Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=CC=1.[H-].[Na+].Br[CH2:32][C:33]1[C:34]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:35][O:36][C:37]=1[CH3:38]>CN(C=O)C>[CH3:38][C:37]1[O:36][N:35]=[C:34]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]=1[CH2:32][N:20]1[CH2:19][CH2:18][O:17][C:16]2[CH:21]=[C:12]([S:9]([NH:8][C:22]3[S:23][CH:24]=[CH:25][N:26]=3)(=[O:10])=[O:11])[CH:13]=[CH:14][C:15]1=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: Cc1onc(-c2ccccc2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1CN1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 12.5 %

Procedure:
To a flask charged with N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (INTERMEDIATE M) (0.104 g, 0.25 mmol) was added DMF (0.7 ml), and cooled in an ice water bath prior to the addition of NaH (60% in mineral oil) (10 mg, 0.25 mmol). The mixture was stirred for 45 min at 0° C., then 30 min at rt. To a separate vial charged with 4-(bromomethyl)-5-methyl-3-phenylisoxazole (Sigma Aldrich) (35 mg, 0.25 mmol) was added DMF (0.3 ml), then the solution of deprotonated amine. The resulting mixture was sealed and shaken at room temperature overnight. The mixture was quenched with the addition of MeOH, then concentrated under reduced pressure and purified with NH4OH modified reverse-phase-HPLC affording 4-((5-methyl-3-phenylisoxazol-4-yl)methyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (14.6 mg, 12%). 1H NMR (500 MHz, DMSO-d6) δ=12.50 (br. s., 1 H), 7.60 (dd, J=1.7, 7.7 Hz, 2 H), 7.48-7.40 (m, 3 H), 7.21 (d, J=4.6 Hz, 1 H), 7.15 (dd, J=2.1, 8.5 Hz, 1 H), 6.99 (d, J=2.2 Hz, 1 H), 6.82-6.75 (m, 2 H), 4.37 (s, 2 H), 4.03-3.95 (m, 2 H), 3.13-3.07 (m, 2 H), 2.47 (s, 3 H); m/z (ESI) 469.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[N+](C1C=CC([CH:39]2[S:43]/[C:42](=[N:44]\[C:45](=O)[O-:46])/[N:41]([C:48]3[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=3[CH:55]([CH3:57])[CH3:56])[C:40]2=[O:58])=CC=1)([O-])=O>>[CH:1]1([CH2:4][N:5]([CH2:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[CH:17][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][C:26]([F:27])([F:28])[F:29])=[CH:23][CH:24]=4)[N:15]=3)=[CH:12][CH:13]=2)[C:45](/[N:44]=[C:42]2\[S:43][CH2:39][C:40](=[O:58])[N:41]\2[C:48]2[CH:53]=[C:52]([CH3:54])[CH:51]=[CH:50][C:49]=2[CH:55]([CH3:56])[CH3:57])=[O:46])[CH2:3][CH2:2]1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(CCNCC4CC4)cc3)n2)cc1
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Product: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)N(CCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)CC2CC2)c1

Procedure:
The title compound was prepared as described in Example 95 using N-(cyclopropylmethyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB27) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as red-orange oil (0.127 g, 60%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[C:20]=1[C:21]([NH2:23])=[O:22].CC1C=CC(S(O)(=O)=O)=CC=1.OS([O-])=O.[Na+]>CC(N(C)C)=O.O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:23][C:21](=[O:22])[C:20]4[C:19](=[CH:27][C:26]([O:28][CH3:29])=[CH:25][C:24]=4[O:30][CH3:31])[N:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(C)=O)CC4)cc3)nc2c1
Temperature: 155 °C
Yield: 88.8 %

