Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C1([Mg]Cl)C=CC=CC=1.[CH:19](=[O:23])[CH:20]([CH3:22])[CH3:21]>C1COCC1>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]([OH:23])[CH:20]([CH3:22])[CH3:21])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CC(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 99.7 %

Procedure:
To a solution of 1-iodo-2-nitrobenzene (1.12 g, 4.5 mmol) in anhydrous THF (15 mL) cooled to minus 40° C. under nitrogen atmosphere, a solution of phenylmagnesium chloride (2 M in THF, 2.4 mL, 4.8 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for five minutes at minus 40° C., followed by addition of isobutyraldehyde (0.545 mL, 6.0 mmol). The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (6 mL), poured into water (80 mL), and extracted with ethyl acetate three times (100 mL). Combined organic phase was washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(2-nitrophenyl)-2-methyl-propanol (0.876 g, 99%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.84 (dd, 1H, J=1.2 and 8.2 Hz, Ph-H), 7.73 (dd, 1 H, J=1.4 and 7.9 Hz, Ph-H), 7.61 (m, 1H, Ph-H), 7.39 (m, 1H, Ph-H), 5.03 (dd, 1H, J=4.5 and 5.8 Hz, Ph-CH), 2.42 (d, 1H, J=4.5 Hz, OH), 2.02 (m, 1H, CH), 0.95 (d, 3H, J=6.7 Hz, CH3), 0.89 (d, 3H, J=6.8 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 148.48 (C), 138.91 (C), 132.95 (CH), 128.85 (CH), 127.95 (CH), 124.21 (CH), 73.79 (CH), 34.30 (CH), 19.66 (CH3), 17.01 (CH3).
Reaction SMILES: [Na].[BH4-].[Cl:3][CH2:4][C:5](O)=O.C1C=CC=CC=1.[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([NH:32][CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:39])(=[O:38])[C:22]=2[CH:40]=1)=[O:17]>C1COCC1>[CH3:14][O:15][C:16]([C:18]1[CH:19]=[C:20]([CH3:41])[C:21]2[O:27][C:26]3[C:28]([Cl:37])=[CH:29][C:30]([N:32]([CH2:5][CH2:4][Cl:3])[CH2:33][CH2:34][CH2:35][Cl:36])=[CH:31][C:25]=3[CH2:24][S:23](=[O:38])(=[O:39])[C:22]=2[CH:40]=1)=[O:17]
Reactant: O=C(O)CCl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCCl)cc(Cl)c1O2
Agent: [BH4-]
Agent: [Na]
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)CCCCl)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Powdered sodium-borohydride (0.33 g, 8.6 mmol) was added in portions at 0° C., to a solution of chloroacetic acid (1.68 g, 17 mmol) in THF (6 mL), and benzene (90 mL). Reaction mixture was warmed to room temperature and stirred for 1 h, and compound of Example 29a (1.3 g, 2.9 mmol) was added. Reaction mixture was refluxed for 3 h. Reaction mixture was cooled and quenched using sodium bicarbonate solution, and extracted with ethylacetate. Organic layer was washed with water (100 mL) and brine (50 mL). The crude product obtained was purified by column chromatography (silica gel, ethylacetate/pet-ether) to obtain the title compound. Yield: 1.25 g (87%); 1H NMR (DMSO-d6, 300 MHz): δ 2.00 (t, 2H, CH2), 2.63 (s, 3H, CH3), 3.66 (t, 2H, CH2), 3.69-3.80 (m, 6H, 3×CH2), 3.85 (s, 3H, OCH3), 5.16 (s, 2H, CH2), 6.74 (s, 1H, Ar), 6.85 (s, 1H, Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (EI) 506 (M+).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
A suspension of sodium methoxide (40.5 g, 0.750 mol) in 200 mL of methanol was slowly added to a solution of 2-chloro-3-nitro-pyridine (79.3 g, 0.500 mol) in 800 mL of methanol at 0° C. The reaction mixture was stirred for 4 hours and then poured into 1000 g of ice. The resulting precipitate was filtered, washed with water, and dried to give 2-methoxy-3-nitro-pyridine (70. g, 0.45 mmol, 90%) as a white solid.
