Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:11][C:10]([C:14]([F:17])([F:15])[F:16])=[N:9]1
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1cc(C(F)(F)F)nn1-c1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (0.26 g, 1 mmol), methyl bromoacetate (0.195 mL, 2 mmol) and K2CO3 (276 mg, 2 mmol) in acetonitrile (2 mL) was shaken overnight at 85° C. After cooling, solid was removed by filtration and washed with acetonitrile. The filtrate was evaporated to give a crude, which was purified by chromatography on silica gel eluting with EtOAc-Hexane (1:4) to give methyl {[1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy}acetate (180 mg). 1H-NMR (CDCl3): δ 7.52 (2H, m), 7.42 (2H, m), 5.91 (1H, s), 4.67 (2H, s), 3.80 (3H, s). MS (ES): 335 [M+H]+
Reaction SMILES: [Br-].[OH:2][CH2:3][CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40]([CH:45]=O)[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]>C1COCC1.CCCCCC>[C:30]([O:33][CH2:34][C@@H:35]1[C@:43]2([CH3:44])[C@@:38]([OH:47])([CH2:39][C@@H:40](/[CH:45]=[CH:5]/[CH2:4][CH2:3][OH:2])[CH2:41][CH2:42]2)[CH2:37][CH2:36]1)(=[O:32])[CH3:31]
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](C=O)CC[C@]12C
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1CC[C@]2(O)C[C@@H](/C=C/CCO)CC[C@]12C
Temperature: -25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a suspension of 23.0 g of (3-hydroxypropyl)triphenylphosphonium bromide in 280 ml of anhydrous THF cooled at -25° C., 36.0 ml of 1.6N n-butyllithium in n-hexane were added dropwise under a nitrogen atmosphere and the mixture was stirred at -25° C. for 1 hr. A solution of 3.20 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-3a-hydroxy-5-formyl-7a-methylperhydroindene in 32 ml of anhydrous THF was added and the reaction mixture was kept at -20° C. for 4 hrs, then warmed to room temperature and stirred for 3 hrs. The mixture was diluted with 5% aqueous NaH2PO4.H2 O, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was purified by flash-chromatography (SiO2) with n-hexane/chloroform/acetone 6:2:2 to give 2.23 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-hydroxy-1-butenyl)-7a-methylperhydro-inden-3a-ol from which, by reaction with tert-butyldimethyl-chlorosilane, following the procedure, described in Prepn. 1, 2.94 g of (1S,3aS,5S,7aR)-1-acetoxymethyl-5-[(E)-4-tert-butyldimethylsilyl-oxy-1-butenyl)-7a-methylperhydroinden-3a-ol were obtained as a white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:26](CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(OCC)(=O)C.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([NH2:26])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1-tert-Butoxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (1.22 g, 4 mmol) was combined with dichloromethane (40 mL). N,N-diisopropylethylamine (0.77 mL, 4.4 mmol, 1.1 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.8435 g, 4.4 mmol, 1.1 eq.), and 1-hydroxybenzotriazole hydrate (HOBT) (0.5946 g, 4.4 mmol, 1.1 eq.) were added. The mixture was allowed to stir at ambient temperature for 15 h. The solution was sparged with NH3 (gas) for 0.5 h and then allowed to stir at ambient temperature for 15 h. The mixture was filtered and the filtrate was concentrated in vacuo to give a residue. The residue was dissolved in ethyl acetate and extracted with saturated NaHCO3 (6X). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give a residue. The residue was recrystallized from diethyl ether to give the title compound:
Reaction SMILES: [N+:1]([C:4]1[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=1)=[N:8][C:7](=[O:13])[CH:6]=2)([O-])=O>C(O)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2
Reactant: O=C1C=c2c([N+](=O)[O-])cccc2=N1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cccc2c1CC(=O)N2

Procedure:
4.43 g (18.45 mmol) of methyl-(2,6-dinitrophenyl)-acetate is added in 38.8 ml of glacial acetic acid and 11 ml of water and mixed with 3.75 g of iron powder and stirred for four more hours. In this case, heating to 40 to 60° C. takes place. The reaction mixture is added to ice water, mixed with ethyl acetate and vigorously stirred for ten minutes. The mixture is filtered through a glass-fiber filter, the organic phase is separated, and the aqueous phase is extracted twice more with ethyl acetate. The combined organic extracts are washed with brine, dried, and the solvent is spun off after the desiccant is filtered off. The residue is chromatographed on silica gel (mobile solvent methanol/dichloromethane). 2.38 g of 4-nitro-indol-2-one is isolated. The nitro compound is mixed again in glacial acetic acid/water with 2.7 g of iron powder, and the above-described cycle is passed through another time. 1.63 g of the desired amine is isolated.
