(C)=CN(C)C
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)ncc1C

Procedure:
The title compound was prepared from N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (298 mg, 0.8 mmol) and ethyl 4-dimethylamino-3-methyl-2-oxo-but-3-enoate (185 mg, 1.0 mmol) using in analogous manner the procedure described in example 139. Obtained as a white solid (30 mg, 8%). MS ISP (m/e): 368.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.45 (s, 1H), 7.83 (d, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 7.17 (d, 1H), 7.02 (dd, 1H), 6.87 (s, 1H), 4.46 (q, 2H), 3.89 (s, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[N:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]1=[N:7]2.Cl>C(O)(=O)C.[Zn]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([OH:18])[N:5]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:6]1=[N:7]2
Reactant: O=c1c2c(Cl)cc(Cl)cc2nc2n1CCCCC2
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: OC1c2c(Cl)cc(Cl)cc2N=C2CCCCCN21

Procedure:
To a solution of 2 g of 1,3-dichloro-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one in 100 mL of glacial acetic acid at 50° C. was added an intimately mixed mixture of 15 g zinc dust and 15 g silica gel (column chromatography grade). To this mechanically stirred suspension was added dropwise concentrated hydrochloric acid, while the progress of the reaction was followed by TLC (20:1 CHCl3 :MeOH, basified aliquots, extracted into chloroform). When the reaction was essentially complete, excess zinc was filtered off (pyrophoric!) the filtrate was concentrated in vacuo, basified, extracted with chloroform, and the crude extract was chromatographed using 20:1 chloroform:methanol as eluent on a silica gel column. The corresponding fractions after concentration in vacuo gave the 1,3-dichloro-6,7,8,9,10,12-hexahydroazepino[2,1-b]quinazolin-12-ol as an off-white crystalline solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:16][CH2:17][CH2:18]Cl.C([O-])([O-])=O.[K+].[K+].[OH-].[K+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[Cl:16][CH2:17][CH2:18][S:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: ClCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: FC(F)(F)c1ccc2c(SCCCl)ccnc2c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 66.6 %

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (800 mg, 3.5 mmol) and 1,2-dichloroethane (10.4 g, 10.5 mmol) were charged in a 50 ml round-bottomed flask equipped with a magnetic stirrer. Then TBABr (600 mg, 1.7 mmol), K2CO3 (500 mg, 3.5 mmol), KOH (500 mg, 0.7 mmol) and water (2 mL) were added and the reaction mixture was stirred for 5 h at 20° C. The reaction mixture was poured in 100 mL of H2O and extracted with CH2Cl2 (150 mL). The organic layer was washed with water (30 mL), brine (2×10 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:EtOAc=8:2 to 5:5) to give after evaporation 4-(2-chloroethylthio)-7-(trifluoromethyl)quinoline 30 (680 mg, 67% yield) as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[SH:33]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:33][C:27]2[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=2[Cl:25])[CH2:8][C@H:7]1[CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1COc1ccc(F)cc1
Reactant: Fc1ccc(S)c(Cl)c1
Product: CCOC(=O)[C@@H]1CC(Sc2ccc(F)cc2Cl)C[C@H]1COc1ccc(F)cc1

Procedure:
The title compound was prepared in analogy to example 68 step 8 using (1R,2R)-2-(4-Fluoro-phenoxymethyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, example 143 and 144 step 3) and 2-chloro-4-fluorothiophenol. Yellow oil (56%). MS (EI): 378.3 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3([CH2:19][O:18][C:17]4[CH:20]=[C:21]5[C:25](=[CH:26][C:16]3=4)[CH2:24][CH2:23][O:22]5)[C:8]2=[O:27])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu]=O>[N:30]1([C:2]2[CH:29]=[CH:28][C:5]([CH2:6][N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]4([CH2:19][O:18][C:17]5[CH:20]=[C:21]6[C:25](=[CH:26][C:16]4=5)[CH2:24][CH2:23][O:22]6)[C:8]3=[O:27])=[CH:4][CH:3]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: O=C1N(Cc2ccc(Br)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: C1COCCN1
Agent: O=[Cu]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Product: O=C1N(Cc2ccc(N3CCOCC3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 130 °C

