Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11].[CH3:26][C@@H:27]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[NH:28]1>>[F:1][C:2]1[CH:7]=[C:6]([N:28]2[C@H:27]([CH3:26])[CH2:31][CH2:30][S:29]2(=[O:33])=[O:32])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(I)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4[C@H](C)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 55.8 %

Procedure:
Using (2,6-difluoro-4-iodophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (743 mg) described in Preparation Example 158 and (R)-3-methylisothiazolidine 1,1-dioxide (220 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (421 mg) was obtained.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCC3(CC2)OCCO3)cc1
Reaction time: 2 h

Procedure:
To a solution of 4-piperidone ethylene ketal (1.43 g, 10 mimol) and triethylamine (10 mmol, 1.4 ml) was added dropwise a solution of 4-methylbenzoyl chloride (1.55 g, 10 mmol) in ethyl acetate (20 ml) and the mixture stirred for 2 h. The mixture was washed twice with water followed by brine, dried over sodium sulphate and evaporated to give an off-white solid, m.p. 59°-61° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[C:2]=[O:3].[CH3:16][N:17]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:26])[C:20]=2[CH:19]=[N:18]1.N1C2C=CC=C(N)C=2C=N1>>[CH3:16][N:17]1[C:25]2[C:20](=[C:21]([NH:26][C:2]([NH:1][CH2:4][C:5]3[CH:10]=[CH:9][C:8]([N:11]4[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)=[O:3])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[N:18]1
Reactant: O=C=NCc1ccc(N2CCCC2)cc1
Reactant: Cn1ncc2c(N)cccc21
Agent: Nc1cccc2[nH]ncc12
Product: Cn1ncc2c(NC(=O)NCc3ccc(N4CCCC4)cc3)cccc21

Procedure:
The title compound was prepared using the procedure described in Example 89B using 1-[4-(isocyanatomethyl)phenyl]pyrrolidine and 1-methyl-1H-indazol-4-amine instead of 1-bromo-4-(isocyanatomethyl)benzene and the product from Example 89A. NMR (DMSO-d6) δ 8.98 (s, 1H), 8.16 (s, 1H), 7.63 (d, 1H), 7.13 (m, 3H), 7.12 (d, 1H), 6.94 (m, 1H), 6.73 (bs, 2H), 4.23 (s, 2H), 3.99 (s, 3H), 3.24 (m, 4H), 1.98 (m, 4H); MS (ESI) (M+H)+ 350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH:23]4[CH2:37][C@@H:26]5[CH2:27][NH:28][CH2:29][C@@H:25]5[CH2:24]4)=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1OC1C[C@H]2CNC[C@H]2C1
Yield: 197.7 %

Procedure:
1,1-Dimethylethyl(3aR,6aS)-5-({[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy})hexahydrocyclo-penta[c]pyrrole-2(1H)-carboxylate (0.23 g, 0.42 mmol) was taken up in methanol (10 mL) and treated with 4.0M hydrogen chloride in dioxane (excess) and heated briefly to reflux. Concentration in vacuo provided N-(3,4-dichloro-phenyl)-6-(methyloxy)-7-{[(3aR,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]oxy}quinazolin-4-amine hydrochloride (0.20 g, 100%). MS (EI) for C22H22Cl2N4O2: 445 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Cl.[C@H:20]12[CH2:26][C@H:23]([NH:24][CH2:25]1)[CH2:22][O:21]2.CCN(C(C)C)C(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:24]2[CH2:25][C@@H:20]3[CH2:26][C@H:23]2[CH2:22][O:21]3)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Fc1ccc(C2CCc3c2nc(Cl)nc3N2C[C@@H]3C[C@H]2CO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (200 mg, 0.706 mmol) in MeOH (7064 μL) was added (1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptane monohydrochloride (115 mg, 0.848 mmol) and DIPEA (271 μL, 1.554 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was then concentrated in vacuo. The resulting oil was purified by flash chromatography (Silica, EtOAc/Hexanes) to give (1S,4S)-5-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-2-oxa-5-azabicyclo[2.2.1]heptane (148 mg, 0.428 mmol, 60.6% yield). LC-MS (M+H)+=346.1. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.21 (2H, m), 7.00-7.08 (2H, m), 5.11-5.21 (1H, m), 4.69-4.74 (1H, m), 4.15-4.26 (1H, m), 3.88-3.94 (2H, m), 3.68-3.86 (2H, m), 3.11-3.21 (1H, m), 2.56-2.69 (1H, m), 1.92-2.11 (2H, m), 1.24-1.42 (2H, m).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][NH:13][N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CN(C)C=O.CO>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3=[CH:12][N:13]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[N:14]=[C:8]3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1[nH]nc2c1CCN(C1CCC1)CC2
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2cc3c(n2)CCN(C2CCC2)CC3)cc1
Temperature: 70 °C