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].[NH:18]1[CH:22]=[CH:21][N:20]=[CH:19]1.C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>C(#N)C.CC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH:2]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6])=[CH:12][CH:13]=1
Reactant: c1c[nH]cn1
Reactant: C=CC(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Solvent: CC#N
Product: C=CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 33.5 %

Procedure:
23 g of crude 5-bromo-5-(4-chlorophenoxy)-3,3-dimethylpent-1-en-4-one, dissolved in 30 ml of acetonitrile, were added dropwise to a solution of 28.6 g (0.42 mol) of imidazole in 250 ml of acetonitrile, in the course of 5 minutes. The mixture was then heated to the boil for a further 3 hours and the solution was concentrated under reduced pressure. The oily residue was taken up in 200 ml of ethyl acetate and the mixture was washed with three times 50 ml of water. After the organic phase had been dried over anhydrous sodium sulphate, it was concentrated by evaporation, the residue was taken up in 200 ml of acetone and a filtered solution of 20.2 g (0.07 mol) of naphthalene-1,5-disulphonic acid in 100 ml of acetone was added. The precipitated salt was filtered off under suction, 100 ml of water and 100 ml of dichloromethane were added to it, and the mixture was then rendered alkaline with 10% strength sodium carbonate solution. The organic phase was separated off and concentrated. The oily residue crystallized on trituration with ether/petroleum ether. 7.4 g (34.7% of theory) of 5-(4-chlorophenoxy)-3,3-dimethyl-5-(imidazol-1-yl)-pent-1-en-4-one of melting point 72° to 74° C. were obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[CH:6][CH:5]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:18]2[C:19]3[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][C:7]4[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=4)=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CCOc2ccc3[nH]ccc3c2)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(CCOc2ccc3c(ccn3Cc3ccc(F)cc3)c2)cc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To 0.2 g of a 60% dispersion of NaH in mineral oil, suspended in 20 ml of anhydrous THF, was added 0.61 g (2.38 mmol) 5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole from Step 1. The slurry was stirred for 15 min upon which time 0.33 ml (2.6 mmol) 4-fluorobenzylbromide was added. The slurry was stirred overnight. The slurry was concentrated under vacuum and the residue was redissolved in ethyl acetate and washed with brine. The organic phase was dried over MgSO4 and concentrated. The residue was chromatographed on silica to afford 0.61 g 1-(4-fluoro-benzyl)-5-[2-(4-fluoro-phenyl)-ethoxy]-1H-indole as a fluffy powder.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[C:30]1(=[O:40])[C:39]2[C:34](=[CH:35][CH:36]=[N:37][CH:38]=2)[CH:33]=[CH:32][NH:31]1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([N:31]3[CH:32]=[CH:33][C:34]4[C:39](=[CH:38][N:37]=[CH:36][CH:35]=4)[C:30]3=[O:40])[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=c1[nH]ccc2ccncc12
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-n3ccc4ccncc4c3=O)sc2c1-c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
To a solution of (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (36.7 mg, 0.076 mmol) and 2,7-naphthyridin-1(2H)-one (14.0 mg, 0.092 mmol) in DMF (0.9 mL) was added CuI (9.0 mg, 0.046 mmol) and trans-N1,N2-dimethylcyclohexane-1,2-diamine (15 μL, 0.092 mmol) and K2CO3 (21.0 mg, 0.152 mmol). The reaction was heated at 110° C. for 2 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with H2O, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C30H29ClN3O4S: 562.2; found: 562.3.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH2:10][C:11]#[N:12])[CH:3]=1.ClC(Cl)C(O)=O.[BrH:19]>>[Br:19][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Br:1])=[CH:9][CH:8]=2)[CH:10]=[C:11]([NH2:12])[N:7]=1
Reactant: N#CCc1cc(Br)ccc1C#N
Reactant: Br
Agent: O=C(O)C(Cl)Cl
Product: Nc1cc2cc(Br)ccc2c(Br)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-Bromo-2-(cyanomethyl)benzonitrile (75 g, 339 mmol) was added to 2,2-dichloroacetic acid (150 mL, 339 mmol). The resulting solution was cooled to 0° C. in an ice-water bath. HBr (27.5 g, 339 mmol) was bubbled through the cold solution until a yellow precipitate crashed out of solution, resulting in a yellow slurry. HBr was bubbled through the slurry for an additional 5 minutes. The solution was allowed to warm to room temperature over 1 hour. The slurry was then cooled to 0° C. in an ice-water bath and diethyl ether (200 mL) was added. The mixture was stirred for 20 minutes at 5° C. The product was recovered as a yellow solid by filtration (42 g, 41%). LCMS (API-ES) m/z: 303 (M+H+).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[F:2].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([O-:8])=[O:7]>C(O)C>[F:2][CH2:1][CH:3]([OH:5])[CH2:4][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:14][CH:13]=2)[CH2:16][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: FCC1CO1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCN(CC(O)CF)CC2)cc1
Yield: 43.9 %

Procedure:
Ethanol (15 mL) solution of 272 mg of epifluorohydrin and 500 mg of 1-(4-nitrophenyl)piperazine was heated under reflux for 15 hours, and then the reaction liquid was concentrated under reduced pressure. The residue was solidified from ethyl acetate to obtain 300 mg of the entitled compound as a yellow solid.
