Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][CH:33]([F:36])[CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.O>[CH3:1][N:2]1[C:6]([O:7][CH2:34][CH:33]([F:36])[F:32])=[C:5]([CH3:8])[C:4]([C:9]([F:11])([F:10])[F:12])=[N:3]1
Reactant: OCC(F)F
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)nn(C)c1OCC(F)F
Yield: 55.7 %

Procedure:
To a solution of 9.0 g (50.0 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 50 ml of tetrahydrofuran were added 14.4 g (55.0 mmol) of triphenylphosphine and 4.5 g (55.0 mmol) of 2,2-difluoroethanol at room temperature, followed by stirring. Furthermore, 12.3 g (60.0 mmol) of diisopropyl azodicarboxylate was added thereto under ice-cooling, followed by stirring at room temperature overnight. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 6.8 g (yield: 55.7%) of 1,4-dimethyl-5-(2,2-difluoroethoxy)-3-trifluoromethyl-1H-pyrazole as a pale yellow liquid.
Reaction SMILES: C(C1C=C(N[CH:11](C2C=CC(OC)=C(OC)C=2)[C:12]([OH:14])=[O:13])C=CC=1)(=O)N.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29]([NH2:31])=[O:30].[CH2:36]([O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[F:45])[CH3:37].O.C(O)(=O)C=O>>[C:29]([C:28]1[CH:32]=[CH:33][C:34]([F:35])=[C:26]([NH:25][CH:11]([C:41]2[CH:42]=[CH:43][C:44]([F:45])=[C:39]([O:38][CH2:36][CH3:37])[CH:40]=2)[C:12]([OH:14])=[O:13])[CH:27]=1)(=[O:30])[NH2:31]
Reactant: CCOc1cc(B(O)O)ccc1F
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1ccc(F)c(N)c1
Agent: O=CC(=O)O
Solvent: O
Product: CCOc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Yield: 50 %

Procedure:
29A was prepared in a procedure similar to that of 1A using 19B, 9B and glyoxylic acid monohydrate. Yield: 50%. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.40 (t, J=7.03 Hz, 3H) 4.10 (q, J=7.03 Hz, 2H) 5.17 (s, 1H) 7.03-7.11 (m, 3 H) 7.13-7.17 (m, 1H) 7.24 (d, J=8.79 Hz, 1H) 7.28 (d, J=9.23 Hz, 1H), LCMS: 351 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]#[CH:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C#Cc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Solvent: CO
Product: C#Cc1cccc(N)c1
Yield: 70 %

