Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])=[C:7]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:32]=[C:31]([C:33]#[N:34])[CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>CN(C)C=O>[C:33]([C:31]1[N:32]=[C:27]([CH2:26][CH:17]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=2[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:28]=[CH:29][CH:30]=1)#[N:34]
Reactant: COc1ccc(CC(=O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Reactant: N#Cc1cccc(CCl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(C(Cc2cccc(C#N)n2)C(=O)C(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
Under an argon atmosphere, to a solution of tert-butyl [5-methoxy-2-(3-methyl-2-oxobutyl)phenyl]carbamate (337 mg) in N,N-dimethylformamide (4 mL) was added sodium hydride (50-72% in oil, 56 mg) under ice-cooling, and the mixture was stirred for 30 minutes. 6-(Chloromethyl)pyridine-2-carbonitrile (167 mg) was added thereto, followed by stirring for 1 hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (271 mg). 1H-NMR (CDCl3) δ ppm: 0.91 (3H, d, J=6.5 Hz), 1.07 (3H, d, J=7.3 Hz), 1.57 (9H, s), 2.56-2.72 (1H, m), 3.18 (1H, dd, J=8.2, 15.9 Hz), 3.61 (1H, dd, J=6.8, 15.9 Hz), 3.77 (3H, s), 4.65-4.74 (1H, m), 6.58 (1H, dd, J=2.8, 8.7 Hz), 6.92 (1H, d, J=8.7 Hz), 7.22-7.29 (1H, m), 7.35 (1H, d, J=2.8 Hz), 7.46-7.60 (2H, m), 7.65 (1H, t, J=7.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[NH2-:13].[Na+]>CN(C)C1C=CC=CC=1>[NH2:13][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH:7]=[CH:8][N:9]=1
Reactant: [NH2-]
Reactant: COc1ccc2ccncc2c1
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: COc1ccc2ccnc(N)c2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
A solution of 8.0 g of 7-methoxyisoquinoline in 45 ml of N,N-dimethylaniline was warmed at 60° C., and then 5.9 g of sodium amide was added. The reaction mixture was heated at 130° C. over a period of 2 hours, and stirred for further 1 hour under the same conditions. After being cooled, the reaction mixture was poured into ice water and extracted with chloroform. The extract was washed with water, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from benzene to give 5.7 g of the title compound as colorless flakes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]#[N:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Ni]>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: N#CC1CN(Cc2ccccc2)CCO1
Agent: [Ni]
Solvent: CO
Product: NCC1CN(Cc2ccccc2)CCO1
Reaction time: 12 h
Yield: 72.7 %

Procedure:
4-benzylmorpholine-2-carbonitrile 2c (0.80 g, 4 mmol) was dissolved in 30 mL of methanol followed by the addition of Raney nickel (0.50 g), filled with hydrogen two times and the resulting solution was stirred for 12 hours, filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (4-benzylmorpholin-2-yl)methanamine 2d (0.60 g) as a colorless oil liquid, which was used in the next step without further furification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[N:7][CH:8]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C(N(CC)CC)C>C1COCC1>[F:9][C:6]1[N:7]=[CH:8][C:3]([CH2:2][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(CBr)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc(CN2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.4 %

Procedure:
A solution of 5-(bromomethyl)-2-fluoropyridine (26.000 g, 137 mmol) in THF (30 mL) was cooled to −30° C. and morpholine (17.88 mL, 205 mmol) was slowly added. After 5 min, triethylamine (57.2 mL, 410 mmol) was slowly added. Following addition, the cooling bath was removed and the mixture was allowed to warm to ambient temperature. After 30 min, the mixture was filtered through a fine-fritted funnel and the filtrate was concentrated to give an orange oil. The crude material was purified by chromatography through a Thompson Instruments pre-packed silica gel (330 gram) column eluting with a gradient of 0% to 100% EtOAc in hexane over 50 min to give 4-((6-fluoropyridin-3-yl)methyl)morpholine (15.767 g, 80 mmol, 58.7% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H); 7.79 (td, J=8.07, 2.45 Hz, 1H); 6.90 (dd, J=8.31, 2.84 Hz, 1H); 3.67-3.72 (m, 4H); 3.49 (s, 2H); 2.39-2.48 (m, 4H). m/z (ESI, +ve ion) 197.1 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>[N+]([O-])(O)=O.O>[CH2:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:1]1
Reactant: C1CCCCC1
Solvent: O=[N+]([O-])O
Solvent: O
Product: C1CCCCCCCCCCC1
Reaction time: 0.5 h

