Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH2:31][OH:32])[CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:43](OC)([CH3:45])[CH3:44].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:33]1[C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)([CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:31][O:32][C:43]1([CH3:45])[CH3:44])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)NC(CO)(CCc1ccc(OCc2ccccc2)cc1)COC(=O)c1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitro-benzoic acid 4-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-2-hydroxymethyl-butyl ester (105 mg, 0.19 mmol) in toluene (2 ml) is added 2,2 dimethoxypropane (0.06 ml, 0.57 mmol, 3 eq) and a catalytic amount of p-toluene sulfonic acid. The reaction mixture is stirred at 95° C. for 6 hours, then concentrated to dryness under negative pressure. 4-[2-(4-Benzyloxy-phenyl)ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxy-methyl)-oxazolidine-3-carboxylic acid tert-butyl ester is isolated as an oil (88 mg, 78%) after purification by flash chromatography (Ethyl acetate/Hexane (1/3)).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 91 %

Procedure:
Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70° C.) solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70° C. for 15 min., then (2S,3S)-1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise. The mixture was stirred at -70° C. for 1 h., then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room temperature for 1 h., water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 91%). 1H NMR (250 MHz, CDCl3) δ 7.5-7.3 (5H, m), 5.8 (1H, br s), 4.2 (1H, br s), 3.4 (1H, m), 2.6 (2H, m), 2.0 (2H, m), and 1.54 (9H, s).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([C@H:23]([C:25]1[CH:30]=[CH:29][N:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:24])=[N+]=[N-]>O1CCCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]([C@@H:23]([NH2:20])[CH3:24])[CH:30]=[CH:29][N:28]=1
Reactant: C[C@H](N=[N+]=[N-])c1ccnc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](N)c1ccnc(Cl)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Triphenylphosphine (9.56 g) was added to a solution of 4-((S)-1-azidoethyl)-2-chloropyridine (4.44 g) in tetrahydrofuran-water (4:1, 50 mL), and the reaction solution was heated and stirred at 60° C. for two hours. The reaction solution was returned to room temperature, and the solvent was evaporated under reduced pressure. Chloroform and 5 N hydrochloric acid were added to the residue, and the aqueous layer was separated. The aqueous layer was made basic with 5 N sodium hydroxide. Chloroform was added to the reaction solution, and the organic layer was separated. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the title compound (2.24 g). The property values of the compound are as follows.
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C@H:36]([C:37]([O-:39])=O)[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:75]([O:82][C:83](=[O:86])[CH2:84][NH2:85])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:25]([N:28]1[C@H:36]([C:37]([NH:85][CH2:84][C:83]([O:82][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:86])=[O:39])[CH2:35][C:34](=[O:40])[C:33]2[CH:41]=[CH:42][CH:43]=[CH:44][C:32]=2[N:31]([CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:30](=[O:52])[C@H:29]1[CH2:53][C:54]12[CH2:63][CH:58]3[CH2:59][CH:60]([CH2:62][CH:56]([CH2:57]3)[CH2:55]1)[CH2:61]2)(=[O:27])[CH3:26]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: NCC(=O)OCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
PyBroP (233 mg, 0.5 mmol) was added to a solution of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate (264 mg, 0.5 mmol), glycine benzyl ester p-toluenesulphonate (170 mg, 0.5 mmol) and diisopropylethylamine (260 μl, 1.5 mmol in dry DCM (5 ml). The reaction mixture was stirred at room temperature for 18 hours, diluted with DCM (20 ml), washed successively with 2N HCl solution (25 ml), brine (25 ml) and dried (MgSO4). Filtration an evaporation of the solvent gave the crude product (350 mg) which was purified by flash chromatography on silica gel with ethyl acetate-DCM (3:7) as eluant, affording the product as a colourless oil. (190 mg, 55%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][C:8](O)=[O:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:3]1>O1CCCC1>[CH3:1][N:2]1[C:6]([CH2:7][CH2:8][OH:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:13][CH:12]=2)=[N:3]1
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CC(=O)O
Solvent: C1CCOC1
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of [2-methyl-5-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-acetic acid (286 mg, 1 mmol) in tetrahydrofuran (4 ml) was treated at 0° C. with a 1 M solution of BH3*THF in tetrahydrofuran (2.5 ml, 3 mmol). The cooling bath was removed and the reaction mixture stirred at ambient temperature for 16 h. Careful quenching with MeOH and ice water, twofold extraction with AcOEt, washing with ice water/brine 1/1, drying over magnesium sulfate, and evaporation of the solvent left a crude product which was refluxed for 30 min in MeOH to liberate quantitatively the free alcohol. The solvent was evaporated in vacuo to yield 273 mg (1 mmol, quant.) of the title compound as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[CH3:14][C:15]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:16]=1[CH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cccc(C)c1Cc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(Cc3c(C)cccc3C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.2 %

