Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[S:25]1[CH:29]=[N:28][N:27]=[C:26]1[NH2:30].Cl>N1C=CC=CC=1>[CH2:1]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:30][C:26]2[S:25][CH:29]=[N:28][N:27]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Nc1nncs1
Reactant: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
To a solution of p-tetradecylbenzenesulfonyl chloride (440 mg, 1.18 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (179 mg, 1.77 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (240 mg, 0.55 mmol, 47% yield), mp 116-117° C.; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, 3H, J=6.9 Hz), 1.25 (m, 22H), 1.60 (m, 2H), 2.64 (t, 2H, J=7.2 Hz), 7.29 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.4 Hz), 8.23 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.1, 22.6, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; MS (LCQ, ESI+) Calcd for C22H36N3O2S2 438.2, found 438.3 (M+H)+; HRMS (ESI+, m/z) Calcd for C22H36N3O2S2 438.2243, found 438.2243 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH2:29][CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:40]([O-])([O-])=O.[K+].[K+]>C(O)(C)C>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19][C:20]([C:22]3[C:23](=[O:38])[N:24]([C:31]4[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=4)[CH:25]=[CH:26][C:27]=3[O:28][CH:29]([CH3:40])[CH3:30])=[O:21])=[C:14]([F:39])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(C)=O)c2)cc1F
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)Nc1cc(Oc2cc(F)c(NC(=O)c3c(OC(C)C)ccn(-c4ccc(F)cc4)c3=O)cc2F)ccn1
Yield: 71.9 %

Procedure:
A mixture of Example 1 (0.400 g, 0.743 mmol) and K2CO3 (0.400 g, 2.89 mmol) in isopropanol (10 mL) was heated at 120° C. for 1 h with microwave irradiation. The solids were removed by filtration and washed with THF. The filtrate was concentrated to dryness. The residue was stirred in water (15 mL) and the remaining solids were collected and crystallized from MeCN to provide N-(4-((2-acetamidopyridin-4-yl)oxy)-2,5-difluorophenyl)-1-(4-fluorophenyl)-4-isopropoxy-2-oxo-1,2-dihydropyridine-3-carboxamide, (0.295 g, 71.9% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 10.58 (s, 1H), 8.29 (dd, J=12.6, 7.2 Hz, 1H), 8.18 (d, J=5.7 Hz, 1H), 7.87 (d, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.50-7.49 (m, 3H), 7.35 (t, J=8.7 Hz, 2H), 6.71 (dd, J=5.7, 2.4 Hz, 1H), 6.55 (d, J=7.9 Hz, 1H), 4.85 (m, 1H), 2.03 (s, 3H), 1.31 (d, J=6.0 Hz, 6H); MS (ESI) m/z: 553.1 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.N1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](B([O-])[O-])[C:22]=2C=C1.BrC1C=CC=CC=1.[OH-].[Na+]>C1COCC1.[Pd]>[C:22]1([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: [O-]B([O-])c1cccc2[nH]ccc12
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: Brc1ccccc1
Solvent: C1CCOC1
Product: c1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (pinacole 4-indoleboronate (2 g, 8.2 mmol) and 3-bromobenzene (0.87 mL, 8.3 mmol) in THF (28 mL) were added Palladium catalyst Pd(PPh3)4 (284 mg, 0.25 mmol) and the freshly prepared sodium hydroxide solution (984 mg in 9 mL of water). The system was degassed and then charged with nitrogen for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column eluting with hexanes:EtOAc 9:1 to give 1.38 g (78%) of 4-phenyl-1H-indole as a colorless liquid.
Reaction SMILES: [I:1]I.C[Si](C)(C)[CH:5]=[CH:6][C:7]1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH:12]=1.C[Si](C)(C)/C=C/C1C(=O)CCC(C)(C)C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.ClCCl>[I:1]/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH:12]=1
Reactant: II
Reactant: CC1(C)C=C(C=C[Si](C)(C)C)C(=O)CC1
Agent: CC1(C)C=C(/C=C/[Si](C)(C)C)C(=O)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C=C(/C=C/I)C(=O)CC1
Reaction time: 6 h

Procedure:
Iodine (657 mg, 2.59 mmol) was dissolved in 5 mL of THF and the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-4,4-dimethyl-2-cyclohexen-1-one (Compound 18, 575 mg, 2.59 mmol) and dichloromethane (15 mL) at room temperature. The solution was stirred for 6 hours, and then treated with 10% aqueous Na2S2O3 to remove the excess iodine. The layers were separated and the aqueous layer was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to give the product as a brown oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16](=[O:21])[NH:17][CH2:18][CH2:19][NH2:20])([CH3:14])([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:20][CH2:19][CH2:18][NH:17][C:16](=[O:21])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNc1nc2ccccc2o1
Temperature: 125 °C
Reaction time: 5 h