Procedure:
6-Cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine (may be prepared as described in Description 31) (0.03, 0.16 mmol) in dimethylformamide (2 ml) was treated with sodium hydride (60% dispersion in oil) (0.007 g, 0.172 mmol). After 20 minutes 4-(bromomethyl)benzonitrile (0.037 g, 0.172 mmol) was added and the mixture was then heated at 70° C. for 18 hours. The reaction was then cooled to room temperature, diluted with methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M solution of ammonia in methanol. The ammonia containing fractions were then combined and reduced and the resulting crude residue was chromatographed on silica gel eluting with a 2:98 mixture of 2M ammonia in methanol and dichloromethane to furnish the title compound (E46); (MS (ES+): [M+H]+ at m/z 307.1
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[C:19]1[CH3:28])S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[CH:2]=[CH2:3].C(ON[C@@H]1C(C)=C[C@@H](CO[Si](C(C)(C)C)(C)C)NC1)C=C>CO.ClCCl>[CH2:1]([O:4][NH:5][C@H:18]1[CH2:23][NH:22][C@H:21]([C:24]([NH2:26])=[O:25])[C:20]([CH3:27])=[C:19]1[CH3:28])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON[C@H]1CN[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C
Solvent: ClCCl
Solvent: CO
Product: C=CCON[C@H]1CN[C@H](C(N)=O)C(C)=C1C
Yield: 68.8 %

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-3,4-dimethyl-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 196, 0.82 g, 2.00 mmol) following the procedure described for Intermediate 12. Silica gel chromatography (0%-10% methanol/dichloromethane) afforded the desired product as a white solid (0.31 g, 68.9%).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[N:30]1([CH2:22][C:20]2[S:19][CH:18]=[C:17]([C:14]3[CH:15]=[C:16]4[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=3)[NH:10][CH:9]=[C:8]4[CH:6]3[CH2:5][CH2:4][S:3](=[O:28])(=[O:27])[C:2]([CH3:1])([CH3:29])[CH2:7]3)[CH:21]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC5)c4)cc23)CCS1(=O)=O
Yield: 36.3 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid and azetidine (0.047 mL, 0.697 mmol) was added. The mixture was left stirring 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring 16 h at 23° C. Based on LCMS only 60-70% of conversion was observed. The sodium triacetoxyborohydride polymer bound was removed by filtration. The crude product was purified by preparative HPLC (NH4OH buffer). The desired fractions were concentrated, giving 12 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C([Li])CCC.CN(C)[C:17](=[O:19])[CH3:18].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH2:1][C:17](=[O:19])[CH3:18])[CH:7]=1
Reactant: COc1ccnc(C)c1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccnc(CC(C)=O)c1
Temperature: 0 °C

Procedure:
To a stirred solution of 2-methyl-4-methoxypyridine (2.03 g) in tetrahydrofuran (20 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 12.1 ml) dropwise at −50° C. under a nitrogen atmosphere, and the mixture was warmed to 0° C. The mixture was cooled to −50° C., and N,N-dimethylacetamide (1.99 ml) was added dropwise. Then the mixture was warmed to room temperature, poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 100 g, n-hexane:ethyl acetate=1:2) to give 1-(4-methoxypyridin-2-yl)propan-2-one (2.35 g).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:8]1[C:9](=[O:24])[CH2:10][CH:11]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[CH2:12][C:13]=1[OH:14])[CH2:6][CH3:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(C(C)=O)C>[C:31]([O:24][C:9]1[CH2:10][CH:11]([C:15]2[C:16]([CH3:23])=[CH:17][C:18]([CH3:22])=[CH:19][C:20]=2[CH3:21])[CH2:12][C:13](=[O:14])[C:8]=1[C:5](=[N:4][O:3][CH2:1][CH3:2])[CH2:6][CH3:7])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)cc2C)CC1=O
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A mixture of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (2.4 g), anhydrous methyl ethyl ketone (25 ml) and anhydrous potassium carbonate (1.65 g) was treated dropwise, with stirring, with benzoyl chloride (1.12 g). The mixture was heated under reflux with stirring for a period of 30 minutes and then filtered. The residue was washed with diethyl ether and the solvent from the combined filtrate and washings was evaporated under reduced pressure. The residue was taken up in ethyl acetate and the solution was washed twice with water, dried, and the solvent was evaporated under reduced pressure to give a dark brown oil. The oil was purified by chromatography on preparative thin layer chromatography plates (silica gel; eluent hexane/diethyl ether 75:25) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-mesitylcyclohex-2-en-1-one (1.9 g).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>CO>[F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([S:23]([CH3:22])(=[O:25])=[O:24])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: CS(=O)(=O)n1cc(F)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 10 h
Yield: 35.5 %

