Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=3[N:31]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=CC=C[CH:3]=1.[F:32]C1(CO)CC1>>[F:32][C:2]1([CH2:1][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:16][C:17]4[CH:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:30])[CH3:29])[CH3:26])[N:20]=[CH:19][C:18]=4[N:31]=3)=[CH:11][CH:10]=2)[CH2:3][CH2:7]1
Reactant: OCC1(F)CC1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCc4ccccc4)cc3)nc2cn1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCC4(F)CC4)cc3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)phenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [K].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([SH:12])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1>CN1CCCC1=O>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([S:12][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(S)cc(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K]
Solvent: CN1CCCC1=O
Product: COc1cc(OC)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 160 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
0.30 g (0.00144 mol) of 3,5-dimethoxythiophenol potassium salt was dissolved in 5 ml of 1-methyl-2-pyrrolidone, treated with 0.21 g (0.00144 mol) of 1-fluoro-4-nitrobenzene and a spatula tip of Cu powder and stirred at 160° C. for about 3 hrs. Thereafter, the solvent was removed by distillation, the residue was partitioned in water/ethyl acetate and the organic phase was washed with sat. sodium chloride solution and dried over MgSO4. After filtration and removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane 1:7. There was obtained 0.255 g (60%) of 1,3-dimethoxy-5-(4-nitrophenylsulphanyl)-benzene as yellow crystals; m.p.: 63-65° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[CH2:11][N:10]([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:9][CH2:8]2.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([S:39](Cl)(=[O:41])=[O:40])[C:34]([F:38])=[CH:35][C:36]=1[F:37]>C(Cl)Cl>[Cl:30][C:31]1[C:36]([F:37])=[CH:35][C:34]([F:38])=[C:33]([S:39]([NH:20][CH2:19][CH2:18][CH2:17][N:10]2[CH2:9][CH2:8][C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH3:3])[CH:6]=3)[CH2:11]2)(=[O:41])=[O:40])[CH:32]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1cc2c(cc1OC)CN(CCCN)CC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)CN(CCCNS(=O)(=O)c1cc(Cl)c(F)cc1F)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of 3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propylamine dihydrochloride (323 mg, 1 mmol), N,N-diisopropylethylamine (517 mg, 4 mmol) in CH2Cl2(15 mL), was added 3-Chloro-4,6-difluorobenzenesulfonyl chloride (259 mg, 1.05 mmol) and was stirred overnight at room temperature. The resulting solution was washed with water (3×20 mL) and dried over Na2SO4, and evaporated to dryness. The free base was dissolved in 2-propanol (5 mL). The product was crystallized in 2-propanol (5 mL) collected by filtration, and vacuum dried to give a white solid (401 mg, 87%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[N:14]=[N:13][C:12]([C:15]23[CH2:22][N:19]([CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=1>CN(C)C=O>[N:1]1([C:9]2[N:14]=[N:13][C:12]([C:15]34[CH2:22][N:19]([CH2:20][CH2:21]3)[CH2:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1ccc(C23CCCN(CC2)C3)nn1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cn(-c2ccc(C34CCCN(CC3)C4)nn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.228 g (3.35 mmol) of imidazole in solution in 4 ml of dimethylformamide is introduced into a 10 ml three-necked round-bottomed flask. 0.137 g (3.42 mmol) of sodium hydride as a 60% dispersion in oil is subsequently added and the mixture is stirred at ambient temperature for 1 hour. The mixture is then added to a solution of (+)-5-(6-chloropyridazin-3-yl)-1-azabicyclo[3.2.1]octane (obtained by resolution of the racemic mixture prepared in stage 1.5 of Example 1, by liquid chromatography on a chiral support) (0.15 g, 0.67 mmol) in dimethylformamide and the reaction medium is heated at 90° C. for 15 hours and then at 110° C. for 3 hours, and the solvent is evaporated off under reduced pressure. The residue is taken up in 10 ml of chloroform and 10 ml of a saturated aqueous sodium carbonate solution. The aqueous phase is extracted again with 10 ml of chloroform and the combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel plate chromatography, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 85/15/1.5. 0.111 g of expected product is obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:31][CH2:32][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:42])[N:37]([CH:43]1[CH2:48][CH2:47][C:46](=[O:49])[NH:45][C:44]1=[O:50])[CH2:36]2>CN(C=O)C>[O:50]=[C:44]1[CH:43]([N:37]2[CH2:36][C:35]3[C:39](=[CH:40][CH:41]=[C:33]([CH2:32][NH:31][C:9](=[O:11])[C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=4)[CH:34]=3)[C:38]2=[O:42])[CH2:48][CH2:47][C:46](=[O:49])[NH:45]1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A mixture of 4-methylsulphonylbenzoic acid (0.28 g, 1.4 mmol) and CDI (0.24 g, 1.5 mmol) was stirred in DMF (30 mL) at 40° C. for 4 hours. 3-(5-Aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) was added and the mixture was stirred at 40° C. for 2 h. The mixture was quenched with 4% aqueous HCl (30 mL) and the resulting precipitate was filtered, washed with water (30 mL) and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-methanesulfonyl-benzamide as a white solid, (0.44 g, 71% yield); mp 260-262° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 50/50 CH3CN/0.1% H3PO4, 4.08 (98.31%); 1H NMR (DMSO-d6) δ 1.96-2.03 (m, 1H), 2.31-2.46 (m, 1H), 2.57-2.63 (m, 1H), 2.86-2.98 (m, 1H), 3.27 (s, 3H), 4.31 (d, 1H, J=17.4 Hz), 4.45 (d, 1H, J=17.4 Hz), 4.63 (d, 2H, J=5.7 Hz), 5.11 (dd, 1H, J=13.2 Hz, J=4.8 Hz), 7.48 (d, 1H, J=8.1 Hz), 7.56 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 8.05 (d, 2H, J=8.4 Hz), 8.14 (d, 2H, J=8.4 Hz), 9.42 (t, 1H, J=6.0 Hz), 10.99 (s, 1H). 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.9, 43.3, 47.1, 51.6, 122.1, 123.0, 127.1, 128.3, 130.4, 138.6, 142.4, 143.0, 143.5, 165.0, 167.9, 171.0, 172.8; LCMS: MH=456; Anal. Calcd for C22H21N3O6S: C, 58.01; H, 4.65; N, 9.23. Found: C, 58.15; H, 4.52; N, 9.04.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31][NH2:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[C:25]1([N:31]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Solvent: CO
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 12 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[4-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (crude 718 mg, 2.13 mmol) in 20 mL of methanol was added phenylhydrazine (345 mg, 3.20 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 3-(1-phenyl-1H-pyrazol-5-yl)-1-[4-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 12% for two steps) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-])=O)[CH2:8][CH2:7]1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[NH2:19])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ccc(Cl)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(c2ccc(Cl)cc2N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.1 %