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:14]=1)[CH:10]=O.C([O-])(O)=O.[Na+]>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:2])[CH:12]=[C:13]([O:15][CH2:16][O:17][CH3:18])[CH:14]=1
Reactant: COCOc1cc(Br)cc(C=O)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1cc(Br)cc(OCOC)c1
Temperature: 0 °C
Yield: 76 %

Procedure:
A solution of n-BuLi (5.65 mL of a 1.6 M solution in Et2O, 9.04 mmol) was added dropwise to a solution of methyltriphenylphosphonium bromide (3.23 g, 9.05 mmol) in THF (15 mL) that was cooled to 0° C. The resulting yellow solution was stirred for 30 m, cooled to −78° C., and a solution of 3-bromo-5-methoxymethoxy-benzaldehyde (1.58 g, 6.46 mmol) in anhydrous THF (15 mL) was added dropwise. The mixture was slowly warmed to RT, stirred for 16 h, and then added to a saturated aqueous solution of NaHCO3 (60 mL). The layers were separated, and the aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were washed with brine (30 mL), and dried with anhydrous MgSO4. The volatile materials were evaporated, and the remaining oil was purified by flash chromatography on silica gel (0% to 3% EtOAc/hexanes) to provide 600 mg (76%) of 1-bromo-3-methoxymethoxy-5-vinyl-benzene (113c).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([CH3:16])[O:7][CH2:6][N:5]1[C:17]([CH3:27])([CH3:26])[C:18]([CH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[CH2:25])=[O:19].IC.[C:30](OCC)(=O)C>O>[CH2:16]([C:8]1[O:7][CH2:6][N:5]([C:17]([CH3:27])([CH3:26])[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][C:21]2=[CH2:25])=[O:19])[C:4](=[O:3])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:30]
Reactant: CCOC(C)=O
Reactant: C=C1CCCC1C(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: C=C1CCCC1C(=O)C(C)(C)N1COC(CC)=C(c2ccccc2)C1=O
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.06 g) was added to a stirred solution of 2-(2,3-dihydro-4-oxo-6-methyl-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-one (0.45 g) at 20° C. After 10 minutes, iodomethane (0.1 ml) was added and stirring continued for 3 hours. Ethyl acetate and water were added and the organic phase dried (magnesium sulphate), evaporated and purified by silica gel column chromatography eluting with n-hexane/ethyl acetate (3:1) to give 2-(2,3-dihydro-6-ethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-one (Compound 1075, 0.15 g), NMR: 1.09(t,3H), 1.49(s,3H), 1.55(s,3H), 1.80-2.00(3H), 2.21(q,2H), 2.25-2.50(3H), 3.89(1H), 4.86(s,1H), 4.98(s,1H), 5.26(d,1H), 5.32(d,1H), 7.20-7.38(5H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH:18]([C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[O:16])=[C:11]([F:31])[CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].[C].C(OCC)(=O)C>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([O:17][CH:18]([C:27]([F:28])([F:29])[F:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH3:26])=[O:16])=[C:11]([F:31])[CH:10]=1
Reactant: CCOCCCCCC(OC(=O)c1ccc(OCc2ccccc2)cc1F)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F

Procedure:
An autoclave was charged with 1 g of 4-benzyloxy-2-fluoro-1-(6-ethoxy-1-trifluoromethylhexyloxycarbonyl)-benzene, 15 ml of ethyl acetate and 0.5 g of a 15 wt % Pd/carbon catalyst, the atmosphere in the autoclave was replaced with nitrogen and then with hydrogen, and the mixture was continuously stirred at room temperature until the hydrogen absorption terminated. After the reaction, the catalyst was filtered off. The ethyl acetate was distilled off to give a crude 4-hydroxy-2-fluoro-1-(6-ethoxy-1-trifluoromethyl-hexyloxycarbonyl)benzene.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].CCN(C(C)C)C(C)C.[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:6]=1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])=[O:36]