Procedure:
2.6 g. (0.02 mole) of 5-fluorouracil and 1.52 g (0.011 mole) of anhydrous potassium carbonate were suspended in 50 ml. of dioxane and then 2.53 g (0.022 mole) of methanesulfonyl chloride in 20 ml. of dioxane was dropwise added thereto. After stirring at 80°C. for 10 hours, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and a resinous residue was obtained. The residue was dissolved in a small amount of methanol and allowed to stand at 0°C. overnight. There was obtained 1.48 g (45.4% yield) of 5-fluoro-1 -methanesulfonyluracil. Recrystallization of the product from methanol gave leaflets melting at 223°-224°C. The results of an elementary analysis thereof were well in agreement with the calculated value as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:14]=1
Reactant: Clc1ccccc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 59.8 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 5, using 2-(4-chlorophenyl)acetic acid (5 g, 29.2 mmol) and chlorobenzene (10.31 g, 91.2 mmol, 2.85 equiv) as reactants. The reaction was quenched by the addition of water/ice. The residue was dissolved in 3% HCl, extracted with 3×20 mL of dichloromethane, and the organic layers combined and concentrated under vacuum. Purification via silica gel column (ethyl acetate/petroleum ether (1:100)) yielded 4.63 g (54%) of 1,2-bis(4-chlorophenyl)ethanone as a white solid.
Reaction SMILES: C([O:4][CH:5](OC(=O)C)[C:6]([CH3:13])=[CH:7][CH2:8][O:9][C:10](=[O:12])[CH3:11])(=O)C.C(O)(=O)C>O>[C:10]([O:9][CH2:8]/[CH:7]=[C:6](\[CH3:13])/[CH:5]=[O:4])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC/C=C(\C)C=O
Yield: 81.6 %

Procedure:
48.8 parts of 1,1,4-triacetoxy-2-methyl-but-2-ene, consisting, according to NMR analysis, of 46.4% of (E)-isomer and 53.6% of (Z)-isomer, are boiled with 500 parts of glacial acetic acid and 18 parts of water for 2.5 hours. After stripping off the acid and water on a rotary evaporator at from 40° to 50° C. under a waterpump vacuum, fractional distillation of the residue gives 23.2 parts of 4-acetoxy-2-methylcrotonaldehyde (81.6% of theory) of boiling point 102°-103° C./23.9 mbar (nD20 =1.4641). According to NMR analysis (aldehyde protons), the aldehyde obtained consists of 98.0% (E)- and 2.0% (Z)-4-acetoxy-2-methylcrotonaldehyde.
Reaction SMILES: N[C@@H]1CCCCN(CC2CC2)C1=O.[CH:14]1([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]([NH:25][C:26](=[O:32])OC(C)(C)C)[C:19]2=[O:33])[CH2:16][CH2:15]1.C(O)(C(F)(F)F)=O.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(N(C(C)C)CC)(C)C.[Cl:63][C:64]1[CH:73]=[C:72]2[C:67]([C:68]([N:75]3[CH2:80][CH2:79][NH:78][CH2:77][CH2:76]3)=[CH:69][C:70]([NH2:74])=[N:71]2)=[CH:66][CH:65]=1>>[NH2:74][C:70]1[CH:69]=[C:68]([N:75]2[CH2:76][CH2:77][N:78]([C:26]([NH:25][C@H:20]3[CH2:21][CH2:22][CH2:23][CH2:24][N:18]([CH2:17][CH:14]4[CH2:15][CH2:16]4)[C:19]3=[O:33])=[O:32])[CH2:79][CH2:80]2)[C:67]2[C:72](=[CH:73][C:64]([Cl:63])=[CH:65][CH:66]=2)[N:71]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCN(CC2CC2)C1=O
Agent: N[C@@H]1CCCCN(CC2CC2)C1=O
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC4CC4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 78, (3R)-3-amino-1-(cyclopropylmethyl)hexahydro-2H-azepin-2-one by de-protection of [(3S)-1-(cyclopropylmethyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid, 1,1-dimethylethyl ester with TFA, p-nitrophenyl chloroformate, diisopropylethyl amine, and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product. LC-MS: 471 (M++1). 1H NMR (CDCl3) δ 7.65 (d, 1H), 7.55 (s, 1H), 7.10 (d, 1H), 6.22 (d, 1H), 6.05 (s, 1H), 4.85 (s, 2H), 4.50 (m, 1H), 3.60 (m, 4H), 3.50 (m, 1H), 3.40 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 3.06 (m, 4H), 2.05 (m, 1H), 1.70–1.90 (m, 3H), 1.40 (m, 2H), 0.90 (m, 1H), 0.45 (m, 2H), 0.20 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:10]([CH3:30])[CH:9]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][C:10]=3[CH3:30])=[O:15])[CH2:21][CH2:20]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C)CC2)c(C)c1
Yield: 44.9 %

