Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>CC(C)=O>[CH3:46][O:45][C:43](=[O:44])[CH2:42][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:10]3[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:18][CH:19]=1
Reactant: COC(=O)CBr
Reactant: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(O)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccccc2)n(Cc2ccccc2)c2ccc(-c3ccc(OCC(=O)OC)cc3)cc12

Procedure:
The desired product was prepared using a procedure similar to step 1 of example 4. Thus, 4-(1-benzyl-3-pentyl-2-phenyl-1H-indol-5-yl)-phenol (0.300 g, 0.673 mmol) was reacted with K2CO3 (0.121 g, 0.875 mmol) and methyl bromoacetate (0.134 g, 0.875 mmol) in acetone (10 ml) to give the product (0.296 g, 0.572 mmol, 85%) as a white, waxy solid, mp 106-109° C. 1H NMR (DMSO-d6) δ 0.72 (t, J=7.0 Hz, 3H), 1.09-1.19 (m, 4H), 1.49-1.56 (m, 2H), 2.64 (t, J=7.5 Hz, 2H), 3.68 (s, 3H), 4.79 (s, 2H), 5.23 (s, 2H), 6.79-6.81 (m, 2H), 6.97 (d, J=8.9 Hz, 2H), 7.09-7.18 (m, 3H), 7.29-7.34 (m, 4H), 7.37-7.47 (m, 3H), 7.55 (d, J=8.9 Hz, 2H), 7.72 (d, J=0.7 Hz, 1H); [ESI(+)], m/z 519 (M+H)+.
Reaction SMILES: [C:1]1([Si:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([O:37][Si](C)(C)C)=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:28]=2)[C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([O:18][Si](C)(C)C)=[C:10]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[C:1]1([Si:7]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:8]2[CH:9]=[C:10]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:11]([OH:18])=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:13]=2)[C:27]2[CH:28]=[C:29]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:30]([OH:37])=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)c1cc([Si](c2ccccc2)(c2ccccc2)c2cc(C(C)(C)C)c(O[Si](C)(C)C)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc([Si](c2ccccc2)(c2ccccc2)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
To a solution of 5.0 g (7 mmol) of diphenylbis(3,5-di-tert-butyl-4-trimethylsilyloxyphenyl)silane in 30 ml of tetrahydrofuran at 0° C. is added dropwise a solution of 4.3 g (14 mmol) of tetrabutylammonium fluoride trihydrate in 35 ml of tetrahydrofuran. The reaction mixture is stirred for 5 minutes at 0° C. and to it is added dropwise a solution of 2.2 g (62 mmol) of concentrated hydrochloric acid in 10 ml of tetrahydrofuran. The solvent is removed in vacuo and to the residue is added 250 ml of diethylether. The solution is extracted (3×100 ml) with water. The organic phase is dried over anhydrous sodium sulfate and the solvent is removed in vacuo to give 4.0 grams of a white solid. The crude product is recrystallized from heptane to give 3.0 g (75%) of product as white crystals; mp. 193°-194.5° C.
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([O:11]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.[CH3:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:27][S:28]([CH2:31][C:32]([NH:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:9]([OH:11])=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12)=[O:33])(=[O:30])=[O:29]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Reactant: CS(=O)(=O)CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CS(=O)(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12

Procedure:
A solution of benzhydryl 7-amino-3-cephem-4-carboxylate (0.78 g, 2 mmol), methylsulfonylacetic acid (0.27 g, 2 mmol), and dicyclohexylcarbodiimide (0.4 g, 2 mmol) in dry tetrahydrofuran (15 ml) is stirred at room temperature overnight. The precipitate is collected and washed with tetrahydrofuran and the combined filtrate and washings are evaporated in vacuo. The residue is treated with a cold soluton of trifluoroacetic acid (10 ml) and anisole (0.5 g) for 15 minutes and then concentrated in vacuo. The residue is dissolved in ethyl acetate and treated with 5% NaHCO3. The aqueous phase is adjusted to pH 2 and the precipitated product is collected and dried.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:20](Cl)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>C(Cl)Cl>[S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
3-t-Butoxycarbonylaminopropanol (10.0 g) is dissolved in methylene chloride (100 ml), and thereto are added with stirring triethylamine (8.66 g) and tosyl chloride (16.3 g) under ice-cooling, and the mixture is stirred at room temperature overnight. The reaction mixture is concentrated, and the residue is dissolved in a mixture of water and ethyl acetate. The organic layer is separated, washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 3-t-butoxycarbonylaminopropyl tosylate (15.37 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([OH:64])[CH2:5][C:4]1=[O:65])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: [H][H]
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.6 %

