Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:21])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(c1cccs1)=CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Temperature: 35 °C

Procedure:
To a solution of methyl 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-2-naphthalenecarboxylate (Compound E5, 430.0 mg, 1.44 mmol) in 3.0 mL of EtOH and 3.0 mL THF was added NaOH (240.0 mg, 6.00 mmol; 3.0 mL of a 2N aqueous solution). The resulting solution was warmed to 35° C. for 6 h, cooled to room temperature and quenched with 1M HCl. The mixture was extracted with EtOAc and the combined organic layers washed with H2O and saturated aqueous Naa before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[N:35]=[CH:36][C:37]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][CH:24]([N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:32])[CH2:3][CH2:4]2)=[O:9])=[CH:38][CH:39]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1ccc(Cl)nc1)N1CCC(N2CCCC2)CC1
Yield: 57 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 169), 2-chloropyridine-5-boronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (57%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[C:11]([C:25]([C:31]([F:34])([F:33])[F:32])([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[H-].[CH:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:36])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:18])([F:17])[F:19])([O:20][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:21]([F:22])([F:23])[F:24])[CH:12]=[C:11]([C:25]([C:31]([F:32])([F:33])[F:34])([O:30][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([O:8][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[C:4]([F:7])([F:6])[F:5]
Reactant: OC(c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(S(=O)(=O)OC(c2cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
4.5 g (7.88 mmol) of 1,3,5-tris-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 40 ml of dry DMF, and 0.95 g (31.5 mmol) of sodium hydride was added while flushing with nitrogen. After dissolution of the hydride, 6.56 g (30 mmol) of 4-isopropylbenzenesulfonyl chloride were added at 0 to 5° C. Slight evolution of heat was observed. The mixture was stirred for 20 hours at 5° C., ethyl acetate was added and the mixture was washed with water, dried, filtered and evaporated down. 9.6 g of crude product were obtained, and said crude product was eluted over a silica gel column with a 1:1 mixture of methylene chloride/hexane. The third fraction obtained was freed from the solvent and gave 6.8 g of 1,3,5-tris-[2,2,2-trifluoro-1-(4-isopropylbenzenesulfonyloxy)-1-trifluoromethylethyl]-benzene. M.p. 105° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15](O)=[O:16])=[CH:12][C:11]=2[CH:18]=1)#[N:6]>>[C:5]([C:7]1[CH:8]=[CH:9][C:10]2[O:14][C:13]([C:15]([Cl:3])=[O:16])=[CH:12][C:11]=2[CH:18]=1)#[N:6]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: O=S(Cl)Cl
Product: N#Cc1ccc2oc(C(=O)Cl)cc2c1

Procedure:
Thionyl chloride (8 ml, 110 mmol) was added to 5-cyano-2-benzofurancarboxylic acid (1.00 g, 5.34 mmol) and the mixture was refluxed under heating for 30 minutes. Thionyl chloride was distilled away under reduced pressure and toluene (3 ml) was added which was again distilled away under reduced pressure to give 5-cyano-2-benzofurancarbonyl chloride. This was dissolved in toluene (20 ml) and pyridine (0.86 ml, 10.7 mmol), 4-dimethylaminopyridine (131 mg, 1.07 mmol) and t-butyl 4-hydroxycyclohexylacetate (1.35 g, 5.88 mmol) were added. The mixture was refluxed under heating for one hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1-5/1) to give 1.12 g of t-butyl [4-[(5-cyano-2-benzofuranyl)carbonyloxy]cyclohexyloxy]acetate as a colorless solid (52%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(NCC2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Yield: 91 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) with tert-butyl 4-(aminomethyl)-1-piperidinecarboxylate as in previous examples gave tert-butyl 4-({[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}methyl)-1-piperidinecarboxylate in 91% yield: mp (CH2Cl2/MeOH) 203-205° C.; 1H NMR (DMSO-d6) δ 8.10-7.60 (m, 3H), 7.41-7.36 (m, 1H), 6.94 (dd, J=7.8, 3.8 Hz, 1H), 3.974 and 3.970 (2s, 3H), 3.95-3.92 (m, 2H), 3.78-3.77 (m, 4H), 3.69 (m, 4H), 3.34-3.24 (m, 2H), 2.69 (m, 2H), 1.77-1.67 (m, 3H), 1.389 and 1.381 (2s, 9H), 1.12-1.00 (m, 2H); Anal. Calcd. for C27H36F2N8O4: C, 56.4; H, 6.3; N, 19.5. Found: C, 56.1; H, 6.3; N, 19.6%
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]2[C:10]=1[C:11](=[O:45])[C:12]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:13][N:14]2[C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30]CC2C=CC(OC)=CC=2)[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:30][C:24]1[N:23]=[C:22]([N:14]2[C:15]3[C:10](=[C:9]([NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:18]([F:19])=[C:17]([F:20])[C:16]=3[F:21])[C:11](=[O:45])[C:12]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:13]2)[C:27]([F:28])=[CH:26][C:25]=1[F:29]
Reactant: CCOC(=O)c1cn(-c2nc(NCc3ccc(OC)cc3)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2F)c2c(F)c(F)c(F)c(NCc3ccccc3)c2c1=O
Reaction time: 0.33 h
Yield: 109.4 %