Procedure:
For the dialysis cell experiments, the Nafion* membrane was routinely prepared by boiling for 0.5 hr. in 10% nitric acid, then boiling briefly in distilled water. For the flow reactor, the membrane tubing was initially prepared by flushing both "tubes" with 10% nitric acid at 60°. Thereafter the reactor was flushed with feed (e.g. cyclohexane) and water (in the appropriate "tubes") at the conclusion of each reaction. For the reactions utilizing cyclohexane, flow in both "tubes" was provided by a calibrated syringe pump. For the reactions with cyclododecane, hydrocarbon flow was provided by pressuring a heated metal cylinder containing the molten ketone-hydrocarbon mixture to 5-10 psi with dry nitrogen, and allowing the mixture to exit through a dip tube and metering valve.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([OH:13])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:14][C:15](O)=[O:16]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([O:13][C:15](=[O:16])[CH3:14])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)CC(O)CC2
Agent: O=S(=O)(O)O
Product: COc1ccc2c(c1)CC(OC(C)=O)CC2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
7-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-ol (4.48 g, from step A) is taken up in AcOH (15 mL) and cooled to 0° C. Concentrated sulfuric acid (10 drops) is added. The mixture is stirred at 0° C. for 20 min and then warmed to room temperature over 10 min. The mixture is partitioned between ice-cold 1 N NaOH and EtOAc. The organic layer is dried over MgSO4 and concentrated to afford acetic acid 7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl ester as a red solid: 1H NMR (CDCl3) δ 7.01 (d, J=8.0 Hz, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.60 (s, 1H), 5.19 (m, 1H), 3.77 (s, 3H), 3.08 (dd, J=16.0, 8.0 Hz, 1H), 2.90-2.70 (m, 3H), 2.05 (s, 3H), 2.05-1.88 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:18])[CH2:15][O:16][CH3:17])[CH2:9][CH2:8]1)=[O:5].[CH2:24]([S:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:24]([S:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[O:33][C:2]1[N:22]=[CH:21][C:20]([F:23])=[CH:19][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14](=[O:18])[CH2:15][O:16][CH3:17])[CH2:9][CH2:8]1)=[O:5])[CH3:25]
Reactant: CCSc1cccc(O)c1
Reactant: COCC(=O)N[C@H]1CC[C@@H](NC(=O)c2cc(F)cnc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)COC)CC2)c1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (110 mg, 0.32 mmol), 3-ethylsulfanyl-phenol (54 mg, 0.35 mmol) and caesium carbonate (156 mg, 0.48 mmol) were suspended in dimethylformamide (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1 ml) and water (1 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate (20 ml). The solvent was removed under reduced pressure and the residue was triturated with diethylether (5 ml) to give 2-(3-ethylsulfanyl-phenoxy)-5-fluoro-N-[cis-4-(2-methoxy-acetylamino)-cyclohexyl]-nicotinamide (57 mg) as an off-white solid.
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@H:34]([OH:50])[CH2:35][O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45])=[CH:28][CH:27]=3)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.Cl.O>CO>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][C@H:34]([OH:50])[CH2:35][O:36][CH2:37][CH2:38][S:39][CH2:40][CH2:41][CH2:42][C:43]([F:49])([F:48])[C:44]([F:45])([F:46])[F:47])=[CH:30][CH:31]=3)[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2c2ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1c1ccc(OC[C@H](O)COCCSCCCC(F)(F)C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
To a solution of 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-(4-(3-(2-(4,4,5,5,5-pentafluoropentylthio)ethoxy)-(R)-2-hydroxypropyloxy)phenyl)chroman (440 mg, 0.613 mmol) in methanol (9 ml) was added 6N HCl (3 ml) at room temperature, which was stirred for 40 minutes at 70° C. Water was added thereto, and the resulting solution was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=3:2) to give the title compound (269 mg, yield 68%) as a white solid.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:34])=[CH:11][C:12]([O:32][CH3:33])=[CH:13][C:14]=3[C:15]32[CH2:22][CH2:21][S:20][C:19]([NH:23]C(=O)C2C=CC=CC=2)=[N:18]3)=[CH:6][CH:5]=1>CO.O>[Br:3][C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[C:10]([F:34])=[CH:11][C:12]([O:32][CH3:33])=[CH:13][C:14]=3[C:15]32[CH2:22][CH2:21][S:20][C:19]([NH2:23])=[N:18]3)=[CH:6][CH:5]=1
Reactant: COc1cc(F)c2c(c1)C1(CCSC(NC(=O)c3ccccc3)=N1)c1cc(Br)ccc1O2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(F)c2c(c1)C1(CCSC(N)=N1)c1cc(Br)ccc1O2
Temperature: 65 °C