Procedure:
A mixture of 4-(4-acetylpiperazin-1-yl)benzaldehyde (1.34 g, 5.77 mmol) and 2-amino-4,6-dimethoxybenzamide (1.03 g, 5.24 mmol) in DMA (30 mL) was treated with p-TsOH (0.100 g, 0.524 mmol) and NaHSO3 (0.578 g, 5.55 mmol). The mixture was heated at 155° C. for 6 hours, cooled to room temperature, diluted with water (400 mL), and filtered to give brown solids. The filtrate was extracted with EtOAc (3×100 mL), concentrated, and combined with the brown solids from the filter cake. The combined solids were purified by silica gel chromatography, eluting with 92:7:1 CHCl3/MeOH/concentrated NH4OH to afford 2-(4-(4-acetylpiperazin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one as a yellow solid (1.9 g, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](Cl)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:20]=2[CH3:21])=[O:15])[CH2:9][C:10](=[O:11])[N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CCNCC
Reactant: Cc1c(C(=O)NC(CC(=O)Cl)c2cccc(Br)c2)cnn1-c1ccc(Cl)c(Cl)c1
Solvent: ClCCCl
Product: CCN(CC)C(=O)CC(NC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.7 %

Procedure:
A solution 3-(3-bromo-phenyl)-3-{[1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-amino}-propionyl chloride (100 mg, 0.19 mmol) in 1,2-dichloroethane (3 mL) is treated with diethylamine (28 mg, 0.38 mmol) in one portion and stirred at room temperature for 2 hours. The reaction mixture is concentrated in vacuo and purified by flash chromatography on silica gel (eluted with 1 to 4% MeOH/CH2Cl2) to afford 1-(3,4-dichloro-phenyl)-5-methyl-1H-pyrazole-4-carboxylic acid [1-(3-bromo-phenyl)-2-diethylcarbamoyl-ethyl]-amide as a white foam (6.0 mg, 6.0%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][N:3]=1.Cl[CH2:16][C:17]([NH:19][C:20](=[O:23])[O:21][CH3:22])=O>>[CH3:22][O:21][C:20]([NH:19][C:17]1[N:1]=[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[CH:4][N:3]2[CH:16]=1)=[O:23]
Reactant: COC(=O)NC(=O)CCl
Reactant: Nc1ccc(Oc2ccccn2)cn1
Product: COC(=O)Nc1cn2cc(Oc3ccccn3)ccc2n1

Procedure:
Reaction of 2-amino-5-(2-pyridyloxy) pyridine with methyl chloroacetylcarbamate as in Example 3 yields 2-(methoxycarbonylamino)-6-(2-pyridyloxy) imidazo [1,2-a] pyridine.
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C(O)C>[I:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(I)c(C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C)c(I)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
To a mixture of methyl 5-iodo-2-methoxy-4-methylbenzoate (3.0 g, 9.80 mmol) in ethanol (10 ml) in a 50 ml RB flask was added an aqueous solution of NaOH (0.784 g, 19.60 mmol, 1M). The reaction mixture was stirred at room temperature overnight. The solvent was removed under vacuum, the solid filtered and dried to give the titled compound (2.2 g, 74%). LCMS: (ES+) m/z=292 (M+H)+; Column. PUROSPHER@star RP-18 (4×55) mm, 3 μm; Buffer: 20 mM NH4OAc IN WATER; Mphase A: Buffer+MeCN (90+10); Mphase B: Buffer+MeCN (10+90); Flow: 2.5 ml/min Time (min.): 0 2 2.5 3; % B: 0 100 100 0; RT: 1.04 min.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11](I)=[C:10]([S:13][CH3:14])[N:9]=[C:8]([NH2:15])[N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[Cl:16][C:17]1[CH:18]=[C:19]([C:11]2[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)=[N:7][C:8]([NH2:15])=[N:9][C:10]=2[S:13][CH3:14])[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CSc1nc(N)nc(-c2ccco2)c1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nc(N)nc(-c2ccco2)c1-c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a stirred solution of 500 mg (1.50 mmol) 4-furan-2-yl-5-iodo-6-methylsulfanyl-pyrimidin-2-ylamine in 20 ml dioxane under argon at room temperature were added 0.5 ml (1.50 mmol) 3,5-dichlorophenylboronic acid (50% solution in THF/water), 173 mg (0.15 mmol) tetrakis(triphenylphosphine)palladium(O) and 3.0 ml (6.0 mmol) 2M aqueous sodium carbonate solution. The reaction mixture was heated at reflux for 16 h, then cooled to room temperature, 1 g of kieselgel added, and the mixture concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed trituration in ether/hexane afforded 328 mg (62%) 5-(3,5-dichloro-phenyl)-4-furan-2-yl-6-methylsulfanyl-pyrimidin-2-ylamine as a beige crystalline solid. ES-MS m/e (%):354 (M{37Cl}+H+, 60), 352 (M{35Cl}+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].CCO[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Nc1ccc(I)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(I)cc1F)C(=O)OCC
Yield: 91.6 %

