Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:18]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:10]=1
Reactant: COc1ccc(-c2cnc3ccccc3c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: Oc1ccc(-c2cnc3ccccc3c2)cc1
Yield: 82 %

Procedure:
The compound is prepared by reaction of 3-(4-methoxyphenyl)quinoline with aluminum trichloride (564 mg, 4.23 mmol, 5 eq) according to method F. Purification by column chromatography with dichloromethane/methanol 99/1 as the eluent yields the desired product in a yield of 82%, 156 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.O1CCC[CH2:28]1>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH3:28])[N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CCOC1
Reactant: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2ccc(F)cc2)ccn1
Solvent: CN(C)C=O
Product: CN1N=C(n2cc(-c3ccnc(N)c3)c(-c3ccc(F)cc3)n2)CCC1=O
Yield: 38 %

Procedure:
The reaction was carried out in the same manner as in Example 33 except for using 100 mg (0.29 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,4,5,6-tetrahydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 50 in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole, and using 3 ml of N,N-dimethylformamide as a solvent in place of tetrahydrofuran to obtain 39.5 mg of the title compound as a white powder. (Yield: 38%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7](Br)[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1.[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1>C(#N)C.CC(C)=O>[C:26]1([S:40]([OH:43])(=[O:42])=[O:41])[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36]([OH:39])(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28][CH:27]=1.[CH2:1]([O:3][C:4](=[O:20])[C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[CH:7]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: CC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(C)(C)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 54.8 %

Procedure:
145 g (0.4 mol) of 4-bromo-4-(4-chlorophenoxy)-2,2-dimethyl-3-keto-butanoic acid ethyl ester were dissolved in 800 ml of acetonitrile. 100 g (1.45 mol) of imidazole were added and the mixture was heated for 20 hours under reflux. The solvent was then distilled off in vacuo, the residue was taken up in 500 ml of methylene chloride and the solution was washed three times with 200 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was dissolved in 800 ml of acetone and 100 g (0.35 mol) of 1,5-naphthalenedisulphonic acid in 300 ml of acetone were added. The resulting crystalline precipitate was filtered off and dried. 122.5 g (62% of theory) of 4-(4-chlorophenoxy)-2,2-dimethyl-4-(imidazol-1-yl)-3-keto-butanoic acid ethyl ester 1,5-naphthalenedisulphonate of melting point 194° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([C:14]([F:17])([F:16])[F:15])=[CH:6]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([C:14]([F:17])([F:16])[F:15])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(C(F)(F)F)cc2c1
Product: COc1ccc2c(Cl)nc(C(F)(F)F)cc2c1
Temperature: 0 °C
Yield: 86 %

Procedure:
A solution of 6-methoxy-3-(trifluoromethyl)isoquinolin-1-ol (271 mg, 1.114 mmol) in POCl3 (3 mL) was refluxed for 4 h. After concentration, the residue was taken into a mixture of 100 mL of DCM and 50 mL of water, cooled to 0° C., neutralized with 3 N NaOH, dried over MgSO4, concentrated and purified via silica gel chromatography (5-20% EtOAc:Hex) to give the pure product 1-chloro-6-methoxy-3-(trifluoromethyl)isoquinoline (250 mg, 0.956 mmol, 86% yield) as an orange solid. MS: MS m/z 262.1(M++1).
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH3:34][C:35]([CH3:42])=[CH:36][CH2:37][CH2:38][C:39](=O)[CH3:40]>>[CH3:40][C:39]([CH2:38][CH2:37][CH:36]=[C:35]([CH3:42])[CH3:34])=[CH:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCC=C(C)C
Agent: [Br-]
Agent: [Li]CCCC
Product: CC(C)=CCCC(C)=CCc1ccccc1
Yield: 17.4 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.48 g, 7.78 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.9 mL, 7.78 mmol, 1.0 equiv.) and 6-methylhept-5-en-2-one (1.48 g, 11.7 mmol, 1.5 equiv.), 0.29 g (17%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[S:27])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C(Nc1cc(F)cc(F)c1)c1ccccn1
Solvent: Cc1ccccc1
Product: Fc1cc(F)cc(NC(=S)c2ccccn2)c1
Yield: 92.3 %