Procedure:
Example 3 was repeated using 25 grams of 3-nitrophenylacetylene (10% wt. conc.) in methanol in the presence of 16.0 grams of a cobalt polysulfide catalyst prepared as per Example 1. The weight ratio of NPA to Co was 25:1. Reaction was carried out at 120° C., 1000 psig (6.9 MPa) of hydrogen pressure for 0.5 hours. Analysis showed quantitative conversion of feed and a 70% yield of 3-aminophenylacetylene. All byproducts were polymeric and easily separated. The results are summarized in Table 1 below.
Reaction SMILES: [CH3:1][Si:2]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:3][C@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C@@H:7]([OH:31])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:23][Si:24]([CH3:30])([CH3:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:5]1.[CH3:37][Si:38]([CH3:72])([C:68]([CH3:71])([CH3:70])[CH3:69])[O:39][C@@H:40]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[CH:42]([C@@H:43]([OH:67])[CH2:44][C@@H:45]3[C@@H:54]2[CH2:53][CH2:52][C@@:50]2([CH3:51])[C@H:46]3[CH2:47][CH2:48][C@@H:49]2[O:59][Si:60]([CH3:66])([CH3:65])[C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:41]1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:36][Si:2]([CH3:1])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:3][C@H:4]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[CH:6]([C:7](=[O:31])[CH2:8][C@@H:9]3[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]3[CH2:11][CH2:12][C@@H:13]2[O:23][Si:24]([CH3:29])([CH3:30])[C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:5]1.[CH3:72][Si:38]([CH3:37])([C:68]([CH3:71])([CH3:70])[CH3:69])[O:39][C@@H:40]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[CH:42]([C:43](=[O:67])[CH2:44][C@@H:45]3[C@@H:54]2[CH2:53][CH2:52][C@@:50]2([CH3:51])[C@H:46]3[CH2:47][CH2:48][C@@H:49]2[O:59][Si:60]([CH3:65])([CH3:66])[C:61]([CH3:62])([CH3:63])[CH3:64])[CH2:41]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)[C@@H](O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@]2(C)C(C1)C(=O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(C1)C(=O)C[C@H]1[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)CC[C@@H]12
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3β,17β-di(dimethyltert-butylsilyloxy)androstane-6α-ol and 3α,17β-di(dimethyltert-butylsilyloxy)androstane-6α-ol (90/10 mixture, 6.30 g) in CH2Cl2 (60 mL) under N2, NMNO (4.07 g), TPAP (0.412 g) and 4 Å molecular sieves (3.50 g) were added. The mixture was stirred for 2 h and then SiO2 was added. The mixture was purified by flash chromatography (SiO2, n-hexane/Et2O 50/50) to give 3β,17β-di(dimethyltert-butylsilyloxy)-androstane-6-one and 3α,17β-di(dimethyltert-butylsilyloxy)androstane-6-one (90/10 mixture, 6.30 g, 100%). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 3.68 (m, 1H), 3.67-3.57 (m, 1H), 2.38-2.30 (m, 1H), 2.20-2.12 (m, 1H), 1.99-1.05 (m, 18H), 0.90 (s, 9H), 0.88 (s, 9H), 0.75 (s, 3H), 0.74 (s, 3H), 0.07-0.03 (s, 12H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:10][C:11]=2[NH2:17].[N:23]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:31]([CH2:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH:43]=[CH:44][CH:45]=1)[CH2:30][CH2:29][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: COC(=O)Cc1cccc(CBr)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCBr)c2n1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CCN3CCOCC3)Cc3cccc(CC(=O)OC)c3)c2n1

Procedure:
Using the compound obtained in Example 2-13 step (i) (500 mg), (2-morpholin-4-ylethyl)amine (1 ml), potassium carbonate (206 mg) and methyl [3-(bromomethyl)phenyl]acetate (180 mg), the same manner to Example 2-29 was conducted to give the titled compound as a white solid. Yield: 100 mg (13%); mp 189-190° C., MS APCI+ve 570 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[C:10]=2[C:9]1=[O:30].FC(F)(F)C([NH:35]OC(C(F)(F)F)=O)=O.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([C:14]#[N:35])=[CH:12][C:11]2[NH:16][N:17]=[C:18]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])[C:10]=2[C:9]1=[O:30]
Reactant: O=Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1cc2[nH]nc(N3C(=O)c4ccccc4C3=O)c2c(=O)n1-c1ccccc1Cl
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 5-(2-chlorophenyl)-3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridine-6-carbaldehyde obtained in Step J (260 mg), 2,2,2-trifluoro-N-(2,2,2-trifluoroacetoxyl)acetamide (140 mg), pyridine (0.100 mL) and benzene (3.10 mL) was refluxed for 1 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (203 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:5]=[C:4]([F:15])[C:3]=1[CH:16]([O:20][CH2:21][CH3:22])[C:17]([OH:19])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCOC(C)=O.Cl.Cl.[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:70]=[CH:69][C:68]([CH2:71][NH2:72])=[CH:67][CH:66]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN(C=O)C>[CH2:53]([O:60][C:61](=[O:73])[NH:62][C:63]([C:65]1[CH:66]=[CH:67][C:68]([CH2:71][NH:72][C:17](=[O:19])[CH:16]([C:3]2[C:4]([F:15])=[CH:5][C:6]([C:8](=[O:14])[NH:9][CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:7][C:2]=2[F:1])[O:20][CH2:21][CH3:22])=[CH:69][CH:70]=1)=[NH:64])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: CCOC(C(=O)O)c1c(F)cc(C(=O)NCC(C)C)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(C(=O)NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1)c1c(F)cc(C(=O)NCC(C)C)cc1F
Yield: 22.9 %