Procedure:
To a solution of 0.800 g (2.49 mmol) of [1-(4-chloro-2-nitro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester in ethanol (30 mL) is added 0.10 g (0.05 mmol) of 5% palladium on carbon. The mixture is placed under an atmosphere of hydrogen and stirred at room temperature overnight. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.710 g (97.7%) of [1-(2-amino-4-chloro-phenyl)-piperidin-4-yl]-acetic acid ethyl ester as a dark foam.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16].N#N>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: N#N
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCC
Temperature: 160 °C

Procedure:
3-Trifiuoromethylbenzylchloride (50 g, 257 mmol) and triethyl phosphite (53.4 g, 321 mmol) were combined,under N2, and heated to 160° C. for 18 hours. The reaction mixture was distillated at 105°-110° C. to give 69.5 g (91.3%) of analytically pure product as a colorless oil. 300 MHz 1H NMR (CDCl3): δ, 3.20 (d,2H, J=21.78 Hz, PCH2). MS: 297 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:20]1([C:26]#[CH:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C.[Cu](I)I>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([C:27]#[C:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=[N:4][CH:5]=1)[CH3:11]
Reactant: C#Cc1ccccc1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cncc(C#Cc2ccccc2)c1
Temperature: 50 °C
Yield: 100.3 %

Procedure:
To a solution of ethyl 5-bromonicotinate (1.15 g, 5 mmol) in ethyl acetate (20 mL) under an N2 atmosphere, was added triethylamine (1.1 mL, 7.5 mmol, 1.5 eq.), phenyl acetylene (0.766 g, 7.5 mmol, 1.5 eq.), dichloro-bis(triphenylphosphine)-palladium(II) (176 mg, 0.25 mmol, 0.05 eq.), and copper iodide (10 mg, 0.05 mmol, 0.01 eq). The reaction mixture was heated at 50° C. for 20 h before being cooled to room temperature, filtered through a pad of celite, and solvent evaporated to provide a dark brown oil. Silica gel column chromatography (9/1-4/1 hexanes/EtOAc elution) provided the title compound as a pale yellow oil (1.26 g, yield 100%). 1H NMR (300 MHz, CDCl3) δ 9.11 (d, J=1.8 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.39 (dd, J=1.8, 2.1 Hz, 1H), 7.56-7.53 (m, 2H), 7.40-7.30 (m, 3H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); ESI-MS m/z 251.9 (M+H)+.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=O)[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:31].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:25]=[CH:26][C:27]=2[O:28][CH3:29])[CH2:10][N:11]2[C:19]3[N:18]=[C:17]([CH:20]([CH3:22])[CH3:21])[NH:16][C:15]=3[C:14](=[S:31])[NH:13][C:12]2=[O:24])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2c(=O)[nH]c(=O)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: COc1ccc(Cn2c(=O)[nH]c(=S)c3[nH]c(C(C)C)nc32)cc1OC1CCCC1
Yield: 151 %