Procedure:
A 2 N solution of lithium hydroxide (22.50 ml, 45.0 mmol) was added to a solution of N-(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)benzamide (7.7 g, 15.00 mmol) in MeOH (250 ml). The reaction mixture was heated to 65° C. for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was purified via column chromatography [0-70% 90/10/1 (DCM/MeOH/ammonia) in DCM] to afford 7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine as a racemic mixture (2 g, 2.443 mmol, 32% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20](O)=[O:21])[CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.C(OC(=O)[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])(C)(C)C.C(Cl)CCl>CN(C=O)C>[NH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([C:15]2[CH:14]=[CH:13][N:12]=[C:11]([NH:10][CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:16]=2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=C(O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: NCCCNC(=O)c1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 9 (1 mmol) was coupled with (3-Amino-propyl)-carbamic acid tert-butyl ester (3 mmol) using EDC (2 mmol) in DMF (10 mL). The DMF was removed by rotary evaporation and the residue purified by flash chromatography on silica gel (ethyl acetate as eluent.) The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 392. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.68 (s, 1H) 8.35-8.5 (m, 3H) 8.1 (d, 1H) 7.7 (m, 1H) 7.48 (d, 1H) 7.2 (d, 2H) 6.68 (d, 2H) 3.8 (m, 2H) 3.55 (m, 2H) 3.05 (m, 2H) 2.9 (m, 4H) 2.0 (t, 2H).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>>[CH3:24][C:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])([CH3:5])[C:3]([OH:25])=[O:2]
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Reactant: ClCc1ccc2ccccc2n1
Product: Cc1cc(CCCC2CN(Cc3ccc4ccccc4n3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.100 g, 0.287 mmole) and 2-chloromethyl-quinoline (0.092 g, 0.431 mmole) to produce an oil (0.023 g, 17%). Mass [EI+] 476 (M+H)+, [EI−] 474 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32]CC1C=NC(OC)=CC=1)[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH:17]=3)=[CH:15][C:10]=2[N:9]=[CH:8]1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:32][C:31]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]4)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)ccc43)cc2OC)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(Cn2cnc3cc(C4CCN(C(=O)OC(C)(C)C)CC4)ccc32)ccc1O
Temperature: 60 °C
Reaction time: 16 h
Yield: 96 %

Procedure:
To a stirred solution of tert-butyl 4-(1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazol-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.56 g, 1.00 mmol) in methanol (15 mL) was added ammonium formate (0.63 g, 10 mmol) and palladium on carbon (0.30 g). The reaction mixture was heated to 60° C. under H2. After 16 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated. The residue was purified by silica gel chromatography (5% methanol/dichloromethane elute) to afford 0.42 g (96%) of tert-butyl 4-(1-(4-hydroxy-3-methoxybenzyl)-1H-benzo[d]imidazol-5-yl)piperidine-1-carboxylate as a light yellow solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:24])([CH3:23])[C:5](=[O:22])[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13]C(=O)C(F)(F)F)=[CH:10][CH:9]=1>CO>[CH3:3][C:4]([CH3:24])([CH3:23])[C:5](=[O:22])[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)COc1ccc(CNC(=O)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C(=O)COc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Add 5N aqueous NaOH (15 mL) to a solution of N-[4-(3,3-dimethyl-2-oxo-butoxy)-benzyl]-2,2,2-trifluoro-acetamide (552 mg, 1.74 mmol) in methanol (0 mL) and stir for 2 h at ambient temperature. Extract the mixture with DCM three times. Dry the combined organic extracts over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (92:8) to give the title compound as a colorless oil (337 mg, 87%). MS (ES+) m/z: 205 M+H−NH3)+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[CH2:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][NH2:36])=[N:27]1)[CH3:25].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH2:35][NH:36][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[N:27]1)[CH3:25]
Reactant: CCn1nc(CN)c2ccccc21
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCn1nc(CNc2ccc(OCc3ccc4ccccc4n3)cc2[N+](=O)[O-])c2ccccc21
Temperature: 80 °C

Procedure:
To a 10 mL round-bottomed flask were added 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (50 mg, 0.17 mmol) and acetonitrile (0.84 mL). To the resulting mixture were added 1-(1-ethyl-1H-indazol-3-yl)methanamine HCl salt (37.4 mg, 0.17 mmol) and K2CO3 (81 mg, 0.59 mmol). The resulting mixture was heated to 80° C. for 3 days. The mixture was cooled to RT and concentrated to dryness. The residue was purified by FCC to give the title compound. MS (ESI): mass calcd. for C26H23N5O3, 453.18; m/z found, 454.2 [M+H]+.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]1[N:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: CCOc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 14.1 %