Procedure:
Using pyrrolidin-2-one (47 mg) and (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (194 mg) described in Preparation Example 118 and by the reaction and treatment in the same manner as in Example 1, the title compound (88 mg) was obtained.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[O:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[O:20]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1ccccc1Oc1ccccc1
Product: O=C(O)c1csc(COc2ccc(-c3ccccc3Oc3ccccc3)cc2)n1

Procedure:
2-(2′-Phenoxy-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 25 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and (2-phenoxy)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=404.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH2:10]([C:13]1[C:21]2[O:20][N:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:17]=2[CH:16]=[CH:15][C:14]=1[O:26][CH2:27][CH2:28][CH2:29]Br)[CH2:11][CH3:12]>>[CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[N:4]([CH2:29][CH2:28][CH2:27][O:26][C:14]2[CH:15]=[CH:16][C:17]3[C:18]([C:22]([F:24])([F:25])[F:23])=[N:19][O:20][C:21]=3[C:13]=2[CH2:10][CH2:11][CH3:12])[C:3]1=[O:8]
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CC1(C)NC(=O)NC1=O
Product: CCCc1c(OCCCN2C(=O)NC(C)(C)C2=O)ccc2c(C(F)(F)F)noc12

Procedure:
5,5-Dimethyl-3-(3-{[7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from 5,5-dimethylimidazolidine-2,4-dione and the bromide from Example 7. After aqueous work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:22][S:23]([O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Yield: 100.4 %

Procedure:
A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (21.5 g, 107 mmol) and triethylamine (30 mL, 214 mmol) in dichloromethane (250 mL) was cooled to 0° C. Methanesulfonyl chloride (12.5 mL, 160.5 mmol) was added dropwise via an addition funnel and the resulting mixture was stirred at 0° C. then gradually warmed to room temperature over 3 h. A 10% aqueous citric acid solution was added and the two layers were separated. The organic layer was washed with 10% aqueous citric acid, sat'd aqueous NaHCO3, and brine. The organic layer was dried over sodium sulfate, filtered and the solvent removed on a rotary evaporator to afford 30 g of (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as an orange oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 4.17 (m, 2H), 3.33 (m, 2H), 3.20 (m, 1H), 3.18 (s, 3H), 3.00 (m, 1H), 2.55 (m, 1H), 2.01 (m, 1H), 1.53 (m, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1I)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:13]=[CH:12][S:11][C:10]=1[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccsc1I
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Yield: 5.9 %

Procedure:
Heat (tert-Butoxy)-N-(2-iodo(3-thiophenyl))carboxamide (16.88 g, 0.52 mol), 4-bromophenylboronic acid (15.65 g, 0.78 mol), Na2CO3 (1.01 g, 1.04 mol) and Pd(PPh3)4 (5.79 g, 0.052 mol) in 375 ml of an anhydrous and deoxygenated 2:1 DME/EtOH mixture to 80° C. under nitrogen atmosphere for 24 h. Evaporate the organic solvents prior to the addition of water (200 mL). Extract the mixture with methylene chloride (3×150 mL) and combine the organic phases, dry (anh MgSO4), filter, and concentrate to furnish a crude mixture as a yellowish solid. Purification by flash chromatography (Silica gel-Hexane/EtOAc 49:1) yields 10.8 g (60%) of (tert-butoxy)-N-[2-(4-bromophenyl)(3-thiophenyl)]carboxamide as a pale yellow solid.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH2:1]([C:4]1[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:2][CH3:3]
Reactant: BrCc1ccccc1
Reactant: CCCc1c(C(=O)OCC)nc2ccccc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(C(=O)OCC)nc2ccccc2c1OCc1ccccc1

Procedure:
A well-stirred mixture of 5 parts of ethyl 3-n-propyl-4-hydroxyquinoline-2-carboxylate, 3 parts of anhydrous potassium carbonate and 3.3 parts of benzyl bromide in anhydrous acetone was boiled under reflux for 16 hours, filtered to remove inorganic salts, and evaporated to remove solvent. A solution of the residual oil in 75 parts of ether, after being washed with N.sodium hydroxide (2 portions each comprising 25 parts) and then water (4 portions each of 40 parts) was dried over magnesium sulphate and evaporated to yield 6.4 parts of crude ethyl 3-n-propyl-4-benzyloxyquinoline-2-carboxylate as a very pale yellow oil.