Procedure:
N-(3,5-Difluorophenyl)-2-pyridinecarboxamide (7.00 g, 29.9 mmol) was treated with Lawesson's reagent (6.28 g, 15.5 mmol) in toluene (90 mL) at reflux temperature for 4 hours. The solvent was removed, and the residue was dissolved in dichloromethane, preadsorbed onto silica gel, and flash chromatographed (300 g of silica gel eluted with 10% ethyl acetate in petroleum ether). Recrystallization from a mixture of ethyl acetate and hexane afforded N-(3,5-difluorophenyl)-2-pyridinecarbothioamide (3.58 g, 48%) as a yellow solid, m.p. 140°-142° C. Overall yield 33%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([C:18]([F:21])([F:20])[F:19])=[CH:7][C:3]=1[C:4](O)=[O:5].CC1C=C(OC2C=CC=CC=2)C(Br)=CC=1C(OC)=O.FC(F)(F)C([O-])=O.[K+].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:61][C:62]([NH2:64])=[NH:63]>[I-].C[N+](C)(C)C.C1COCC1>[NH2:63][C:62]([NH2:64])=[N:61][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([C:18]([F:21])([F:20])[F:19])[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(Oc2ccccc2)c(C(F)(F)F)cc1C(=O)O
Reactant: N=C(N)N
Agent: COC(=O)c1cc(Br)c(Oc2ccccc2)cc1C
Agent: C[N+](C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccccc2)c(C(F)(F)F)cc1C(=O)N=C(N)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.5 g of 2-methyl-4-phenoxy5-trifluoromethylbenzoic acid [obtainable by reaction of methyl 2-methyl-4-phenoxy-5-bromobenzoate with potassium trifluoroacetate in the presence of Cul and tetramethylammonium iodide and subsequent hydrolysis] and 300 mg of carbonyldiimidazole in 15 ml of THF is stirred at room temperature for two hours and then added to 383 mg of guanidine. The mixture is stirred for a further two hours. After customary working up, N-diaminomethylene-2-methyl-4-phenoxy-5-trifluoromethylbenzamide is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH:22]1[C:27]([NH2:29])=[O:28].C(N(CC)CC)C>COCCO>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][NH:21][CH:22]([C:27]([NH2:29])=[O:28])[CH2:23]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(N(CCCCCl)c2ccc(F)cc2)cc1
Reactant: NC(=O)C1CNCCN1
Solvent: COCCO
Solvent: CCN(CC)CC
Product: NC(=O)C1CN(CCCCN(c2ccc(F)cc2)c2ccc(F)cc2)CCN1
Temperature: 70 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 17.7 parts of N-(4-chlorobutyl)-4-fluoro-N-(4-fluorophenyl)benzenamine, 23.3 parts of 2-piperazinecarboxamide, 17.6 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 48 hours at 70° C. The reaction mixture was evaporated and the residue was taken up in water and a small amount of methanol. The product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fraction was collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and acetonitrile (80:20 by volume). The product was filtered off and dried, yielding 12.82 parts (55.0%) of 4-[4-[bis(4-fluorophenyl)amino]butyl]-2-piperazinecarboxamide; mp. 67.4° C. (int. 28).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[C:20]([O:25]C)=[N:21][CH:22]=[CH:23][N:24]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[I-].[Na+].Cl[Si](C)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[O:1]1[C:5]2[C:6]([CH2:10][CH2:11][CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][C:19]4[C:20](=[O:25])[NH:21][CH:22]=[CH:23][N:24]=4)[CH2:14][CH2:13]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COc1nccnc1CN1CCC(CCc2cccc3ccoc23)CC1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1[nH]ccnc1CN1CCC(CCc2cccc3ccoc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
After dissolving 218 mg of 3-[4-[2-(benzofuran-7-yl)ethyl]piperidino]methyl-2-methoxypyrazine in 20 ml of acetonitrile, 914 mg of sodium iodide and 0.39 ml of chlorotrimethylsilane were added while stirring on ice, and the stirring was continued for 30 minutes. After further stirring for 1 hour at room temperature, ice water and aqueous sodium carbonate solution were added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water, aqueous sodium thiosulfate solution and saturated brine in that order and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (70 mg, 34% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]([O:17][CH3:18])=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[C:5]([N+:19]([O-:21])=[O:20])[CH:4]=1.[CH3:22][O:23][SiH:24]([O:27][CH3:28])[O:25][CH3:26]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:22][O:23][Si:24]([O:27][CH3:28])([O:25][CH3:26])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:15]=[C:16]([O:17][CH3:18])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:19]([O-:21])=[O:20]
Reactant: CO[SiH](OC)OC
Reactant: C=CCCCCOCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: COc1cc(COCCCCCC[Si](OC)(OC)OC)c([N+](=O)[O-])cc1OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A 20-ml eggplant type flask was purged with nitrogen, and charged with 2.95 g (10.0 mmol) of 5-hexenyl 4,5-dimethoxy-2-nitrobenzyl ether, 1.47 g (12 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20:1) as the eluent, 1.4 g (3.35 mmol) of the desired product was obtained in a 34% yield. Its Rf value (for the aforesaid eluent) was 0.1.
Reaction SMILES: [NH2:1][CH:2]([C:9]1([CH3:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][C:19]([F:24])=[C:18](Cl)[N:17]=1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[N:17]=[C:18]([NH:1][C@@H:2]([C:9]2([CH3:14])[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]([F:24])=[CH:20][C:21]=1[C:22]#[N:23]
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.40 g, 2.01 mmol) and 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.46 g, 2.41 mmol) in THF (20 mL) was added triethylamine (0.67 mL, 4.82 mmol). The reaction mixture was stirred at 90° C. in a pressure tube for 18 hours. The reaction mixture was filtered and the resulting filtrate was concentrated in vacuo. The product was purified by silica gel chromatography (25% EtOAc/Hexanes) to afford 380 mg of the desired product as a racemic mixture: 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J=9.7 Hz, 1H), 5.56 (d, J=8.9 Hz, 1H), 4.68 (td, J=9.6, 3.6 Hz, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.77-1.62 (m, 4H), 1.61-1.49 (m, 2H), 1.47-1.37 (m, 1H), 1.35-1.26 (m, 1H), 1.19 (t, J=7.1 Hz, 3H), 1.01 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.81 minutes (M+H) 354.98. The racemic mixture was submitted to SFC chiral separation to give the individual enantiomers, 143a and 143b. The (R)-enantiomer, 143a, was taken forward into the next synthetic step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH2:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26][NH:27][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: Fc1ccc2c(-c3ccc(OCCCBr)cc3)noc2c1
Reactant: NCc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc2c(-c3ccc(OCCCNCc4ccc(F)c(F)c4)cc3)noc2c1