Procedure:
A solution of 2-fluoro-4-iodoaniline (15 g, 63.29 mmol) and diethyl ethoxymethylene malonate (41.05 g, 0.19 mol) in toluene (75 mL) was heated to reflux with a Dean-Stark condenser for 7 h. The mixture was cooled, concentrated and washed with methyl tert-butyl ether (500 ml). The methyl tert-butyl ether layer was then concentrated and the residue was washed with heptane (500 ml), yielding a white solid that precipitated out of the yellow solution. This solid was then collected, yielding 23.6 g (91%) of diethyl 2-((2-fluoro-4-iodophenylamino)methylene)malonate.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.C[Al](C)C.CCCCCC.C([O:20][C:21]([C:23]1[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=1)=O)C>O1CCOCC1>[CH3:7][N:4]1[CH:5]=[CH:6][C:2]([NH:1][C:21]([C:23]2[C:28]([Br:29])=[CH:27][CH:26]=[C:25]([CH3:30])[N:24]=2)=[O:20])=[N:3]1
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Cn1ccc(N)n1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution 3-Amino-1-methyl-pyrazole (1.39 g, 14.3 mmol, 3.5 equiv.) in 25 ml of dry dioxane were added 7.17 ml of a 2M solution of trimethyl aluminium in hexane (14.3 mmol, 3.5 equiv.) and the mixture was stirred for 1 h at r.t. Then 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester (1.00 g, 4.1 mmol) were added and the reaction was refluxed for 2 h. After allowing the reaction to cool to r.t., the reaction was quenched with water (0.5 ml), stirred for 10 min, dried by addition of magnesium sulfate and filtered over Dicalite which was further washed with methylene chloride. The filtrate was concentrated in vaccuo. The residue (1.66 g, yellow oil) was purified by flash chromatography (heptane/ethyl acetate 2:3) to yield the title compound as a yellow solid (total 0.99 g, 82%), MS (ISP): m/e=295.2, 297.2 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[N:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].N#N>CN1CCCC1=O.CN(C1C=CN=CC=1)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[N:13]=1)(=[O:9])[NH2:10]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: Cc1nc(Nc2cc(Cl)nnc2C(N)=O)ccc1F
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CN1CCCC1=O
Product: Cc1nc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)ccc1F
Temperature: 150 °C
Yield: 46.1 %