Reactant: COc1ccc(-c2csc(N)c2C(=O)OC(C)(C)C)cn1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2csc(NC(=O)c3cccc(F)c3)c2C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 16 (31 mg 0.1 mmol) in DCM (5 ml) was added DIEA (0.052 ml, 0.3 mmole), 3-fluorobenzoyl chloride (0.018 ml, 0.15 mmol) and catalytic amount of DMAP. The mixture was stirred at rt for 17 hrs, diluted with DCM (15 ml), washed with water, saturated sodium bicarbonate (aq.), water, 10% citric acid (aq.) and brine, dried over anhydrous sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under vacuum. The crude product was used in the next step without further purification. LC-MS for C22H21FN2O4S: 428; found: 429.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][CH:39]1[O:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>>[CH3:45][C@H:43]1[O:44][C@@H:39]([CH3:38])[CH2:40][N:41]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42]1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC1CNCC(C)O1
Product: C[C@@H]1CN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)C[C@H](C)O1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2,6-dimethylmorpholine according to conditions described in general procedure C. Mp: 118-120° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.01-1.02 (m, 6 H), 2.39 (t, J=11.7 Hz, 2 H), 3.25-3.30 (m, 4 H), 3.75-3.77 (m, 4H), 4.20 (bs, 2 H), 6.18-6.20 (m, 1 H), 7.02-7.06 (m, 1 H), 7.25-7.27 (m, 1 H), 7.42-7.44 (m, 1 H), 7.49 (s, 1 H), 7.57-7.62 (m, 3 H), 7.82-7.84 (m, 1 H), 8.00 (d, J=8.0 Hz, 1 H), 8.26-8.28 (m, 1 H), 10.47 (s, 1 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O=S(Cl)Cl.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCOCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of tetrahydropyran-4-yl-carboxylic acid (910 mg, 6.99 mmol) and SOCl2 (5.0 mL) was stirred for 1 h at 60° C. and concentrated in vacuo. To the residue were added benzyl alcohol (1.52 g, 14.1 mmol) and tetrahydrofuran (5.0 mL) at ambient temperature. The resulting mixture was stirred for 13 h at ambient temperature and concentrated in vacuo. The residue was purified by preparative thin layer chromatography (silica gel, eluting with hexane/ethyl acetate (2:1)) to give 1.08 g (70%) of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[C:9]([Si](C)(C)C)[NH:8][C:5]2=[N:6][CH:7]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c([Si](C)(C)C)[nH]c2ncc(Br)cc12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c[nH]c2ncc(Br)cc12
Yield: 53.2 %

Procedure:
To a solution of 5-bromo-3-methyl-2-(trimethylsilyl)-1H-pyrrolo[2,3-b]pyridin (B-5-3) (5 g, 17.8 mmol) in THF (50 mL) was added 2 N HCl (20 mL). The mixture was stirred at reflux overnight. HPLC showed the reaction was complete. After the mixture was concentrated under reduced pressure, the residue was dissolved in aqueous NaHCO3 (20 mL) and extracted with EtOAc (10 mL×3). The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4 and concentrated to give crude product, which was purified via prep. HPLC to give 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (B-5-4) (2 g, 53.2%) as a pale solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:27][C:28]([C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)([F:30])[CH3:29]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:34]3[CH:35]=[CH:36][C:31]([C:28]([F:30])([F:27])[CH3:29])=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC(F)(F)c1ccc(I)cc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(C)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 1-(1,1-difluoroethyl)-4-iodobenzene.
Reaction SMILES: Cl.[Br:2][C:3]1[N:8]=[C:7]([CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:18]([CH2:20][C:21](O)=[O:22])#[N:19].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C>[Br:2][C:3]1[N:8]=[C:7]([CH2:9][NH:10][C:21](=[O:22])[CH2:20][C:18]#[N:19])[CH:6]=[CH:5][CH:4]=1
Reactant: NCc1cccc(Br)n1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CCC(=O)NCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
6-Bromo-2-pyridinemethanamine hydrochloride (0.25 g, 1.12 mmol) was taken up in DMF (8.4 mL) and triethylamine (0.31 mL, 2.24 mmol) was added. After five minutes, cyanoacetic acid (0.095 g, 1.12 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.12 mmol), 1-hydroxybenzotriazole hydrate (0.18 g, 1.14 mmol) were added and the reaction was maintained at room temperature overnight. Upon completion the mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography to yield the title compound.