Procedure:
A mixture of methyl thiosalicylate (0.17 g, 1.0 mmol), 2-cyano-6-ethoxypyridine (0.15 g, 1.0 mmol), triethylamine (0.21 ml, 1.5 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure. The residue was subjected to a column chromatography and eluted with hexane-ethyl acetate (3:1, v/v). The obtained crystals were recrystallized from ethyl acetate-hexane to give the titled compound (0.04 g, 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[CH:5][CH:4]=1.[I:15]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:15][C:14]1[CH:13]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1
Reactant: COc1ccc(Cc2nc[nH]n2)cc1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1ccc(Cc2nc[nH]n2)cc1I
Reaction time: 72 h

Procedure:
To a solution of 3-(4-methoxybenzyl)-1H-1,2,4-triazole (335 mg, 1.770 mmol) in MeOH (5 ml) under nitrogen at RT was added silver sulfate (552 mg, 1.770 mmol) followed by iodine (449 mg, 1.770 mmol). Added a second equivalent of silver sulfate and stirred for 3 days. The reaction did not go to completion. The solids were filtered washing with MeOH, the filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel, eluting with MeOH in DCM to afford the title compound contaminated with ca. 20% of starting material. Mass spectrum (ESI) 316.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:29][C:28]4[CH2:27][NH:26][CH2:25][C:24]=4[CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>>[CH:8]1([CH2:11][CH2:12][NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([N:22]3[CH2:29][C:28]4[CH2:27][N:26]([C:34](=[O:35])[C:33]5[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=5[C:31]([F:30])([F:41])[F:42])[CH2:25][C:24]=4[CH2:23]3)=[N:20][CH:21]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: O=C(NCCC1CC1)c1cnc(N2CC3=C(CNC3)C2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC1CC1)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 23 %

Procedure:
N-(2-cyclopropylethyl)-2-(3,4,5,6-Tetrahydro-1H-pyrrolo-[3,4-c]pyrrol-2-yl)pyrimidine-5-carboxamide; compound with trifluoroacetic acid (300 mg, 0.726 mmol) was reacted with 2-trifluoromethylbenzoyl chloride analogously to example 3F. Yield: 23%, M+H+: 472.16.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([CH3:19])[CH:15]=2)=[CH:6][CH:5]=1)(=[S:3])[NH2:2].Cl[CH2:23][CH:24]=O>C(O)C>[CH3:19][C:16]1[CH:15]=[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([C:1]3[S:3][CH:23]=[CH:24][N:2]=3)=[CH:21][CH:20]=2)[O:18][N:17]=1
Reactant: O=CCCl
Reactant: Cc1cc(CCCCCOc2ccc(C(N)=S)cc2)on1
Solvent: CCO
Product: Cc1cc(CCCCCOc2ccc(-c3nccs3)cc2)on1
Yield: 55.6 %

Procedure:
A suspension of 7.5 g 5-[5(4-thiocarbamylphenoxy)pentyl]-3-methylisoxazole and 24.6 g chloroacetaldehyde (50% in water) in 150 ml absolute ethanol was refluxed for 3.5 hours. The reaction mixture was concentrated in vacuo and the residue recrystallized from ethyl acetate-hexane to give 4.5 g 3-methyl-5-{5-[4-(2-thiazolyl)phenoxy]pentyl}isoxazole, m.p. 78-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.ClC(N(C)C)=C(C)C.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[N:36]1[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]1)=[CH:33][CH:32]=[CH:31][CH:30]=2.N1C=CC=CC=1>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:25][C:26]2[CH:27]=[N:28][C:29]3[C:34]([C:35]=2[N:36]2[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (28.5 mg, 0.118 mmol) in DCM (0.5 mL), a solution of 1-chloro-N,N,2-trimethylpropenylamine (45.0 mg, 0.337 mmol) in DCM (1.0 mL) was added slowly. The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (from step 2 in Example 1, 36.9 mg, 0.108 mmol) in DCM (2.0 mL) was added, followed by pyridine (93.2 mg, 1.18 mmol). The mixture was then stirred at room temperature for a further 2 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a pale yellow oil (57.4 mg, 94%). LCMS calc. for C29H30F2N5O3S (M+H)+: m/z=566.2. found 566.2.