Procedure:
To a solution of 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxamide (109 mg, 387 μmol) in N-methyl-2-pyrrolidinone (2.4 mL) was added DMAP (50.7 mg, 406 μmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (166 mg, 774 μmol) and the mixture was heated to 150° C. for 1.5 d. A steam of N2 was blown into the mixture while still heating at 140° C. to evaporate the NMP, then the reaction mixture was purified by chromatography (silica, 50 μm, 40 g, Analogix, 97:2.75:0.15 to 84:15.2:0.8 dichloromethane:MeOH:NH4OH, 30 min) to provide tert-butyl (1S,2R)-2-(6-carbamoyl-5-(5-fluoro-6-methylpyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (82 mg, 23%) as a brown oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.43 (s, 1H) 8.24 (s, 1H) 8.08 (br. s., 2H) 7.22-7.37 (m, 1H) 6.66-6.77 (m, 1H) 5.64 (d, J=3.28 Hz, 1H) 4.02 (br. s., 2H) 2.49 (d, J=3.03 Hz, 3H) 1.67-1.92 (m, 2H) 1.35-1.65 (m, 8H). LCMS (EI/CI) m/z: 460 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([F:33])([F:32])[C:10]([F:31])([F:30])[C:11]([F:29])([F:28])[C:12]([F:27])([F:26])[C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:6])=[O:5].C(N(CC)CC)C.[Cl-].C([NH+](CC)CC)C>O1CCCC1>[CH:3]([S:4]([CH2:7][CH2:8][C:9]([F:33])([F:32])[C:10]([F:30])([F:31])[C:11]([F:28])([F:29])[C:12]([F:26])([F:27])[C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(CCCl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 14.3 %

Procedure:
2-(Perfluorooctyl)ethanyl 2-chloroethanyl sulfone (RF =C8F17, 5.74 g, 10.0 mmole) was dissolved in 40 ml of tetrahydrofuran (THF) at 45°, while stirring in a constant temperature oil bath. Triethylamine (1.52 g, 2.10 ml, 15.0 mmole) in 10 ml of THF was added and an exotherm carried the temperature to 51°. A precipitate of white solid triethylammonium chloride immediately began to form. After 1 hour at 45° the slurry was filtered while hot (Buchner funnel), rinsed with diethyl ether twice, and the clear filtrate evaporated on a rotary evaporator. The dry solid Et3N HCl weighed 1.35 g, 98.8% of theory. The evaporated solid 2-(perfluoro-octyl)ethanyl vinyl sulfone was taken to 40°/15 mm and weighed 5.38 g, 100% of theory; mp sinter 92° melt 93°-94.5°. The sulfone was heated further to 155° without evidence of decomposition. The sulfone was soluble in chloroform, and insoluble in carbon tetrachloride, benzene or ligroine (bp 60°-70°). The sulfone dissolved in hot benzene, but was insoluble in hot ligroine. A 1.00 g sample was dissolved in 8.0 ml of benzene by heating on a steam bath, with care to prevent foaming over; 8.0 ml of ligroine was added and the clear, colorless solution when cool gave 0.77 g of solid, mp sinter 94° melt 95°-96°. When concentrated to 4.0 ml volume a fraction, 0.11 g, mp 96°-97° was obtained. The original sample gave a single spot in TLC analysis. The infrared spectrum was identical to that of the C6 homolog of Example 1. The NMR spectrum was consistent with the proposed structure and resembled closely that obtained from the C6 homolog.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:37])=[C:21]([NH:25][S:26]([C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][Zn]C>>[F:36][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]([F:35])[C:29]=1[S:26]([NH:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:38])[N:7]=2)[C:20]=1[F:37])(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1c(F)cccc1F
Reactant: C[Zn]C
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (300 mg, 0.529 mmol) and dimethylzinc (529 μl, 1.058 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (60 mg, 31% yield). MS (ESI): 547.1 [M+H]+
Reaction SMILES: [OH:1][CH:2](P(=O)(O)O)[CH2:3][CH2:4][CH2:5][CH3:6].[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12]1.CCCCC=O.[P]>>[CH2:3]([CH:2]1[O:11][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:12][O:1]1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(O)P(=O)(O)O
Reactant: CCCCCCCCCCC1CO1
Agent: [P]
Solvent: CCCCC=O
Product: CCCCCCCCCCC1COC(CCCC)O1
Temperature: 25 °C