Reaction SMILES: C(OC(N1C(C(=O)N[C@H](C(OC)=O)CC2C=CC(C3C=CC(C#N)=CC=3)=CC=2)CC2C=C3C([O:13][C@@H:14]([C:46]4[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=4)C(=O)N3)=CC=2C1)=O)(C)(C)C.Cl.C[O:55][C:56](=[O:111])[C@@H:57]([NH:73][C:74]([CH:76]1[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:96]=[CH:95][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:109])[F:108])[CH:100]=5)=[CH:93][CH:92]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78][NH:77]1)=[O:75])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([C:65]2[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=2)=[CH:61][CH:60]=1>>[C:14]([N:77]1[CH:76]([C:74]([NH:73][C@@H:57]([CH2:58][C:59]2[CH:60]=[CH:61][C:62]([C:65]3[CH:70]=[CH:69][C:68]([C:71]#[N:72])=[CH:67][CH:66]=3)=[CH:63][CH:64]=2)[C:56]([OH:55])=[O:111])=[O:75])[CH2:89][C:88]2[CH:87]=[C:86]3[C:81]([O:82][C@@H:83]([C:91]4[CH:92]=[CH:93][C:94]([O:97][CH2:98][C:99]5[CH:104]=[CH:103][C:102]([O:105][CH3:106])=[C:101]([C:107]([F:110])([F:108])[F:109])[CH:100]=5)=[CH:95][CH:96]=4)[C:84](=[O:90])[NH:85]3)=[CH:80][C:79]=2[CH2:78]1)(=[O:13])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(OC)c(C(F)(F)F)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(O)cc1)C(=O)N3
Agent: Cl
Product: COc1ccc(COc2ccc([C@@H]3Oc4cc5c(cc4NC3=O)CC(C(=O)N[C@@H](Cc3ccc(-c4ccc(C#N)cc4)cc3)C(=O)O)N(C(=O)c3ccccc3)C5)cc2)cc1C(F)(F)F

Procedure:
(S)-7-[(S)-2-(4′-Cyano -biphenyl-4-yl)-1-methoxycarbonyl-ethylcarbamoyl]-3-(4-hydroxy-phenyl)-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6-carboxylic acid tert-butyl ester was converted to (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following the general procedure L and C. Title compound (9 mg) was prepared from (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-3-[4-(4-methoxy-3-trifluoromethyl-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-propionic acid methyl ester hydrochloride following general procedures F and B. LC-MS (m/z): 882.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]([Cl:25])([Cl:24])[CH:7]1[O:12][CH:11]([C:13]([Cl:16])([Cl:15])[Cl:14])[C:10]2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:9]=2[O:8]1>S(=O)(=O)(O)O>[N+:1]([C:20]1[C:9]2[O:8][CH:7]([C:6]([Cl:5])([Cl:24])[Cl:25])[O:12][CH:11]([C:13]([Cl:16])([Cl:14])[Cl:15])[C:10]=2[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=1)([O-:4])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc2c(c([N+](=O)[O-])c1)OC(C(Cl)(Cl)Cl)OC2C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Nitric acid (d=1.54, 10 ml.) was added to a stirred suspension of 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylic acid (5 g.) in concentrated sulphuric acid (25 ml.), and the resulting suspension was stirred at room temperature for 2 hrs. The reaction mixture was filtered, and the solid product was crystallised from a mixture of petroleum ether (b.p. 60°-80° C.) and ether to give 8-nitro-2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylic acid, m.p. 211°-212° C.