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (37 mg in 2 ml ethanol) was added 4 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 1.5 hours, the mixture was filtered over Celite, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (19.5 mg).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:37]1[CH:38]=[CH:39][C:40]2[C:41]3[N:50]([CH2:51][CH:52]([CH3:54])[CH3:53])[C:49]([CH2:55][CH2:56][CH2:57][CH3:58])=[N:48][C:42]=3[C:43]([NH2:47])=[N:44][C:45]=2[CH:46]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[NH2:47][C:43]1[C:42]2[N:48]=[C:49]([CH2:55][CH2:56][CH2:57][CH3:58])[N:50]([CH2:51][CH:52]([CH3:53])[CH3:54])[C:41]=2[C:40]2[CH:39]=[CH:38][C:37](/[CH:3]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4])=[CH:46][C:45]=2[N:44]=1
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CC(C)C
Temperature: 100 °C
Yield: 72.3 %

Procedure:
A thick walled glass tube, equipped with stir bar, was charged with palladium (II) acetate (18 mg, 0.08 mmol), acetonitrile (2 mL), methyl acrylate (69 mg, 0.8 mmol), triethylamine (240 mg, 2.4 mmol), tri-o-tolylphosphine (49 mg, 0.16 mmol) and 7-bromo-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (U.S. Patent Application Publication No. US 2004/0147543 Example 1, 300 mg, 0.8 mmol). The reaction mixture was purged with nitrogen and the tube was sealed and heated to 100° C. in an oil bath. The mixture became an amber homogeneous solution after approximately 5 minutes. The reaction was maintained at 100° C. for 32 hours and then concentrated to dryness. The reaction mixture was taken up in water and dichloromethane. Saturated aqueous potassium carbonate solution was added, adjusting to pH 11. The organic layer was separated and concentrated to a golden syrup. The crude product was purified by flash chromatography on silica gel (eluting with 5% methanol/dichloromethane). The resulting tan solid (230 mg) was recrystallized from acetonitrile to give 220 mg of Methyl(2E)-3-[4-amino-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a pale gold solid, mp 193-194° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:4]2[CH:3]=[C:2]([B:26]([OH:31])[OH:27])[CH:7]=[CH:6][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=P(O)(O)O
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Temperature: -70 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(3-bromophenyl)piperazine-1-carboxylate (3.8 g, 11.14 mmol, 1.00 equiv) in toluene/tetrahydrofuran=1:1 (40 mL). This was followed by the addition of n-BuLi (4.9 mL, 2.5M/L) dropwise with stirring at −70° C. The resulting solution was stirred for 30 min at −70° C. To this was added triisopropyl borate (2.5 g, 13.30 mmol, 1.19 equiv) dropwise with stirring at −70° C. The mixture was warmed to 0° C., the reaction was then quenched by the addition of 13 mL of saturated ammonium chloride and 3.4 mL of water. Phosphoric acid (85 wt %, 1.5 g, 1.2 equiv) was added and the mixture was stirred for 30 min. The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was dissolved in 20 mL of toluene. The product was precipitated by the addition of 80 mL of heptane. The solids were washed with 20 mL of heptane and collected by filtration. This resulted in 2.9 g (85%) of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC1C=C[C:35]2[NH:34][CH:33]=[C:32]3C(=O)N(C4C=CC=CC=4)N=C3[C:30]=2[N:29]=1>>[C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[C:18]([N:29]5[CH2:30][CH2:35][NH:34][CH2:33][CH2:32]5)=[N:17][CH:16]=[CH:15][C:14]=4[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3c(N4CCNCC4)nccc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described in Step 4 for synthesis for 6a using 16 instead of 5a. 1H-NMR (DMSO-d6) δ (ppm): 3.2 (4H, brm), 3.48 (4H, brm), 7.13 (1H, m), 7.46 (2H, m), 7.78 (1H, d, J=5.2 Hz), 8.18 (2H, d, J=7.7 Hz), 8.30 (1H, d, J=5.2 Hz), 8.50 (1H, s). m/z 347.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5]I.[CH2:12]([O:14][P:15]([O:19]CC)[O:16][CH2:17][CH3:18])[CH3:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[F:10])[CH2:5][P:15](=[O:19])([O:16][CH2:17][CH3:18])[O:14][CH2:12][CH3:13]
Reactant: CCOP(OCC)OCC
Reactant: Fc1cc(CI)cc(F)c1F
Product: CCOP(=O)(Cc1cc(F)c(F)c(F)c1)OCC
Temperature: 135 °C
Reaction time: 8 h