Procedure:
To 600 mg of ethyl 5-benzylamino-1-[3,5-difluoro-6-(p-methoxybenzylamino)pyridine-2-yl]-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate was added 2 ml of trifluoroacetic acid, and the mixture was allowed to stand at room temperature for 20 minutes. The solution was concentrated under reduced pressure, and 3 ml of ethanol was added to the residue, and the solution was again concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration and washed with ethanol to obtain 530 mg of the title compound as a yellow powder.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>CC(C)=O>[CH2:19]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCC1(C(=O)OCC)CCCC1=O
Yield: 89.52 %

Procedure:
Under mechanical agitation, 31.20 g (purity of 90%) of ethyl 2-oxocyclopentane carboxylate was added to 76.04 g (purity of 98%) of ground anhydrous potassium carbonate, and after stirring for several minutes, to the mixture was added 100 ml of acetone. The reaction mixture was further stirred for about 15 minutes, then thereto was dropwise added 45.86 ml (purity of 98% of 1-bromo-n-pentane. Upon the completion of the addition, the reaction mixture was heated for reflux for 6 hours. The reaction mixture was filtered under the reduced pressure, and the filter cake was washed with diethyl ether until its color was purely white. Pale yellow filtrate was collected and dried over anhydrous magnesium sulfate, then the solvent was removed. The residue was distilled under reduced pressure, and 36.42 g of colorless liquid as a distillate cut of 156-162° C./22 mmHg was collected. Yield: 89.52%. MS: m/e 227(M+″+1), 226(M+″), 198, 181, 169, 156, 141, 127, 110, 95.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:10][N:9]=1)=[O:7])C>CO>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][CH2:13][C:11]1[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=1
Reactant: CCOC(=O)c1cc(CCCC(C)C)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCCc1cc(C(=O)O)n[nH]1
Yield: 80.2 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 4.97 mmol) was added to a stirring, room temperature solution of 17 (0.2229 g, 0.994 mmol) in MeOH (12.4 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (20 min): The reaction was concentrated and then dissolved in 2.0 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.1565 g (80.2%) of 18. 1H (CD3OD, 400 MHz): 66.56 (1H, s), 2.68 (2H, t, J=7.6 Hz), 1.67 (2H, quint, J=7.8 Hz), 1.63-1.51 (1H, m), 1.23 (2H, dt, J=8.8, 7.1 Hz), 0.89 (6H, d, J=6.4 Hz) ppm. 13C (CD3OD, 100 MHz): δ 163.79, 149.69, 142.80, 107.65, 39.46, 28.92, 28.11, 26.90, 22.91 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.91; CH2 carbons: 39.46, 28.11, 26.90; CH carbons: 107.65, 28.92 ppm. HPLC: 8.579 min.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:10](OC)=[O:11])=[C:6]([NH2:18])[N:5]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:3]=1.[OH-].[Li+].Cl>C(O)C.O>[NH2:18][C:6]1[C:7]2[N:8]([C:14]([O:16][CH3:17])=[O:15])[CH2:9][C:10](=[O:11])[NH:1][C:2]=2[N:3]=[C:4]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[F:35])[N:20]=2)[N:5]=1
Reactant: COC(=O)CN(C(=O)OC)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)N1CC(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
3.5 g (7.285 mmol) of the crude compound from example 55A were dissolved in ethanol (25 ml) and water (25 ml), and 174 mg (7.285 mmol) of lithium hydroxide were added. After stirring at RT for 30 min, the mixture was adjusted to pH=6 with dilute hydrochloric acid and extracted with ethyl acetate. After separation of the phases, the organic phase was washed with saturated aqueous sodium chloride solution and then dried with sodium sulfate, filtered and concentrated to dryness. The residue was slurried in acetonitrile and ethyl acetate, and insoluble constituents were filtered off. The filtrate was concentrated and the residue was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 38 mg of the title compound were obtained (1% of theory).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH2:29][CH2:30][CH2:27][CH2:26]3)=[CH:4][CH:5]=2)[C:12](=[O:25])[CH:13]=1
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 mg (0.45 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one in 5.0 mL DCM is added 186 μL (1.34 mmol) triethylamine and subsequently 69 μL (0.89 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT and 74 μL (0.89 mmol) pyrrolidine is added. The mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[CH:4]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:4]1[C:5]2[C:6]3[CH:17]=[CH:16][S:15][C:7]=3[C:8](=[O:14])[NH:9][C:10]=2[C:11]([CH3:13])=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1
Reactant: O=C1CCC(=O)N1Br
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 83 %