Procedure:
(RS)-(2,6-Difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid (71 mg) was dissolved in DMF (3.5 ml) and [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride [Prepared according to Ch. Lila, Ph. Gloanec, L. Cadet, Y. Hervé, J. Fournier, F. Leborgne, T. J. Verbeuren, G. De Nanteuil, Synthetic Communications 1998, 28, 23, 4419–4429] (88 mg), disopropylamine (114 mg) and 2-(1H-benzotriazole-1-yl) 1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (80 mg) were subsequently added. After 30 min stirring at rt AcOEt (10 ml) was added and the organic layer was washed with 1 N HCl (2×10 ml), H2O (10 ml) and brine. The aqueous layers were extracted with more AcOEt (10 ml). After drying (MgSO4) the solvent was evaporated and the crude product was purified by HPLC to obtain 30 mg (23%) of (RS)-[(4-{[2-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-2-ethoxy-acetylamino]-methyl}-phenyl)-imino-methyl]-carbamic acid benzyl ester. White solid. MS 581.4 ([M+H]+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27]2)[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:24]2[N:25]=[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)[CH:21]=[N:22][CH:23]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Clc1cncc(N2CCc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CCN2c1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 90 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.205 mmol, 1 eq) and 1-(6-chloropyrazin-2-yl)indoline (88) 423 mg, 0.185 mmol, 0.9 eq) in DME (7 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.410 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional minutes was performed. The reaction mixture was heated at 90° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(6-(indolin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 134 in 12 mg quantity. The compound 134 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.06 (s, 2H), 8.59 (s, 1H), 8.60 (s, 1H), 8.55 (s, 1H), 8.44 (m, 1H), 8.16 (s, 1H), 7.41 (m, 1H), 6.99 (m, 1H), 4.21 (m, J=8.53, 2H), 3.33 (m, J=341.82, 2H); MS m/z 313.9 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(N)CCCCC1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: NC1CCCCC1
Product: O=C(O)CCC(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 45 %

Procedure:
Prepared analogous to Example 25 from 4-(4'-nitro-4-biphenylyl)-4-oxo-butyric acid. Yield: 45% of theory; m.p. 153° C. (decomp.); melting point of the cyclohexylamine salt: 178°-179° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[N:18][CH:19]3[CH2:21][CH2:20]3)[CH:12]=2)=[O:9])[CH:3]=1.C1(C)C(S([CH2:31][N+:32]#[C-:33])(=O)=O)=CC=CC=1.C1(N)CC1>C(COC)OC.CO>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[N:18]([CH:19]4[CH2:21][CH2:20]4)[CH:33]=[N:32][CH:31]=3)[CH:12]=2)=[O:9])[CH:3]=1
Reactant: O=C(Nc1cccc(C=NC2CC2)c1)c1cc(Br)ccn1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Agent: NC1CC1
Solvent: COCCOC
Solvent: CO
Product: O=C(Nc1cccc(-c2cncn2C2CC2)c1)c1cc(Br)ccn1
Temperature: 52 °C
Reaction time: 14 h
Yield: 10.1 %

Procedure:
To a solution of 4-bromo-N-(3-((cyclopropylimino)methyl)phenyl)-picolinamide (970 mg, 2.83 mmol) in dimethoxyethane/methanol (2:1, 0.1M) were added toluenesulfonylmethyl isocyanide (1.10 g, 5.65 mmol) and cyclopropylamine (392 μL, 5.65 mmol). The reaction mixture was stirred for 14 hours at 52° C., and additional toluenesulfonylmethyl isocyanide (550 mg, 2.83 mmol) was added. The reaction mixture was stirred an additional 6 hours, the solvent removed under reduced pressure, concentrated, and the residue purified by flash chromatography (2-8% methanol in methylene chloride) to afford 110 mg of 4-bromo-N-(3-(1-cyclopropyl-1H-imidazol-5-yl)phenyl)picolinamide. M+1=383.1
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][C:8]=1[OH:9].C[O:16][C:17](=O)[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>O>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]2[C:10]3[C:8](=[C:7]([CH3:6])[C:13]([OH:14])=[CH:12][CH:11]=3)[O:9][C:17](=[O:16])[CH:18]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1c(O)cccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1c(O)ccc2c(-c3ccc(F)cc3)cc(=O)oc12
Reaction time: 40 h