Procedure:
A mixture of 2-chlorobenzoxazole (0.6 mL, 5.16 mmol) and N-(2-aminoethyl) carbamic acid tert-butyl ester (2.4328 g, 15.18 mmol)) was stirred in a preheated oil bath at 125° C. for 5 h, then held at room temperature overnight. The solidified mixture was dissolved in chloroform (125 mL), washed with aqueous sodium bicarbonate (2×150 mL), then brine (1×150). The organic layer was dried over sodium sulfate, then filtered and concentrated in vacuo. The resulting residue was purified by flash column chromatography, eluting with 60% ethyl acetate in heptane to yield tert-butyl 2-(benzo[d]oxazol-2-ylamino)ethylcarbamate as a beige powder.
Reaction SMILES: [Cl-].[Li+].[Cl-].[Al+3].[Cl-].[Cl-].[C:7]1([O:13][CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClC(Cl)C>[CH3:14][O:13][C:7]1[CH:12]=[CH:11][C:10]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To an agitated mixture of lithium Chloride (3.18 g., 0.075 mole) and aluminium chloride (20 g., 0.15 mole) in dichloroethane cooled to below -10° C. was added anisole (5.41 g.,-0.05 mole) and benzoyl chloride (7.03 g., 0.05 mole) in dichloroethane (10ml). The reaction mixture was held below -10° C. for one hour then allowed to come to room temperature overnight. The 4-methoxybenzophenone produced (9.55 g., 90.1% yield) had a gas chromatograph/mass spectrometer estimated purity of over 95% with 2% ortho isomers.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C1(C[C@H](N2CC3C(=C([F:48])C=CC=3)C2=O)C(O)=O)CCCCC1.NC1SC=CN=1.[CH:56]1([CH2:62][C@H:63]([N:72]2[CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=3)[C:73]2=[O:81])[C:64]([NH:66][C:67]2[S:68][CH:69]=[CH:70][N:71]=2)=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1>>[CH:56]1([CH2:62][C@H:63]([N:72]2[CH2:80][C:79]3[C:74](=[CH:75][CH:76]=[CH:77][C:78]=3[F:48])[C:73]2=[O:81])[C:64]([NH:66][C:67]2[S:68][CH:69]=[CH:70][N:71]=2)=[O:65])[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2cccc(F)c2C1=O
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nccs1
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2c(F)cccc2C1=O
Yield: 30 %

Procedure:
BOP coupling of (S)-3-cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic and (S)-3-cyclohexyl-2-(7-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (499 mg; 1.63 mmol, as a 1:1 mixture of regioisomers) and 2-aminothiazole (376 mg; 3.64 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Biotage 40M; eluent: 30% ethyl acetate/hexanes) (S)-3-Cyclohexyl-2-(4-fluoro-1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (221 mg): EI-HRMS calcd for C20H22FN3O2S (M+) 387.1417, found 387.1422; and impure (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide which was further purified by radial chromatography (eluent:35% ethyl acetate/hexanes) providing 48 mg of pure (S)-3-Cyclohexyl-2-(7-fluoro-1-oxo-1,3dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamideas a white foam: EI-HRMS m/e calcd for C20H22FN3O2S (M+) 387.1417, found 387.1415.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1N
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J3) (207 mg, 0.75 mmol) and 3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K5) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow oil (322 mg).
Reaction SMILES: [NH3:1].[C:2]1([S:12](Cl)(=[O:14])=[O:13])[C:3]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=1>C(O)C.C1(C)C=CC=CC=1>[S:12]1(=[O:14])(=[O:13])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8](=[O:10])(=[O:9])[NH:1]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1S(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=S1(=O)NS(=O)(=O)c2ccccc21
Yield: 91 %

Procedure:
A solution of 0.65 mol of ammonia in 1,050 ml of absolute ethanol is added dropwise, with stirring, to 0.13 mol of 1,2-benzenedisulphonyl chloride in 720 ml of absolute toluene at 25° C. The mixture is stirred a further hour, slight cloudiness is removed by filtration through a layer of kieselguhr, and the filtrate is evaporated to dryness. The ammonium salt of 1,3,2-benzodithiazole 1,1,3,3-tetroxide is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Al+3].[Cl-].[Cl-].[Cl-].ClC1C=C2C(=CC=1Cl)N(CC(O)=O)C(=O)C=C2>>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:9][C:10](=[O:19])[CH:11]=[CH:12]2
Reactant: Cc1ccc(NC(=O)/C=C/c2ccccc2)cc1C
Agent: O=C(O)Cn1c(=O)ccc2cc(Cl)c(Cl)cc21
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc2ccc(=O)[nH]c2cc1C
Reaction time: 2 h