Procedure:
The title compound is prepared from a mixture of 3-[4-(3-bromo-propoxy)-phenyl]-6-fluoro-benzo[d]isoxazole, 3,4-difluorobenzylamine, potassium carbonate, potassium iodide and 4% aqueous acetonitrile essentially as described above in Example 13. Purity by LC/MS=96%, [M+H]+=413.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:24][CH:23]=2)([S:16][CH2:17][Si](C)(C)C)[CH2:13][C@H:12]1[C:34]([OH:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@:14]([C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)([S:16][CH3:17])[CH2:13][C@H:12]1[C:34]([OH:36])=[O:35])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-((trimethylsilyl)methylthio)pyrrolidine-2-carboxylic acid (453 mg, 0.872 mmol) in THF (10 mL) was added Tetrabutylammonium fluoride (2.61 mL, 2.61 mmol). The formed light yellow solution was stirred at room temperature overnight. Diluted with EtOAc, washed with 5% citric acid, and brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-1-(benzyloxycarbonyl)-4-(biphenyl-4-yl)-4-(methylthio)pyrrolidine-2-carboxylic acid (390 mg, 0.784 mmol, 90% yield) as a white foam. LC-MS (retention time: 3.14 min, method B), MS m/z 448 (M+H), 400 (M-MeSH).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[CH:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[N+:21]([O-])=O)[CH3:5].[H][H]>O1CCCC1.[Ni]>[CH3:1][O:2][CH:3]([O:24][CH3:25])[CH:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[NH2:21])[CH3:5]
Reactant: [H][H]
Reactant: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1N

Procedure:
A solution of 2-[5-(benzyloxy)-2-nitroanilino]propionaldehyde dimethyl acetal (24.0 g, 0.0715 mole) in tetrahydrofuran is treated with Raney nickel (10 g) and placed in a Parr shaker hydrogenation apparatus under 20.5-37 psig hydrogen at ambient temperature. After the uptake of the theoretical quantity of hydrogen, the mixture is filtered and the filtrate is concentrated in vacuo to afford the title product as a dark-colored syrup. The product is identified by infrared and mass spectral analyses.
Reaction SMILES: [OH-].[K+].Br[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(B(CC)[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][O:14][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH:13]=[CH:12]2
Reactant: CCB(CC)c1cccnc1
Reactant: COc1cccc2ccc(Br)nc12
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: COc1cccc2ccc(-c3cccnc3)nc12
Yield: 82.3 %