Procedure:
A suspension of 1′-(4-bromobenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.45 g, 1.0 mmol), morpholine (0.26 g, 3.0 mmol), dicyclohexyloxalylhydrazide (0.14 g, 0.5 mmol), tetrabutylammonium bromide (0.34 g, 1 mmol), copper (II) oxide (0.05 g, 0.6 mmol) and cesium carbonate (0.65 g, 2.0 mmol) was heated in microwave reactor at 130° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography with dichloromethanemethanol (100:1-10:1) to afford 1′-(4-morpholin-4-ylbenzyl)-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.35-6.74 (m, 8H), (0.09 g, 19%), 6.45 (s, 1H), 6.41 (s, 1H), 4.87 (ABq, 2H), 4.81 (ABq, 2H), 4.52 (t, J=8.7, 8.7 Hz, 2H), 4.01-3.74 (m, 4H), 3.25-3.07 (m, 4H), 3.05-2.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.8, 161.8, 161.3, 142.1, 132.8, 128.6 (2C), 123.8, 123.3, 120.2, 119.9, 118.9, 116.0, 109.3, 93.2, 80.6, 72.3, 66.6, 57.7, 49.4, 43.6, 29.0; MS (ES+) m/z 454.87 (M+1).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[C:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2.CC[OH:34]>O>[CH3:1][S:2]([CH2:3][C:4]1[C:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[N:6][C:7]2[C:12]([C:13]=1[C:14]([NH:16][C@H:17]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][CH3:19])=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:34]
Reactant: CC[C@H](NC(=O)c1c(CSC)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: CCO
Solvent: O
Product: CC[C@H](NC(=O)c1c(CS(C)=O)c(-c2ccccc2)nc2ccccc12)c1ccccc1

Procedure:
A solution of 3-[(methylthio)methyl]-2-phenyl-N-[(1S)-1-phenylpropyl]quinoline-4-carboxamide (9)(1.7 g, 3.98 mmol) in EtOH (40 mL) was cooled to 0° C., and to this, with stirring, was added a solution of NaIO4 (1.02 g, 4.78 mmol) in H2O (20 mL). The cooling bath was removed and reaction allowed to stir for 3 h, and then concentrated under reduced pressure to remove most of the EtOH. It was then diluted with EtOAc, washed with H2O (containing some NaCl to reduce emulsion), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-35% EtOAc/CH2Cl2) to give the desired products (two diastereomers) each as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH2:23]([N:26]=[C:27]=[S:28])[CH2:24][CH3:25]>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:27]([NH:26][CH2:23][CH2:24][CH3:25])=[S:28])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCN=C=S
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)NCCC
Yield: 66.7 %

Procedure:
Using the general method of Example 150, 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with propyl isothiocyanate (560 mg, 5.55 mmol) to provide 1.34 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-propylthiourea as a crystalline solid, m.p. 144.5–145.5° C. Analysis: Calculated for C21H30N6S.0.56 H2O: % C, 61.72; % H, 7.68; % N, 20.56; Found: % C, 61.72; % H, 7.67; % N, 20.56.
Reaction SMILES: C(O)=O.Cl[C:5]1[CH:6]=[C:7]([N:12]2[CH2:16][CH:15](C)[C:14]([NH:18][CH:19]=[O:20])=[N:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]>O>[Cl:11][C:10]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:15][C:14]([NH:18][CH:19]=[O:20])=[N:13]2)=[CH:8][CH:9]=1
Reactant: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: O
Product: O=CNC1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A mixture of 15.0 g. of the above crude product and 85.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours. The reaction mixture is poured into water and filtered to collect the solid. The solid is washed with a solution of saturated sodium bicarbonate, then water. The material is dried, dissolved in dichloromethane, then is columnized and recrystallized as above to give 12.0 g. of the desired product as pale yellow crystals. A 5.0 g. amount of this material is recrystallized as above to give 4.70 g. of the desired product, m.p. 164°-166° C.