Procedure:
A mixture of (2E)-N-(3,4-dimethylphenyl)-3-phenyl-2-propenamide (5.86 g, 23.3 mmol) and AlCl3 (15.6 g, 116.57 mmol) was heated slowly until the mixture became liquefied and then subsequently congealed to form a solid cake. Ice was slowly added to break up the hardened material. The mixture was vigorously stirred for 2 h. The solid material was collected and washed with 2 N HCl solution, water, and ether to obtain a white mixture of product A and B above (3.8 g, 94%), MS (ES) m/e 176 [M+H]+
Reaction SMILES: CN([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)C.O.C(=O)([O-])[OH:24].[Na+]>Cl.CS(C)=O>[OH:24][CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CN(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12

Procedure:
A solution of 1.4 g of 10-dimethylaminomethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 35 ml of 5N hydrochloric acid is stirred for 30 minutes at a temperature in the region of 25° C. After addition of 60 ml of distilled water and neutralization with 120 ml of saturated aqueous sodium hydrogen carbonate solution, the solid formed is separated out by filtration, washed twice with 60 ml in total of distilled water and air-dried. The product obtained (1.1 g) is dissolved in 120 ml of dimethyl sulphoxide and, after addition of 120 ml of distilled water, the solid formed is separated out by filtration, washed twice with 10 ml in total of distilled water and twice with 10 ml in total of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is thus obtained as a 60/40 mixture of the Z and E forms, decomposing without melting at 290° C. [N.M.R. spectrum: (200 MHz; DMSO d6 ; δ in ppm): a 60/40 mixture of isomers is observed: from 7.20 to 7.40 (mt, 2H: --H7 and --H8); 7.56 and 7.64-8.29 and 8.79 (4s broad, twice 1H: --H of the imidazole); from 7.80 to 8.15 (mt, 2H: --H6 and --H9); 8.21 and 8.24 (2s, 1H in total: =CH--O--); 12.43 (cplx, 1H: --NH--)].
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.C(N(CC)C(C)C)(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>O1CCCC1>[CH:39]1([S:42]([N:23]2[CH2:22][C:21]([CH2:25][C:26]#[N:27])([N:19]3[CH:20]=[C:16]([C:15]4[C:10]5[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:28])([CH3:1])[CH3:29])[C:11]=5[N:12]=[CH:13][N:14]=4)[CH:17]=[N:18]3)[CH2:24]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(S(=O)(=O)C5CC5)C4)c3)ncnc21
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 81.4 %