Procedure:
3,4,5-trifluorobenzyl iodide (5.075 g, 22.55 mmol) was combined with triethylphosphite (11.6 mL, 67.7 mmol) and the mixture heated and stirred at 135° C. overnight. The mixture was put under hi-vacuum and heated to 70° C. for 12 hours. The final product was a clear oil (6.10 g, 96% yield). 1H NMR (400.14 MHz, CDCl3) δ 6.93 (m, 2H), 4.07 (quint, J=7.10 Hz, 4H), 3.06 (d, J=21.7 Hz, 2H), 1.28 (t, J=7.05 Hz, 6H). 13C{1H} NMR (100.62 MHz, CDCl3) δ 150.8 (dddd, J=249.7, 9.8, 3.8, 3.8 Hz, 2C), 138.74 (dtd, J=250.6, 15.2, 3.9 Hz), 128.2-127.9 (m), 113.9-113.6 (m, 2C), 62.30 (d, J=6.74 Hz, 2C), 32.93 (d, J=139.8 Hz), 16.20 (d, J=6.01 Hz, 2C). 31P{1H} NMR (202.45 MHz, CDCl3): δ 24.96. Analysis calculated (found) %: C 46.82 (46.72), H 5.00 (4.96). MS (FAB, m/z): 269 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 269.05544 (269.05616).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.I[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCN1CCC(C(N)=O)CC1
Yield: 59.8 %

Procedure:
Prepared from isonipecotamide (3.3, 25.7 mmol), 1-iodopentane (5.1 g, 25.7 mmol) and potassium carbonate (3.54 g, 25.7 mmol) according to the procedure used for Example 8 (Step A) to give 3.05 g of the title compound as an off-white solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1