Procedure:
A 200 mL round bottom flask equipped with a magnetic stirring bar was charged with a solution of 0.86 g. of 1-hydroxyamylphosphonic acid, 1.97 g. of 1,2-epoxydodecane and 51 g. of n-valeraldehyde. No new phosphorus compounds were detected by 31PNMR after stirring for two weeks at room temperature. After an additional week at room temperature, there was no apparent reaction between the 1-hydroxyamylphosphonic acid and 1,2-epoxydodecane as ascertained from the 31PNMR. The reaction mixture was then washed three times with 5% sodium bicarbonate solution. The extractate contained no phosphorus component evident in the 31PNMR. The extractate was washed once with distilled water, dried over anhydrous magnesium sulfate and stripped on a rotary evaporator to give a colorless oil weighing 10.1 g. A major high boiling component of this solution, as determined by gas chromatographic mass spectroscopy was 2-n-amyl-4-n-decyl-1,3-dioxolane. These results indicate that no apparent reaction of 1-hydroxyamylphosphonic acid with 1,2-epoxydodecane occurs under conditions where 1,2-epoxydodecane reacts with the n-valeraldehyde to form 2-n-butyl-4-n-decyl-1,3-dioxolane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH2:26])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([C@@H:42]([OH:45])[CH2:43]Br)=[CH:38][C:37]=1[NH:46][CH:47]=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:27])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:43][C@@H:42]([C:39]2[CH:40]=[CH:41][C:36]([O:35][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:37]([NH:46][CH:47]=[O:48])[CH:38]=2)[OH:45])[CH3:25])=[CH:17][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CNc1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Reactant: CC(N)CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(CCCc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C

Procedure:
A suspension composed of compound 26 (0.59 g, 1.60 mmol), compound 5 (0.42 g, 1.19 mmol); K2CO3 (0.23 g, 1.68 mmol) and chloroform (25 mL) was heated to reflux for 72 h, then cooled to ambient temperature. The solid was vacuum filtered and washed with chloroform (3×10 mL). The filtrate and the washings were combined and concentrated. The residue was subjected to column chromatography eluting with 0-10% methanol in dichloromethane. The un-reacted starting material 26 (0.39 g; 66% recovery) was recovered in the separation. A mixture of two diastereomers of the desired products 27, which were not separable in this step, was obtained (0.29 g, 28%) as a colorless, viscous oil: 1H NMR (500 MHz, CDCl3) δ 1.08 (d, 3H), 1.37 (m, 2H), 1.48-1.68 (m, 6H), 2.55 (m, 4H), 2.74 (br, 2H), 2.92 (m, 1H), 3.18 (m, 2H), 3.58 (m, 1H), 3.72 (m, 1H), 4.70 (m, 1H), 4.80 (br, 1H), 5.08 (m, 4H), 6.92 (m, 1H), 7.08 (m, 5H), 7.22 (t, 1H), 7.34 (m, 10H), 7.92 (s, 1H), 8.31 (s, 1H); m/z (ESI) 638 [C39H47N3O5+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1)#[N:2].[OH-].[Na+].C([O:33]CCOCCO)C>O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][C:19]2[C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[O:24][C:18]=2[CH2:17]1)(=[O:33])[NH2:2]
Reactant: CCOCCOCCO
Reactant: N#Cc1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 36.9 g of 2-[4-(5-cyano-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine (obtainable from the corresponding 5-formyl compound via the oxime), 27.1 g of NaOH, 520 ml of water and 420 ml of diethylene glycol monoethyl ether is stirred at a bath temperature of 140° for 3 hours. The mixture is cooled, the usual working up is carried out, and 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:13])([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH:8]2[OH:13])([O-:3])=[O:2]
Reactant: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc2c1CCC2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 4-nitro-2,3-dihydro-1H-inden-1-one (149 mgs, 0.84 mmol, 1.0 equiv) in MeOH (2 mL) was added NaBH4 (10 mg, 0.26 mmol, 0.33 equiv) as a solid in one portion. After stirring for 1 h at 0° C., the solvent was removed in vacuo, and water (3 mL) was added to the residue. The aqueous suspension was extracted three times with EtOAc, and the combined organic layers were dried over sodium sulfate. The solution was filtered and concentrated in vacuo. The desired product was used without further purification (135 mg, 90%).