Procedure:
Following Step 4 from General Procedure A, 8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (6.4 g, 26 mmol) was reacted with N-bromosuccinimide (5.0 g, 26 mmol) to afford the desired product (7.0 g, 82%) as a brown solid: ESI MS m/z 329 [C12H7BrFNO2S+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[F:16])[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:4].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[F:16])[NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[O:4])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CS(=O)(=O)Nc1ccc(F)c(C(=O)CBr)c1
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(F)c(C(=O)CN(Cc2ccccc2)Cc2ccccc2)c1
Yield: 84.8 %

Procedure:
3'-(2-Bromoacetyl)-4'-fluoromethanesulfonanilide (30 g) was dissolved in 200 ml of N,N-dimethylformamide, a solution of 38 g of dibenzylamine in N,N-dimethylformamide was added with ice-cooling and stirring and the mixture was made to react at room temperature for 1 hour. The reaction mixture was added to water followed by extracting with ethyl acetate. The extract was washed with water, dried, the solvent was evaporated therefrom and the residue was crystallized from diisopropyl ether to give 35 g of 3'-(2-dibenzylaminoacetyl)-4'-fluoromethanesulfonanilide. The crystals were made into hydrochloride to give 35 g of crystals, m.p. 185°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[C:12]([NH:20][C:21]3[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Fc1ccc(S)cc1
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccc(F)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 4-fluoro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(4-fluoro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 351 (MH+).
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:12][NH2:13]>C(O)CCC>[F:10][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:13][NH:12][C:2]2=[N:9][CH:8]=1
Reactant: N#Cc1cc(F)cnc1Cl
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Nc1n[nH]c2ncc(F)cc12
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of compound 4 (50 g, 321.7 mmol) in 1-butanol (1 L) was added hydrazine monohydrate (150 mL, 3.2 mol), and the mixture was refluxed for 4 h. The mixture was cooled to room temperature and concentrated. The precipitate was successively washed on filter with water (2×) and Et2O (2×) and dried in vacuo overnight to give compound 5 (44 g, 88%) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): δ 5.53 (s, 2H); 7.94 (dd, 1H); 8.35 (dd, 1H); 12.02 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1.C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:27][CH2:28][C:29](Cl)=[O:30]>O>[CH3:1][O:2][CH:3]([O:12][CH2:13][CH3:14])[CH2:4][N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:29](=[O:30])[CH2:28][Cl:27]
Reactant: CCOC(CNCC1OCCO1)OC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(CN(CC1OCCO1)C(=O)CCl)OC