Reaction SMILES: II.[I-].[K+].[SH:5][C:6](=[CH:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8]>O.C(#N)C>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[CH:10]=[C:6]([S:5][S:5][C:6](=[CH:10][C:11]1[O:12][CH:13]=[CH:14][CH:15]=1)[C:7]([OH:9])=[O:8])[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C(S)=Cc1ccco1
Agent: II
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(O)C(=Cc1ccco1)SSC(=Cc1ccco1)C(=O)O

Procedure:
Iodine is added to a solution of 100 g of potassium iodide in 500 ml of water to saturation. This saturated solution is added dropwise to a solution of α-mercapto-β-(2-furyl)acrylic acid in 500 ml of acetonitrile and 30 ml of water until the color of iodine persists. The crude product which precipitates is recrystallized from methanol. M.P. 215° C.
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([CH:15]=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2].[O-:19]Cl=O.[Na+]>C(O)(C)(C)C.CC(=CC)C.O>[C:1]([Si:5]([CH3:18])([CH3:17])[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]([OH:19])=[O:16])[CH:14]=[C:9]2[CH:8]=[CH:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(C=O)cnc21
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(C(=O)O)cnc21
Yield: 16.4 %

Procedure:
To a stirred and cooled (0° C.) solution of aldehyde 16 (115 mg, 0.44 mmol) in tert-butanol (3.1 mL) and 2-methyl-2-butene (0.77 mL) was added a solution of NaClO2 (194 mg, 2.1 mmol) and NaH2PO4.H2O (244 mg, 1.8 mmol) in water (2.31 mL) dropwise. When 16 was consumed (TLC) the mixture was partitioned between AcOEt and water. The organic layer was washed with saturated brine (1×), dried (MgSO4), filtered and concentrated to afford acid 11 (20 mg, 16%) as an off-white solid. 1H NMR (400 MHz; CDCl3) δ 0.66 (s, 6H), 0.94 (s, 9H), 6.65 (s, 1H), 7.32 (s, 1H), 8.61 (s, 1H) and 9.03 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].Cl>CN(C=O)C.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)CBr
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)c1c(-c2ccc3cc(OCC(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (1.01 g, 2.93 mmol) in DMF (10 mL) was added sodium hydride (0.21 g, 5.25 mmol of 60% dispersion on mineral oil). It was stirred for 50 minutes at room temperature then chilled in an ice bath. Ethyl bromoacetate (0.48 mL, 4.3 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The mixture was poured into excess water, acidified with 2N hydrochloric acid, and extracted with diethyl ether. The ethereal extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 5-6% tert-butyl methyl ether in hexane as an eluant. The title compound was obtained as a yellow gum (0.749 g, 59%); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 7.9-8.1 (m, 3H), 7.8-7.9 (m, 1H, 7.7-7.8 (m, 1H), 7.3-7.5 (m, 4H), 4.95 (s, 2H), 4.2 (q, 2H, J=7.2 Hz), 2.7 (t, 2H, J=7.6 Hz), 1.45-1.65 (m, 2H), 1.0-1.3 (m, 5H), and 0.7 ppm (t, 3H, J=7.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:25]=[C:26]([CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:1][C:28]3[CH:29]=[CH:24][CH:25]=[C:26]([CH:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN1CCC(c2cccc(Br)c2)CC1
Reactant: CN(c1ccccc1-c1cccn2nc(N)nc12)S(C)(=O)=O
Agent: Cl
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCC(c2cccc(Nc3nc4c(-c5ccccc5N(C)S(C)(=O)=O)cccn4n3)c2)CC1