Procedure:
Concentrated H2SO4 (27 ml) was added to a mixture of methyl resorcinol (12.41 g, 100 mmol) and methyl-4-fluorobenzoylacetate (21.8 g, 110 mmol) at 0° C. The resulting suspension was set aside for 40 h. Water (1 L) was added and the mixture was stirred for 1 h. The residue was filtered, washed with water (2 L) and dried to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:11](=O)(O)[O-:12].[Na+].C(O)(=O)C>CO>[Br:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:12][CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cccc(CBr)c1Br
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1cccc(C)c1Br
Yield: 99 %

Procedure:
To a stirred solution of 2-bromo-3-methylbenzylbromide (5.2 g, 0.0197 mol) in methanol (30 ml) was added saturated sodiumbicarbonate (5 ml) and the mixture was refluxed overnight. The mixture was neutralised with acetic acid and the solvent was evaporated under reduced pressure. Chromatography of the residue on silica gel using hexane: methylene chloride (7/3) as eluent gave 4.2 g (99%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH2:20])[CH3:16]>O1CCCC1>[ClH:12].[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH:20][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1)[CH3:16]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)CCN
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(NS(C)(=O)=O)cc1
Product: Cl

Procedure:
To 100 ml of anhydrous tetrahydrofuran is added 10 g (0.0429 mole) of 4-[(methylsulfonyl)amino]benzoyl chloride and the reaction is cooled in an ice bath. A solution of 5.0 g (0.043 mole) of N,N-diethylethylenediamine in 25 ml of tetrahydrofuran is added over 15 minutes. The solvent is decanted and the precipitate is triturated with 100 ml of ether and crystallized from 100 ml of acetone with three drops of methanol. After cooling, the resultant solid is washed with acetone and dried in vacuo to provide the title compound.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:28][C:13]1[C:14]2[C@:19]([CH3:20])([CH2:18][CH2:17][C:16](=[O:27])[CH:15]=2)[C@@H:21]2[C@H:11]([C@H:10]3[C@:24]([CH3:25])([CH2:23][C@@H:22]2[OH:26])[C@@H:7]([C:6](=[O:30])[CH2:5][OH:4])[C@H:8]([CH3:29])[CH2:9]3)[CH:12]=1
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@H]1C(=O)CO

Procedure:
A solution of 2.95 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-4,6-pregnadiene-3,20-dione in 80 ml. of methanol is combined with 800 mg. of potassium carbonate and stirred for 5 minutes at room temperature under argon. After adding 5 ml. of acetic acid and 5 ml. of water, the reaction solution is completely evaporated under vacuum. The residue is chromatographed on silica gel. With 42-50% acetone-hexane and after recrystallization from acetone-diisopropyl ether, 1.55 g. of 6-chloro-11β,21-dihydroxy-16α-methyl-4,6-pregnadiene-3,20-dione is obtained, m.p. 229° [α]D25 =+175° (methanol). UV: ε285 =19,850 (methanol).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:18]=1[O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([S:27](Cl)(=[O:29])=[O:28])=[CH:22][C:21]=1[Cl:31].[NH2:39][CH2:40][C@H:41]([OH:50])[CH2:42][O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[Cl:31][C:21]1[CH:22]=[C:23]([S:27]([NH:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[CH2:14][CH2:13][CH:12]([NH:39][CH2:40][C@H:41]([OH:50])[CH2:42][O:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)(=[O:29])=[O:28])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][C:18]1[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:17]=1[Cl:16]
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Cl)cc2Cl)c(Cl)c1
Agent: Cl
Product: O=[N+]([O-])c1ccc(Oc2c(Cl)cc(S(=O)(=O)Nc3ccc(N4CCC(NC[C@H](O)COc5ccccc5)CC4)cc3)cc2Cl)c(Cl)c1

Procedure:
The title compound was prepared from 1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained in Example 224), 4-(2-chloro-4-nitrophenoxy)-3,5-dichlorobenzenesulfonyl chloride, and (2S)-1-amino-3-phenoxy-propan-2-ol according to the procedure of Example 346; MS (ES) m/z: 723.2, 725.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:10])[CH:6]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2ccccc2Cl)cc1F
Yield: 55.1 %