Procedure:
321 ml. (4.7 moles) of chlorosulfonic acid and 79 g. (0.5 moles) of 4-chloro-nitrobenzene are stirred at 130° C. for 6 hours. The reaction mixture is then cooled to a temperature below 10° C. and is poured onto 750 ml. of icy water. The mixture is filtered at room temperature and the substance collected on the filter is washed acid-free with about 2 liters of water. The crude 2-chloro-5-nitrobenzene sulfonyl chloride obtained is subjected to the subsequent reaction steps without purification. 118 g. (0.935 moles) of anhydrous sodium sulfite and 20 g. of sodium bicarbonate are dissolved in 250 ml. of water, and to the solution obtained a mixture of the crude 2-chloro-5-nitrobenzene sulfonyl chloride and 20 g. of sodium bicarbonate is added at a temperature of 23° to 25° C., in one hour. The reaction mixture is stirred for two hours at a temperature of 23° to 25° C., and, after the addition of 200 ml. of toluene, for further 15 minutes. The mixture is stirred at 25° C. and the substance filtered off is washed with 100 ml. of toluene. The sodium 2-chloro-5-nitrobenzene sulfinate obtained is dissolved in 400 ml. of water at 40° C., and the solution is admixed with 200 ml. of toluene. The insoluble part is filtered off and the toluene phase is separated from the filtrate. The aqueous phase is cooled to 10° C., acidified with 100 ml. of concentrated aqueous hydrochloric acid solution and the precipitated crystals are stirred, filtered off at 10° C. and dried. 61 g. of 2-chloro-5-nitrobenzene sulfinic acid are obtained. Yield: 55% of theoretical related to 4-chloro-nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:23])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:24](I)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([O:23][CH2:24][CH3:25])[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(c2ccc(Cl)c(Cl)c2)C1
Product: CCOC1(c2ccc(Cl)c(Cl)c2)COCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (6RS)-6-(3,4-dichlorophenyl)-6-hydroxy-1,4-oxazepane-4-carboxylate (158 mg) and ethyl iodide (0.052 mL), and by a method similar to that of Example 17, step A), the title compound (160 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19](OC)=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.O.[NH2:26][NH2:27]>C(O)C>[F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:14]3[CH:15]=[C:16]([C:19]([NH:26][NH2:27])=[O:20])[CH:17]=[CH:18][C:13]=3[O:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc2occ(-c3cccc(OC(F)(F)F)c3)c2c1

Procedure:
A solution of methyl 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carboxylate (6.80 g, 20.2 mmol) and hydrazine monohydrate (9.92 mL, 202.2 mmol) in ethanol (70 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration to give 3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-carbohydrazide.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH3:15])=[CH:10][CH:9]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O1CCOCC1>[CH3:16][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:15])[S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:29])[F:30])=[CH:24][CH:23]=2)(=[O:27])=[O:26])=[CH:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNc1ccc(C#CCCCN(C)C)cc1
Solvent: C1COCCO1
Product: CN(C)CCCC#Cc1ccc(N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 173 mg (0.8 mmol) of [4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-methyl-amine in 2 ml dioxane was treated with 0.15 ml (0.88 mmol) Huinigsbase and 247 mg (1 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction mixture was stirred over night at room temperature and extracted with aqueous 10% KHSO4/EtOAc (3×). The aqueous phase was treated with NaHCO3 (pH 7-8) and extracted with CH2Cl2 (3×). The organic phase was dried over Na2SO4 and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (9:1) yielded 223 mg (65%) of N-[4-(5-Dimethylamino-pent-1-ynyl)-phenyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide, MS: 425 (MH+).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2]([O:4][CH2:5][CH3:6])=[O:3].C[Si](C)(C)[O-].[K+:16]>CCOCC>[C:2]([O:4][CH2:5][CH3:6])(=[O:3])[C:1]([O-:8])=[O:7].[K+:16]
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)[O-]
Temperature: 25 °C
Yield: 79.2 %