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+. 130b) N-[2-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (625.0 mg, 2.934 mmol) and N-methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1000.0 mg, 3.2133 mmol) in a manner analogous to Example 2c. Product was isolated as white solid (0.479 g, 51%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.52 (d, J=6.5 Hz, 1H), 7.62 (d, J=7.4 Hz, 1H), 7.55-7.42 (m, 3H), 7.35 (d, J=7.2 Hz, 1H), 6.94 (t, J=7.1 Hz, 1H), 5.94 (s, 2H), 3.10 (s, 3H), 2.85 (s, 3H). MP=209-211° C. MS=318 (MH)+. 130c) N-Methyl-N-(2-{2-[3-(1-methyl-piperidin-4-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[2-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 4-(3-bromo-phenyl)-1-methyl-piperidine; hydrochloride (76.0 mg, 0.262 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.099 g, 85%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.48 (dd, J=6.8, 0.9 Hz, 1H), 7.59-7.36 (m, 7H), 7.28-7.23 (m, 1H), 6.98 (t, J=7.1 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 3.17 (s, 3H), 3.02-2.95 (m, 2H), 2.74 (s, 3H), 2.53-2.43 (m, 1H), 2.34 (s, 3H), 2.10-2.00 (m, 2H), 1.89-1.78 (m, 4H). MS=491 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.C([O:20][B:21](OC(C)C)OC(C)C)(C)C.Cl>C1COCC1>[CH3:9][C:8]1([CH3:10])[O:11][B:21]([OH:20])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC(C)(O)c1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(O)c2ccccc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To a solution of 2-(2-bromo-phenyl)-propan-2-ol (4.0 g, 18.6 mmol, prepared as described in Egan, W. et al. J. Am. Chem. Soc., 1971, 93, 6205) in 60 mL of anhydrous THF under argon at −78° C. was slowly added n-butyl lithium (15 mL, 2.5 M). The mixture was stirred at −78° C. for 2 h, and then triisopropylborate (5.5 mL, 24.2 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and stirred at room temperature for 12 h. The mixture was then cooled to 0° C. and hydrochloric acid (10 mL, 1N) was added to the mixture until pH was <5. The mixture was then stirred at room temperature for 1 h. The two layers were separated. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to afford a yellow oil. The oil was purified by chromatography (silica, EtOAc: hexanes,1:3) to afford a white solid (1.16 g, 40%). 1H NMR (400 MHz, CDCl3) δ (ppm): 7.53 (m, 1H), 7.36 (m, 2H), 7.28 (m, 1H), 1.62 (s, 3H), 1.61 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:26])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=2[C:15]2[N:16]=[N:17][N:18]([CH3:20])[N:19]=2)[CH:7]=1
Reactant: Cn1nnc(-c2c(F)cccc2-c2cncc(Cl)c2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1nnc(-c2c(F)cccc2-c2cc(Cl)c[n+]([O-])c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine (2.90 g, 9.98 mmol) and 3-chloroperoxybenzoic acid (2.238 g, 12.97 mmol) in 40 mL CH2Cl2 was stirred at room temperature overnight. Additional 3-chloroperoxybenzoic acid (861 mg, 4.99 mmol) was added in the morning to drive the reaction to completion. The solution was washed with 0.5 N NaOH and brine, dried over Na2SO4, filtered and concentrated under vacuum to provide 3-chloro-5-[3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]pyridine 1-oxide that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 306.13 for M+H+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Br[C:18]1[S:22][C:21]([C:23]([O:25]C)=[O:24])=[CH:20][CH:19]=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[S:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: CC(C)CSc1ccc(B(O)O)cc1C#N
Product: CC(C)CSc1ccc(-c2ccc(C(=O)O)s2)cc1C#N

Procedure:
Using [3-cyano-4-(isobutylthio)phenyl]boronic acid and methyl 5-bromothiophene-2-carboxylate, 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was obtained in accordance with the method of Example 2. Then, 333 mg of the resulting 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylic acid was suspended into 10 ml of ethanol, and 1.05 ml of a 1 M aqueous sodium hydroxide solution was added to the suspension, followed by stirring at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, the residue was suspended into 2-propanol, and the precipitate was collected by filtration to obtain 256 mg of sodium 5-[3-cyano-4-(isobutylthio)phenyl]thiophene-2-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([OH:28])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](OC1C=CC=CC=1/C=C/C1C=CC(C(OC)=O)=C(OC)C=1)C1C=CC=CC=1.C(OC1C=CC=CC=1/C=C/C1C=CC(C(OC)=O)=C(O)C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([O:28][CH3:29])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1OC