Procedure:
The title compound (0.140 g) was prepared from 2,6-difluoro-4-bromo aniline (0.22 g, 1.06 mmol) and 2-chlorophenylboronic acid (0.21 g, 1.38 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.52-7.50 (m, 1H), 7.40-7.35 (m, 3H), 7.00 (d, J 2.1, 7.6, 2H), 5.39 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12].[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@H:23]1[CH2:24][NH:25]2>>[CH3:21][N:22]1[CH2:27][C@@H:26]2[CH2:28][C@:23]1([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=1[CH:4]=[CH:5][N:6]3[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(=[O:13])=[O:12])[CH2:24][NH:25]2
Reactant: CN1C[C@@H]2C[C@H]1CN2
Reactant: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Product: Cc1ccccc1S(=O)(=O)n1ccc2c([C@@]34CN[C@H](CN3C)C4)cccc21
Yield: 19 %

Procedure:
The compound was prepared from 4-bromo-1-(2-methyl-benzenesulfonyl)-1H-indole and (1S,4S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane according to Method 1 to give 25 mg (19%) of a white solid: 1H NMR (CD3OD) δ 7.91-6.44 (m, 9H), 4.67-4.63 (m, 1H), 4.35-4.33 (m, 1H), 4.09-4.07 (m, 1H), 3.99-3.95 (m, 1H), 3.72-3.70 (m, 1H), 3.21-3.17 (m, 1H), 2.95 (s, 3H), 2.33-2.31 (m, 2H); MS (ESI) 382.1 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:19]([F:22])([F:21])[F:20])[O:8][C:9]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=2[C:11]=1[CH:12]=[CH2:13])=[O:5])C.[H][H]>CO.[Pd]>[Cl:18][C:15]1[CH:16]=[CH:17][C:9]2[O:8][CH:7]([C:19]([F:21])([F:20])[F:22])[C:6]([C:4]([OH:5])=[O:3])=[C:11]([CH2:12][CH3:13])[C:10]=2[CH:14]=1
Reactant: [H][H]
Reactant: C=CC1=C(C(=O)OCC)C(C(F)(F)F)Oc2ccc(Cl)cc21
Agent: [Pd]
Solvent: CO
Product: CCC1=C(C(=O)O)C(C(F)(F)F)Oc2ccc(Cl)cc21
Reaction time: 0.42 h
Yield: 70.7 %

Procedure:
Ethyl-6-chloro-4-ethenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylate (Example 142, Step 5)(0.433 g, 1.30 mmol) was dissolved in methanol (10 mL). Palladium (5 wt % on activated carbon)(0.150 g) was slowly added. The reaction vessel was charged with hydrogen 25 psi) and was stirred for 25 minutes. Gas chromatographic analysis indicated that the reaction was complete. The reaction mixture was filtered through Celite and evaporated to yield a orange oil. The oil was purified by flash column chromatography (100% hexanes) to yield the desired product as a yellow oil (0.282 g, 65%): 1H NMR (CDCl3 /300 MHz) 7.43 (d, 1H, J=2.4 Hz), 7.25 (dd, 1H, J=2.4, 8.7 Hz), 6.92(d, 1H, J=8.7 Hz), 5.75 (q, 1H, J=7.0 Hz), 4.38-4.24 (m, 2H), 3.05-2.95 (m, 2H), 1.35 (t, 3H, J=7.2 Hz), 1.25, (t, 3H, J=7.6 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[NH:25][N:26]=[C:10]3[C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([N:14]3[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]3)[N:11]3[C:24](=[O:27])[N:25]([CH2:42][CH3:43])[N:26]=[C:10]3[C:9]=2[C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3n[nH]c(=O)n23)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCNC1(C(N)=O)CN(c2nc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c3nn(CC)c(=O)n23)C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.7 %

Procedure:
To a solution of 1-(7,8-bis(4-chlorophenyl)-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-c]pyrimidin-5-yl)-3-(ethylamino)azetidine-3-carboxamide (25 mg, 0.05 mmol) in DMF (0.5 mL) at room temperature under argon was added K2CO3 (10 mg, 0.07 mmol), followed by iodoethane (10 mg, 0.064 mmol). The reaction mixture was stirred at 60° C. in a pre-heated oil bath for 30 min. After the reaction mixture was cooled to room temperature, water (5 mL) and EtOAc (5 mL) were added. The layers were separated. The organic layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product thus obtained was purified by preparative reverse phase HPLC (without TFA) to obtain 21.5 mg of the title compound as a white solid. HPLC/MS: retention time=3.465 min, [M+H]30 =526.