Procedure:
3.59 g of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-xanthine and 2.40 g of phosphorus pentasulfide were heated under reflux in 60 ml of pyridine for 8 hours. At -5° C., 11.9 ml of 2N NaOH were added slowly. The suspension was evaporated to dryness, the residue suspended in 100 ml of water, neutralized to pH 8, and the solid, collected, washed and dried to give the crude 6-thioxanthine (3.45 g). Purification by filtration chromatography (SiO2, 15 g; chloroform) yielded a solid which was reprecipitated from NaOH by addition of HCl, to pH 6.5, collected, washed and dried to give the monohydrate of the title compound (3.38 g) as a white solid, mp 192-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.C([O-])([O-])=O.[K+].[K+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N+:3]=1[O-:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(Br)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7630.9 %

Procedure:
To a solution of 2-bromo-5-methylpyridine (4 g, 2.3 mmol) in dichloromethane (500 mL) was added m-CPBA (52 g, 304 mmol) at 0° C. The reaction mixture was stirred at room temperature for 20 hours and the then the pH was adjusted to about 9 with a saturated solution of K2CO3. The organic layers were separated and concentrated to give a residue which was purified by flash silica chromatography eluted with petroleum ether/ethyl acetate (1:1) to give 2-bromo-5-methylpyridine 1-oxide (33 g; 75%). 1H NMR (CDCL3): δ ppm 8.25 (s, 1H), 8.75 (d, 1H, J=8.4 Hz), 6.95-6.94 (m, 1H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:12][C:13]([NH2:15])=[S:14])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:17]([CH:23]([CH3:25])[CH3:24])[C:18](OCC)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH:12][C:13]3[S:14][CH:17]([CH:23]([CH3:25])[CH3:24])[C:18](=[O:19])[N:15]=3)[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: NC(=S)NC1(c2ccc(Cl)cc2)CCC1
Product: CC(C)C1SC(NC2(c3ccc(Cl)cc3)CCC2)=NC1=O

Procedure:
Synthesis was performed from N-[1-(4-chlorophenyl)cyclobutyl]thiourea and ethyl 2-bromo-3-methylbutanoate according to Method D.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.B.C1COCC1>C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2ccccc12
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]c2ccccc2c1CCCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of ethyl 3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (2.82 g) in THF (40 mL) was added IM borane-THF (40 mL). The mixture was stirred at room temperature for 16 hours, quenched with methanol (100 mL) and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-25% ethyl acetate/hexanes.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38]S(CC1C=CC=CC=1)(=O)=O)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:49][C:50]1[CH:51]=[C:52]([S:57](Cl)(=[O:59])=[O:58])[CH:53]=[C:54]([Cl:56])[CH:55]=1>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:57]([C:52]1[CH:51]=[C:50]([Cl:49])[CH:55]=[C:54]([Cl:56])[CH:53]=1)(=[O:59])=[O:58])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3cc(Cl)cc(Cl)c3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 60 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step6, Example 1) was added 3,5-dichlorobenzenesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[CH:9]([CH:11]([CH3:17])[C:12](OCC)=O)=[O:10]>C(O)C>[CH3:17][C:11]1[C:9](=[O:10])[N:1]=[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH:12]=1
Reactant: NC1=NCCCCC1
Reactant: CCOC(=O)C(C)C=O
Solvent: CCO
Product: Cc1cn2c(nc1=O)CCCCC2
Reaction time: 24 h
Yield: 37 %