Reactant: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1O
Agent: COC(=O)c1ccc(/C=C/c2ccccc2OCc2ccccc2)cc1O
Product: COC(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1OC

Procedure:
Methyl 4-[3-(2-benzyloxyphenyl)-propyl]-2-methoxybenzoate was synthesised from methyl 4-[3-(2-benzyloxyphenyl)-propyl]-2-hydroxybenzoate (prepared as described in Example 15) as described in Example 14 for the synthesis of methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-methoxybenzoate from methyl 4-[2-(2-benzyloxyphenyl)-(E)-ethenyl]-2-hydroxybenzoate.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:26]([O-:28])=[O:27])[CH:21]=[C:22]([Cl:25])[C:23]=1[CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(c2c(Cl)cc([N+](=O)[O-])cc2Cl)C(=O)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of 30.98 g (0.221 mol) of 5,5-dimethyl-1,3-cyclohexanedione and 76.36 g (0.553 mol) of anhydrous potassium carbonate in 300 ml of dimethylformamide was heated to 75° C. with stirring under N2 for one hour. The 3,4,5-trichloronitrobenzene (50.0 g, 0.221 mol) was dissolved in 100 ml of dimethylformamide and added to the reaction mixture, while stirring and maintaining the temperature at 75° C. A deep red-colored solution was formed, and when the addition was complete the temperature was raised to 100° C. and the mixture stirred over night at this temperature. Most of the dimethylformamide was removed by vacuum distillation, and 21 of water was added to the residue. The aqueous solution was extracted three times with 500 ml portions of benzene, then N2 was passed through the aqueous solution while warming to remove dissolved benzene. The solution was cooled in an ice bath and acidified with 6 N HCl to give 63.8 g (87%) of 2-(2',6'-dichloro-4'-nitrophenyl)-5,5-dimethyl-1,3-cyclohexanedione as a tan powder, m.p. 288°-290° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[C:24]([Cl:37])=[C:25]([CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:26]=[N:27][CH:28]=1>>[Cl:37][C:24]1[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)=[CH:28][N:27]=[CH:26][C:25]=1[CH2:29][NH:30][S@@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)[S@@](=O)NCc1cncc(Br)c1Cl
Product: CN1C(=O)CCc2cc(-c3cncc(CN[S@](=O)C(C)(C)C)c3Cl)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 45, 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to (R)—N-((5-bromo-4-chloropyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (intermediate A-58) to give the title compound as an orange solid. MS: 406.4 (M+H+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7].[I:10][C:11](=[C:24]([I:26])[I:25])[CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>CN(C)C=O>[I:10][C:11](=[C:24]([I:26])[I:25])[CH2:12][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cccn1CC(I)=C(I)I
Temperature: 10 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 125 mg (1 mmole) of methyl pyrrole-2-carboxylate in 5 ml of dry N,N-dimethylformamide were added 590 mg (1 mmole) of 2,3,3-triiodoallyl-p-toluenesulfonate and 50 mg (1.2 mmoles) of powdery sodium hydroxide while cooling at 10° C. and the resulting mixture was stirred for one hour. The reaction mixture was extracted with ethyl acetate and water, the ethyl acetate layer was separated, washed with water and then dried. The ethyl acetate layer was concentrated under reduced pressure, the residual oily substance was allowed to stand with 1.0 ml of methanol, thereby separating a crystalline substance, 1-(2',3',3'-triiodoallyl)-2-methoxycarbonylpyrrole. It was then recovered by filtration. Yield 127 mg (23% yield), mp 88°-90° C.