Procedure:
To a solution of methyl 3-(4-hydroxyphenyl)propanoate (180 mg), 3-(2,6-dimethylbenzyl)benzyl alcohol (226 mg) and triphenylphosphine (286 mg) in toluene (2 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution 500 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified by silica gel column chromatography with ethyl acetate-hexane (gradient of 1:9 to 3:2 by volume ratio) to give the title compound (125 mg, yield 32%) as a pale-yellow oil.
Reaction SMILES: BrC1C=CC2C3N(C[O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])N=CC=3C(=O)NC=2C=1.BrC1C=CC2C3NN(COCC[Si](C)(C)C)CC=3C(=O)NC=2C=1.CC1(C)C(C)(C)OB(C2C=CN=CC=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:70]1[CH:75]=[CH:74][C:73]([C:76]2[CH:77]=[CH:78][C:79]3[C:80]4[NH:89][N:88](OCC[Si](C)(C)C)[CH2:87][C:81]=4[C:82](=[O:86])[NH:83][C:84]=3[CH:85]=2)=[CH:72][CH:71]=1>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:70]1[CH:75]=[CH:74][C:73]([C:76]2[CH:77]=[CH:78][C:79]3[C:80]4[N:89]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[N:88]=[CH:87][C:81]=4[C:82](=[O:86])[NH:83][C:84]=3[CH:85]=2)=[CH:72][CH:71]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(=O)[nH]c3cc(Br)ccc3c21
Reactant: C[Si](C)(C)CCON1Cc2c(c3ccc(-c4ccncc4)cc3[nH]c2=O)N1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccncc2)OC1(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOn1ncc2c(=O)[nH]c3cc(-c4ccncc4)ccc3c21
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
To a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one [described in Step 3.1] (18.2 g, 46.2 mmol) in 150 mL of DMF placed in a microwave reactor are successively added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (11.4 g, 55.4 mmol), aqueous 2M K3PO4 solution (47 mL, 92.4 mmol) and the catalyst PdCl2(dppf) (1.88 g, 2.31 mmol) under nitrogen. The reactor is sealed and the reaction mixture is stirred for 20 minutes at 150° C. under microwave irradiation. After concentrating the reaction mixture, purification by flash chromatography on silica (DCM/MeOH: 0/100 to 95/5) gives 12.4 g of 7-(pyrid-4-yl)-1-[2-(trimethylsilyl)ethoxy]-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-(pyrid-4-yl)-2-[2-(trimethylsilyl)ethoxy]-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a white solid (yield: 54%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:13]([N:14]2[N+:18]([O-:19])=[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[N:15]2)=[CH:12][C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=1.[CH2:24](Br)[C:25]#[CH:26].O>CN(C)C=O>[CH2:26]([N:8]1[C:7]2[CH:12]=[C:13]([N:14]3[N+:18]([O-:19])=[C:17]4[CH2:20][CH2:21][CH2:22][CH2:23][C:16]4=[N:15]3)[C:4]([F:3])=[CH:5][C:6]=2[S:10][C:9]1=[O:11])[C:25]#[CH:24]
Reactant: C#CCBr
Reactant: O=c1[nH]c2cc(-n3nc4c([n+]3[O-])CCCC4)c(F)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21