Procedure:
To a solution of 11.2 g. of 7-amino-3,4,5,6-tetrahydro-2H-azepine in 100 ml. ethanol 13.1 g. of ethyl 2-formyl-propionate are added at room temperature and the reaction mixture is stirred for 24 hours and boiled for 3 hours. Ethanol is then evaporated at reduced pressure and the residue is treated with a mixture of acetone and petroleum ether. The precipitated crystals are filtered. 6.6 g. (37%) of 3-methyl-2-oxo-2,6,7,8,9,10-hexahydro-pyrimido[1,2-a]azepine are obtained, melting at 202° C. after boiling in acetone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:16][C:17]1[C:22]([CH3:23])=[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:20]([CH3:32])=[C:19]([CH3:33])[C:18]=1[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]O)[CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:40][C:36]3[CH:35]=[C:34]([C:18]4[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]([O:24][CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])=[C:20]([CH3:32])[C:19]=4[CH3:33])[CH:39]=[CH:38][CH:37]=3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1c(C)c(-c2cccc(CO)c2)c(C)c(C)c1OCCCS(C)(=O)=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)c(C)c(OCCCS(C)(=O)=O)c(C)c4C)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.5 %

Procedure:
A solution of methyl[(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.208 g, 1.00 mmol), {2′,3′,5′,6′-tetramethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methanol (0.377 g, 1.00 mmol) and tributylphosphine (0.324 g, 1.60 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.404 g, 1.60 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr under nitrogen atmosphere. Hexane (8 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-80:20) to give the title compound (0.462 g, yield 82%) as a colorless oil.
Reaction SMILES: [C:1]([NH:11][S:12]([NH:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:23]O>[Pd]>[CH3:23][O:18][C:17](=[O:19])[CH:16]([NH:15][S:12]([NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])(=[O:14])=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)O
Reactant: CO
Agent: [Pd]
Product: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)OC
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid (46.7 g) , methanol (350 mL) and 10% palladium on carbon (3.0 g) was hydrogenated at 55 psi for about 2 hours. The catalyst was removed by filtration through CELITE®, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ethyl acetate/hexane to afford 25.6 g (90%) of 2-(aminosulfonylamino) pentanoic acid methyl ester (Formula XIV: R=CH3 ; R1 =H; R2 =propyl; R3 =H), m.p. 63°-64° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[CH:7][CH:8]=1.[CH2:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:10]([O:16][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15]
Reactant: COc1cccc(O)c1
Reactant: C=CCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCCCCOc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To a stirred solution of 3-methoxy phenol (1.24 g, 10 mmol), 5-hexen-1-ol, 4a (1.4 mL, 12 mmol) and Ph3P (3.14 g, 12 mmol) in THF (20 mL) at 0° C. was added diisopropylazodicarboxylate (2.3 mL, 12 mmol) dropwise. After stirring the solution for 30 min at 0° C. the reaction mixture was warmed to 23° C. and stirred for 3 h. The reaction mixture was concentrated in vacuo and the residue was subjected to column chromatography (98:2 hexanes:EtOAc) to yield 1.98 g of 5a (96% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.58-1.66 (m, 2H), 1.80-1.88 (m, 2H), 2.15-2.20 (m, 2H), 3.82 (s, 3H), 3.98 (t, J=6.4 Hz, 2H), 5.02-5.12 (m, 2H), 5.83-5.92 (m, 1H), 6.52-6.56 (m, 3H), 7.19-7.24 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 25.3, 28.7, 33.4, 55.1, 67.6, 100.9, 106.0, 106.6, 114.7, 129.8, 138.5, 160.3, 160.8; FT-IR (film, NaCl) νmax=3075, 2939, 1599, 1493, 1287, 1200, 1152, 1046 cm−1; CI LRMS m/z (ion): 207.25 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)#[N:3].C(O)(=[O:30])C>>[C:2]([C:4]1[C:9](=[O:10])[C:8]2[CH:11]=[C:12]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[C:13]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][C:7]=2[O:6][CH:5]=1)(=[O:30])[NH2:3]
Reactant: CS(=O)(=O)Nc1cc2occ(C#N)c(=O)c2cc1Oc1ccccc1F
Reactant: CC(=O)O
Agent: Cl
Product: CS(=O)(=O)Nc1cc2occ(C(N)=O)c(=O)c2cc1Oc1ccccc1F
Yield: 42.1 %

Procedure:
30 ml of concentrated hydrochloric acid and 60 ml of acetic acid were added to 3.74 g of 3-cyano-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one. The mixture was refluxed for 30 minutes. After the completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was washed with water and then recrystallized from acetic acid to obtain 1.65% (yield: 42.1%) of 3-carbamoyl-6-(2-fluorophenoxy)-7-methylsulfonylamino-4H-1-benzopyran-4-one having a melting point of 249°-251° C.