Procedure:
To a oven dried 2 L round bottom flask equipped with the overhead stirring, a nitrogen inlet, a septa and a thermocouple was charged anhydrous tetrahydrofuran (THF, 800 mL), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (16, 38.6 g, 94.2 mmol) and N,N-diisopropylethylamine (DIEA, 22.0 mL, 126 mmol, 1.34 equiv) at room temperature. The resulting solution was then cooled to 0-5° C. before being charged with cyclopropanesulfonyl chloride (14.3 mL, 134 mmol, 1.42 equiv) portion wise over eight minutes via syringe at 0-5° C. After 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm gradually to room temperature. When HPLC showed that the reaction was complete after 22 h, the reaction mixture was concentrated under reduced pressure to remove about 400 mL of solvent. The residue was treated with ethyl acetate (EtOAc, 500 mL) and the resulting solution was washed with 20% aqueous sodium chloride solution (NaCl, 300 mL). The aqueous layer was back extracted with ethyl acetate (EtOAc, 150 mL). The combined organic fractions were dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to yield the crude product (25) as an amber oil. The crude product was then purified by flash column chromatography (SiO2, 50% to 70% ethyl acetate/hexane gradient elution) to afford {1-(cyclopropylsulfonyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25, 39.4 g, 48.4 g theoretical, 81.4% yield) as a light yellow oil, which solidified upon standing at room temperature in vacuum. For 25: 1H NMR (DMSO-d6, 300 MHz) δ 8.98 (s, 1H), 8.78 (s, 1H), 8.50 (s, 1H), 7.81 (d, 1H, J=3.8 Hz), 7.20 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 4.66 (d, 2H, J=9.5 Hz), 4.28 (d, 2H, J=9.3 Hz), 3.69 (s, 2H), 3.52 (t, 2H, J=7.8 Hz), 2.84 (m, 1H), 1.01 (m, 4H), 0.82 (t, 2H, J=8.4 Hz), −0.12 (s, 9H) ppm; C23H31N7O3SSi (MW, 513.69), LCMS (EI) m/e 514 (M++H) and 536 (M++Na).
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.O1CCCC1.[Cl:19][CH2:20][C:21]([OH:23])=O.C(OC)(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1>[CH2:20]([Cl:19])[C:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: O=C(O)CCl
Reactant: COC(=O)c1ccccc1
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
Under the atomosphere of nitrogen gas, diisopropylamine (0.6605 g) was added to 6.67 mL of 0.9 M n-butylmagnesium chloride/tetrahydrofuran (6 mmol). The mixture was stirred a room temperature for 4 hours, after which it was cooled to 0° C. Then, a solution of 284 mg (3.0 mmol) of monochloroacetic acid and 136 mg (1 mmol) of methyl benzoate in 5 mL of tetrahydrofuran was added portionwise for 1 minutes. This mixture was stirred at 0° C. for 30 minutes and, while the temperature was allowed to rise to room temperature, further stirred for 30 minutes. This reaction mixture was poured in 1N-HCl (30 mL) and extracted with ethyl acetate (30 mL×2). The extract was washed with saturated aqueous NaHCO3 solution (30 mL×1) and water (30 mL×1) in that order and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to provide a light-yellow oil. Comparative HPLC analysis of this oil with an authentic sample revealed that the oil was predominantly composed of the objective phenacyl chloride (reaction yield 73.7%). Diisopropylbenzamide (reaction yield 0.4%) was obtained as a byproduct.
Reaction SMILES: C(OC([C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8](=[N:10][OH:11])[NH2:9])=O)C.[OH-].[Na+].O.Cl.[CH2:20]([OH:22])C>>[C:7]1([C:8]2[N:9]=[C:20]([OH:22])[O:11][N:10]=2)[CH:6]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCO
Reactant: CCOC(=O)c1ccccc1C(N)=NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Oc1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In accordance with the known process [Yakugaku Zasshi, 84(11), 1061 (1964)], 27 g (0.13 mol) of o-ethoxycarbonylbenzamidoxime were added to a liquid mixture consisting of 10 g (0.25 mol) of sodium hydroxide, 600 ml of water and 150 ml of ethyl alcohol, followed by stirring at room temperature for 3 hours. The reaction mixture was neutralized with dilute hydrochloric acid. Crystals thus formed were collected by filtration and then washed with water, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:26]([F:29])([F:28])[F:27])[C:6]=1[CH3:30].COC(=O)CC1C2C(=NC=CC=2)NC=1C.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.BrCC1C=CC(S(CC)(=O)=O)=CC=1C(F)(F)F>CN(C=O)C>[CH2:24]([S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[C:6]2[CH3:30])=[C:16]([C:26]([F:28])([F:29])[F:27])[CH:17]=1)(=[O:23])=[O:22])[CH3:25]
Reactant: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)OC)c3cccnc32)c(C(F)(F)F)c1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CCS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: COC(=O)Cc1c(C)[nH]c2ncccc12
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(Cn2c(C)c(CC(=O)O)c3cccnc32)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[1-(4-Ethanesulfonyl-2-trifluoromethyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester: To a stirred solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.77 g, 3.78 mmol) in dry DMF (12 ml) under an inert atmosphere of Argon is added dropwise, BEMP (1.75 ml, 6.04 mmol). The mixture was allowed to stir at room temperature for 1 hour and then treated with 1-bromomethyl-4-ethanesulfonyl-2-trifluoromethyl-benzene (2 g, 6.04 mmol). Stirring continues for a further 2 hours after which time, the reaction mixture is partitioned between ethyl acetate/diethyl ether (80 ml of a 1:1 mixture) and water (100 ml). The organic portion is separated and washed with brine and concentrated in vacuo. Purification of the crude by chromatography on silica eluting with iso-hexane/ethyl acetate (3:1 increasing to 2:1) yields the titled product. (MH+ 455)
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOC(=O)c1nc(C#C[Si](C)(C)C)c2sccc2c1O
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43a, 165 mg, 0.5 mmol), ethynyl-trimethyl-silane (87 μl, 0.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (11 mg, 0.015 mmol), CuI (5 mg, 0.025 mmol), and triethylamine (1.5 ml) was heated in a microwave oven at 100° C. with stirring for 15 min. After cooling to ambient temperature water (20 ml) was added and the mixture was extracted with diethylether (1×30 ml). The organic phase was dried over MgSO4. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a dark oil (75 mg); MS-(+)-ion: MS-(+)-ion: M+1=348.4.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([O:17]CC)=[O:16])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>C(O)C.O1CCOCC1>[C:3]([NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[C:15]([OH:17])=[O:16])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cccc(NC(=O)c2ccccc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
4N Aqueous solution of sodium hydroxide (2 ml) was added to a solution of ethyl 3-(benzoylamino)benzoate (695 mg) in ethanol (5 ml) and 1,4-dioxane (5 ml). After stirred at 50° C. for 1 hour, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated to give 3-(benzoylamino)benzoic acid (595 mg) as solid.