Procedure:
To a dispersion of sodium hydride (60% oil; 31 mg) in dry N,N-dimethylformamide (3 ml) was added 2-[6fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (220 mg) at 0° C., and the resultant mixture was stirred at the same temperature for 30 minutes, followed by addition of propargyl bromide (94 mg). The mixture was allowed to react at 50° to 60° C. for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and toluene (1:9) as an eluent to give 2-[3-(2-propynyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-4,5,6,7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 5; 120 mg). n25.4D 1.5988.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:18]([OH:20])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][C:34]1[NH:38][N:37]=[N:36][N:35]=1>>[NH:35]1[C:34]([NH:33][C:18]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:13]=3)[N:5]=2)=[O:20])=[N:38][N:37]=[N:36]1
Reactant: Nc1nnn[nH]1
Reactant: CC(=O)Nc1ccc(-c2cc(C)cc(C(=O)O)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(=O)Nc1ccc(-c2cc(C)cc(C(=O)Nc3nnn[nH]3)n2)cc1
Yield: 72.1 %

Procedure:
In the same manner as described in Example 1-(1), 4-methyl-6-(4-acetylaminophenyl)-2-pyridinecarboxylic acid (1.0 g), carbonyldiimidazole (0.72 g) and 5-aminotetrazole (0.38 g) are reacted to give N-(5-tetrazolyl)-4-methyl-6-(4-acetylaminophenyl)-2-pyridinecarboxamide (0.9 g). M.P. 309°-310° C. (decomp.) (wetted at about 290° C.) (recrystallized from dimethylformamide-ethanol)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([F:15])([F:14])[F:13].[CH3:16][O:17]C1C=CC(CC(F)(F)F)=CC=1C=O>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH2:11][C:12]([F:14])([F:13])[F:15])=[CH:5][C:6]=1[CH:16]=[O:17]
Reactant: COc1ccc(CC(F)(F)F)cc1C=O
Reactant: COc1ccc(CC(F)(F)F)c(OC)c1
Product: COc1cc(OC)c(CC(F)(F)F)cc1C=O

Procedure:
This compound was prepared from Compound 84 in the same manner of Compound 46.
Reaction SMILES: CP(C)CCP(C)C.[Br:9][C:10]1[CH:11]=[C:12]([Cl:16])[CH:13]=[CH:14][CH:15]=1.[B]1OC(C)(C)C(C)(C)[O:18]1.B.OOS([O-])=O.[K+]>CC(C)=O.O.C1CC=CCCC=C1.C1C=C[C]2[CH][CH][CH][C]2C=1.[Ir]>[Br:9][C:10]1[CH:15]=[C:14]([OH:18])[CH:13]=[C:12]([Cl:16])[CH:11]=1
Reactant: CC1(C)O[B]OC1(C)C
Reactant: Clc1cccc(Br)c1
Agent: [Ir]
Agent: B
Agent: C1=C\CC/C=C\CC/1
Solvent: CC(C)=O
Solvent: C1=CCCC=CCC1
Solvent: O
Product: Oc1cc(Cl)cc(Br)c1
Temperature: 150 °C
Reaction time: 3.5 h
Yield: 62 %

Procedure:
Under an atmosphere of dry nitrogen, 103 mg 1,5-cyclooctadiene(H5-indenyl)iridium (I) was put in a 25 mL Pyrex bottle. Subsequently were added 0.04 mL 1,2-bis(dimethylphosphino)ethane, 0.61 mL 3-bromochlorobenzene and 1.52 mL pinacolborane. The mixture was stirred at 150° C. for 3.5 h. After cooling to room temperature, the borane adduct was taken up in 17 mL acetone to give a clear solution. This solution was added slowly to 17.41 mL of a 0.30 M solution of oxone in water cooled in an ice bath. The mixture was stirred vigorously for 15 min. at room temperature and extracted three times with DCM. The combined organic phases were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM) to yield 750 mg (62%) of a beige solid. 1H NMR complies with known data (compound (I), Maleczka, 2003).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=2)=[C:17]([F:30])[C:16]=1[O:31][CH3:32]
Reactant: COc1c(Cl)ccc(B2OC(C)(C)C(C)(C)O2)c1F
Reactant: CC(=O)Nc1cc(Cl)c(C=O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(Cl)ccc(-c2cc(NC(C)=O)ncc2C=O)c1F
Temperature: 85 °C
Yield: 33.8 %