Procedure:
Powdered potassium hydroxide (675 mg) was added to a stirred mixture of 2-bromo-8-methoxyquinoline (956 mg), diethyl(3-pyridyl)borane (590 mg), tetrakis(triphenylphosphine)-palladium(0) (250 mg) and tetra-n-butylammonium iodide (740 mg) in anhydrous tetrahydrofuran (60ml). The stirred mixture was refluxed under an inert atmosphere for 1.25 h. The solvent was removed in vacuo and the residue partitioned between dichloromethane (100 ml) and water (80ml). The aqueous phase was reextracted with dichloromethane (2×50 ml) and the combined organic phases were dried (magnesium sulfate), filtered through a small pad of Celite and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate to yield the title compound (780 mg) as a clear oil.
Reaction SMILES: C([C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:6]=2[CH:5]=1)(O)=O.N1C2C(=CC=CC=2)C=CC=1>C(OC(C)C)(C)C.[Cu]>[Cl:13][C:12]1[C:6]2[CH:5]=[CH:4][S:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)c1cc2c(Cl)cccc2s1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CC(C)OC(C)C
Product: Clc1cccc2sccc12
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 2-carboxy-4-chlorobenzo[b]thiophene (7.24 g), quinoline (36 ml), and copper powder (1.45 g) was stirred at 145 to 155° C. for 1 hour. After the mixture was allowed to cool to room temperature, the mixture was diluted with diisopropyl ether (145 ml), and insoluble materials were removed by filtration. The filtrate was washed with dilute hydrochloric acid (40 ml of 35% concentrated hydrochloric acid+200 ml of cold water) and with water, then dried over magnesium sulfate, and concentrated. A trace amount of precipitates was further removed from the concentrate by filtration to obtain 4-chlorobenzo[b]thiophene.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH2:12].S(OC)(O[CH3:17])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(OCC)(=O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][CH3:17]
Reactant: Nc1cccc2cc(Br)cnc12
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNc1cccc2cc(Br)cnc12
Temperature: 95 °C
Reaction time: 17 h
Yield: 21.9 %

Procedure:
A DMF (2 ml) solution containing 3-bromoquinolin-8-amine (223 mg), dimethyl sulfate (189 mg), potassium carbonate (415 mg), and sodium iodide (20 mg) were added to a tube and the tube was sealed, followed by stirring at 95° C. for 17 hours. The reaction solution was cooled to room temperature, ethyl acetate was added, an insoluble precipitate was removed, and the organic layer was washed with 1M hydrochloric acid, water, and saturated saline. Subsequently, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=0:1 to 1:1), and a yellow solid of 3-bromo-N-methylquinolin-8-amine (52 mg) was thus obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])[N:3]=1.[CH3:31][OH:32]>C1COCC1>[CH3:31][O:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:12]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)[CH3:13])[N:3]=1
Reactant: CO
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc(Cl)c4ccccc4n3)CC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc(OC)c4ccccc4n3)CC2)cc1
Temperature: 60 °C
Yield: 11.2 %

Procedure:
In a test tube containing of 4-Chloro-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (38.0 mg, 0.089 mmol) in THF (2 ml) was added MeOH (280.0 mg, 8.9 mmol). The reaction was heated at 60° C. for 0.5 hour. The solution was concentrated under reduced pressure. The residue was partitioned between water (2 ml) and dichloromethane (5 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The solvent was removed under vacuum. The resulting residue was re-dissolvent in MeOH (2 ml) and purified by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase). The product was collected and dried under reduced pressure to give 4-Methoxy-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-quinazoline (Yield 4.43 mg, 11.13%). MS m/z calc. 442.17, found (ESI); 443.4 (M+1)+. Retention time 2.40 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[C:36]([O:41][CH2:42][CH2:43]O)=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:31][CH2:30]1)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[N:32]1([C:35]2[C:36]([O:41][CH2:42][CH2:43][O:9][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])=[N:37][CH:38]=[CH:39][N:40]=2)[CH2:33][CH2:34][NH:29][CH2:30][CH2:31]1
Reactant: Oc1c(F)cccc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Fc1cccc(F)c1OCCOc1nccnc1N1CCNCC1

Procedure:
The title compound was prepared according to the procedure of Example 77 starting from 2,6-difluorophenol (239 mg, 1.84 mmol), TMAD (384 mg, 2.25 mmol), 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (600 mg, 1.86 mmol; prepared in Example 52, Step 2), and triphenylphosphine (969 mg, 3.69 mmol) to give 279 mg (45%) of a solid: mp 101-102° C. HRMS m/z calcd for C16H18F2N4O2 (M)+ 336.1398, found 336.1403.