Procedure:
N-(2-Methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)amine (0.05 mole), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is cooled to a temperature of from 5° to 10° C and chloroacetyl chloride (0.05 mole) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture has reached room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2-methoxy-2-ethoxyethyl)-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[O:7][CH2:6]1)=[N+]=[N-]>CO.[Pd]>[O:7]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:14][C@@H:5]([CH2:4][NH2:1])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@H]1COc2cccnc2O1
Agent: [Pd]
Solvent: CO
Product: NC[C@H]1COc2cccnc2O1
Yield: 100.2 %

Procedure:
Dissolve (3S)-3-(azidomethyl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (7.5 g, 39.03 mmol) in MeOH (390 mL). Degas the mixture by subjecting it to reduced pressure then back filling with nitrogen (3×); add 10% Pd/C (2.08 g, 1.95 mmol); and again degas the mixture. Stir the resulting degassed mixture at ambient temperature under a hydrogen atmosphere for 17 hours. Filter the resulting mixture through Celite® and remove solvents of the filtrate under reduced pressure to provide the title compound (6.5 g, 100%) as an oil. MS (m/z): 167 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].CC(C)=O>CO>[OH:4][CH2:3][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(CO)s1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Sodium borohydride (218 mg, 5.76 mmol) was added to a solution of commercially available 5-formyl-2-thiophenecarboxylic acid (599 mg, 3.84 mmol) in methanol (19 mL), and the mixture was stiffed under nitrogen atmosphere at room temperature for 4 hours and 30 minutes. Acetone was added to the reaction mixture, and the mixture was concentrated under vacuum. 2 M hydrochloric acid and ethyl acetate were added to the residue for partition, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum and the precipitate was washed with diethyl ether and n-hexane to obtain the title compound (529 mg, 87%).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:4]=1[C:5]#[N:6].Cl.N1C=CC=CC=1>>[F:11][C:7]1[C:4]([C:5]#[N:6])=[C:3]([OH:2])[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc(F)c1C#N
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1c(O)cccc1F
Yield: 66.4 %

Procedure:
7.8 g of 2-methoxy-6-fluorobenzonitrile and 18.0 g of pyridine hydrochloride were heated for 5 hours at 195° C. under dry nitrogen. After cooling, the batch was partitioned between 50 ml of water and 50 ml of tert-butyl methyl ether, and the organic phase was subsequently extracted with 40 ml of 2N NaOH. The alkali extract was brought to pH 5 and subsequently extracted twice with in each case 40 ml of tert-butyl methyl ether. After the solvent had been evaporated, 4.7 g of the desired product were obtained as an oil (HPLC: 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[NH:15][C:14]3=[O:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16](=[O:24])[N:15]([CH3:28])[C:14]3=[O:25])=[CH:11][CH:12]=2)=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1NC(=O)N(c2ccc(Oc3ccc(Cl)cc3)cc2)[C@H]1c1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)[C@H](c2ccccc2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-chloro-phenoxy)-phenyl]-5-(S)-phenyl-imidazolidine-2,4-dione (10.0 mg, 0.026 mmol) in anhydrous DMF (0.5 mL) are added K2CO3 (7.3 mg, 0.052 mmol) and MeI (4.93 μL, 0.078 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is purified by preparative LC/MC to provide the title compound; 1H NMR (CDCl3, 400 MHz) δ 7.42-7.31 (m, 7H), 7.26 (d, 2H), 6.90 (m, 4H), 5.42 (s, 1H), 3.16 (s, 3H); HPLC-MS calculated for C22H17ClN2O3 (M+H+) 393.1, found 393.1.