Procedure:
A stirred solution of N-(4-chloro-5-formylpyridin-2-yl)acetamide (1.947 g, 8.72 mmol) (prepared as described in Example 18, Part D), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 8.72 mmol), cesium carbonate (5.69 g, 17.45 mmol) and Pd(PPh3)4 (0.504 g, 0.436 mmol) in a mixture of dioxane (30 mL) and water (5 mL) was purged with nitrogen for 5 minutes then heated to 85° C. for 14 h. The reaction mixture was cooled to rt and diluted with water (10 mL). The mixture was extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulphate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to yield N-(4-(4-chloro-2-fluoro-3-methoxyphenyl)-5-formylpyridin-2-yl)acetamide (1.78 g, 2.95 mmol, 34% yield) as a white solid. LCMS (ESI) m/e 322.9 [(M+H)+, calcd for C15H13ClFN2O3 323.1]; LC/MS retention time (Method F): tR=0.89 min.
Reaction SMILES: Cl[C:2]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3].[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([CH3:20])[CH:14]=1.C(N(CC)CC)C>>[Br:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]([CH:4]([CH2:10][CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:3])=[C:15]([CH3:20])[CH:14]=1
Reactant: CCOC(=O)C(CC)C(=O)Cl
Reactant: Cc1cc(Br)ccc1N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CC)C(=O)Nc1ccc(Br)cc1C
Yield: 66.7 %

Procedure:
Ethyl 2-(chlorocarbonyl)butanoate (5.8 grams, 0.03 mole), 4-bromo-2-methylaniline (5.0 grams, 0.03 mole) and triethylamine (3.27 grams, 0.03 mole) were reacted under conditions similar to that described for Example I to give 7.4 grams (0.02 mole) of ethyl 2-(4-bromo-2-methylphenylaminocarbonyl)butanoate as a white solid having a melting point of 98° C.-100° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH2:10]([C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:23]3[C:32]([CH3:34])([CH3:33])[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:35](O)=[O:36])[CH:29]=4)[NH:24]3)[CH:20]=[CH:21][CH:22]=2)[N:15]=[N:14][N:13]=1)[CH3:11].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH2:10]([C:12]1[N:16]([C:17]2[CH:18]=[C:19]([CH:23]3[C:32]([CH3:33])([CH3:34])[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:35]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:36])[CH:29]=4)[NH:24]3)[CH:20]=[CH:21][CH:22]=2)[N:15]=[N:14][N:13]=1)[CH3:11]
Reactant: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nnnn1-c1cccc(C2Nc3ccc(C(=O)NS(=O)(=O)C4CC4)cc3CC2(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a suspension of 60% sodium hydride (160 mg, 3.9 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (484 mg, 4.0 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.4 mmol) and 1,1′-carbonyldiimidazole (136 mg, 0.84 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(5-ethyl-tetrazol-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (77 mg, 40%) as a white solid: LC/MS m/e calcd for C24H28N6O3S (M+H)+: 481.59, observed: 481.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=5)=[C:36]([O:49][CH2:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:28])([F:29])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N+:42]=5[O-:61])=[C:36]([O:49][CH2:50][CH3:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:52]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)ccn4)c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cc(C)cc[n+]4[O-])c(OCC)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methylpyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.68 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.28 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was concentrated and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-ethoxy-4-[hydroxy(4-methyl-1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.89 g) as colorless amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4].[Br:15]Br>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:15])[CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4]
Reactant: BrBr
Reactant: COC(=O)c1cccc2c1SCCC2
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c1SCCC2
Yield: 82.2 %

Procedure:
A solution of methylthiochroman-8 carboxylate (0.300 g, 1.44 mmol) (D6a) in dichloromethane (20 ml) was treated with bromine (0.106 ml, 2.07 mmol) and the reaction mixture left at room temperature. After 4 days the reaction mixture was washed with sodium metabisulphile solution. The organic layer was then dried (Na2SO4) and evaporated under reduced pressure to give the title compound as a colourless oil (0.340 g, 82%).