Procedure:
The procedure of Example 1 was followed using diethyl oxalate (3.0 mL, 22 mmol), potassium trimethylsilanolate (3.85 g, 22 mmol), dry ether (70 mL), an ice bath to maintain room temperature initially, and a 1.5 h reaction time. Potassium ethyl oxalate (2.72 g, 79% yield) was isolated as a white solid: 1H NMR (D2O) δ 1.3 (t, J=7.2 Hz, CH3, 3H), 4.2 ppm (q, J=7.2 Hz, CH2, 2H). Anal. Calcd. for C4H5KO4 : C, 30.76; H, 3.23; K, 25.04. Found: C, 30.39; H, 3.29; K, 25.30.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].Br[C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([Cl:17])=[C:14]([CH3:16])[CH:15]=1>O1CCCC1.CN(C)C=O>[Cl:18][C:12]1[CH:11]=[C:10]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:15]=[C:14]([CH3:16])[C:13]=1[Cl:17]
Reactant: C=C([Zn+])C(F)(F)F
Reactant: Cc1cc(Br)cc(Cl)c1Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=C(c1cc(C)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (19 mL) was added a solution of 5-bromo-2,3-dichlorotoluene (2.2 g) in N,N-dimethylformamide (10 mL), then tetrahydrofuran was distilled off under reduced pressure. Dichlorobis(triphenylphosphine)palladium(II) (0.26 g) was added to the residual N,N-dimethylformamide solution, which was stirred at 100° C. for 3.5 hours under nitrogen atmosphere and then cooled to room temperature. To the resulting mixture was added tetrahydrofuran-hexane 2:5 mixture (200 mL) and filtered, and the filtrate was washed with water (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a brown oil (2.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]([S:13]([CH3:16])(=[O:15])=[O:14])S(C)(=O)=O)=[CH:6][C:5]([C:17]2[S:21][C:20](Cl)=[N:19][C:18]=2[CH3:23])=[CH:4][N:3]=1.[CH3:24][NH2:25]>C(O)C>[Cl:1][C:2]1[C:7]([NH:8][S:13]([CH3:16])(=[O:14])=[O:15])=[CH:6][C:5]([C:17]2[S:21][C:20]([NH:25][CH3:24])=[N:19][C:18]=2[CH3:23])=[CH:4][N:3]=1
Reactant: CN
Reactant: Cc1nc(Cl)sc1-c1cnc(Cl)c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Solvent: CCO
Product: CNc1nc(C)c(-c2cnc(Cl)c(NS(C)(=O)=O)c2)s1
Temperature: 120 °C

Procedure:
A mixture of N-[2-chloro-5-(2-chloro-4-methyl-1,3-thiazol-5-yl)pyridin-3-yl]-N-(methylsulfonyl)methanesulfonamide (94 mg) and a 13% solution of methylamine in ethanol (5.0 mL) was stirred and heated to 120° C. in a sealed glass tube in a microwave reactor for 2.5 hours. The resultant mixture was evaporated. Ethanol was added and the mixture was re-evaporated. The material so obtained was purified by reversed phase preparative HPLC. There was thus obtained the title compound (25 mg); 1H NMR Spectrum: (DMSOd6) 2.23 (s, 3H), 2.83 (d, 3H), 3.13 (s, 3H), 7.76 (s, 1H), 7.82 (s, 1H), 8.23 (s, 1H), 9.77 (s, 1H); Mass Spectrum: M+H+ 333.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C@@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22])=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])=[CH:6][CH:7]=1.C(C1C=CC(OC)=C(C2N=C(N[C@@H](C(C)C)[CH2:43][OH:44])C([N+]([O-])=O)=CC=2)C=1)(C)C>C(O)C.[Pd]>[OH:22][CH2:21][C@@H:20]([N:19]1[C:3]2=[N:4][C:5]([C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=3[O:17][CH3:18])=[CH:6][CH:7]=[C:2]2[NH:1][C:43]1=[O:44])[CH:23]([CH3:25])[CH3:24]
Reactant: COc1ccc(C(C)C)cc1-c1ccc([N+](=O)[O-])c(N[C@H](CO)C(C)C)n1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(N)c(N[C@H](CO)C(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc2[nH]c(=O)n([C@H](CO)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-2-(3-Amino-6-(5-isopropyl-2-methoxyphenyl)pyridin-2-ylamino)-3-methylbutan-1-ol. A solution of (S)-2-(6-(5-isopropyl-2-methoxyphenyl)-3-nitropyridin-2-ylamino)-3-methylbutan-1-ol (0.33 g, 0.88 mmol) in ethanol (30 mL) was purged with nitrogen for several min. Following addition of palladium on carbon (0.038 g, 0.35 mmol), the flask was evacuated and a hydrogen filled balloon was placed on the reaction. After stirring at room temperature for 18 h, the reaction was filtered and the solvent removed under reduced pressure to afford the title compound (0.30 g, 99% yield). MS (ESI) m/z 344.3 [M+1]+.