Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:21][CH:20]=4)=[N:16][N:15]=3)[C:11]([NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[N:10][CH:9]=2)=[CH:4][CH2:3]1.CCN(CC)CC.[C:50](Cl)(=[O:53])[CH2:51][CH3:52]>C(Cl)Cl>[C:39]([O:38][C:36]([NH:35][C:11]1[C:12]([C:14]2[O:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([CH2:25][N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:23][CH:24]=3)=[N:16][N:15]=2)=[N:13][C:8]([C:5]2[CH2:6][CH2:7][CH:2]([NH:1][C:50](=[O:53])[CH2:51][CH3:52])[CH2:3][CH:4]=2)=[CH:9][N:10]=1)=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCC(=O)Cl
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(C4=CCC(N)CC4)cnc3NC(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CC=C(c2cnc(NC(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)CC1
Yield: 110.5 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-(4-aminocyclohexen-1-yl)-3-(tert-butoxycarbonylamino)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (20 mg, 0.03 mmol) in anhydrous DCM (200 μL) was added Et3N (5 mg, 7 μL, 0.05 mmol) and the reaction mixture was cooled in an ice water bath. A solution of propanoyl chloride (3.843 mg, 3.625 μL, 0.04154 mmol) in DCM (0.1 mL) was added dropwise to the above reaction mixture. The reaction mixture was diluted with DCM and washed once with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography using 10% MeOH in EtOAc to yield tert-butyl N-[[4-[5-[3-(tert-butoxycarbonylamino)-6-[4-(propanoylamino)cyclohexen-1-yl]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (21 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:9]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:42])=[CH:21][CH:20]=4)[CH:16]=[CH:17][CH:18]=3)[CH2:11][C:10]([C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CS(=O)c1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(Cl)cc3)c2)cc1

Procedure:
The compound of Example 40 was prepared in accordance with the same procedures as in Example 37, using the compound prepared in Example 23 and meta-chloroperbenzoic acid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]1([Sn+](C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(O[Hg]C1C=CC=CC=1)=O.C(OO)(=O)C>>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: c1ccc([Sn+](c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)[O-]
Agent: CC(=O)OO
Agent: CC(=O)O[Hg]c1ccccc1
Product: CC(=O)Oc1ccccc1
Yield: 58 %

Procedure:
The procedure of Example 1 is repeated except that 5 mmols of triphenyl tin acetate are employed instead of the phenyl mercuric acetate of Example 1, and 30 mmols of peracetic acid is used. After 4 hours of reaction at 75° C. there is obtained phenyl acetate in a yield of about 58%, and in a selectivity of about 68%, at a triphenyl tin acetate conversion of about 85%.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2].[NH2:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:24][CH:25]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(CN2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1
Yield: 79.2 %

Procedure:
4-carboxyphthalic anhydride (0.5 g, 0.0026 mol) and 4-(aminomethyl)benzoic acid (0.39 g, 0.0026 mol) were refluxed as above overnight. Crystallisation of the product from 1,4-dioxane/H2O yielded 0.67 g (79%) of 108 as a white solid: mp=365-366° C.; Rf0.76 (A): Rf0.71 (C): Rf0.50 (D): IR (cm−1): 2800-3100 (OH), 3071 (C═CH), 2678 (C—H), 1782 (C═O), 1712 (bs, C═O), 1611 (C═C), 1577 (C═C), 1428 (C═C), 1391 (C—O), 1300 (C—O), 1105 (C—O), 734 (C═CH); MS m/z (rel intensity) 325 (20), 324 (100).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6]2=[N:7][CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:10]=[C:5]2[N:4]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:18]=2[CH3:34])[CH2:3]1.C1C(=O)N([Br:43])C(=O)C1>C(#N)C>[Br:43][C:8]1[N:7]=[C:6]2[C:2]([CH3:35])([CH3:1])[CH2:3][N:4]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]=[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)[C:18]=3[CH3:34])[C:5]2=[CH:10][C:9]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21
Solvent: CC#N
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2nc(Br)c(N3CCOCC3)cc21
Reaction time: 0.25 h

Procedure:
To a stirred solution of 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline (250 mg, 0.489 mmol) in acetonitrile (6 mL) at 0° C. was added dropwise via syringe over 5 min a solution of n-bromosuccinimide (76 mg, 0.426 mmol) in acetonitrile (4 mL). The reaction was stirred at this temperature for 15 min. After this time the reaction was partitioned between EtOAc (40 mL) and water (15 mL). The separated organic layer was washed with NaHCO3 (15 mL, saturated aqueous solution) and Na2S2O3 (15 mL, saturated aqueous solution) and dried over MgSO4, filtered and evaporated in vacuo to give 4-(5-bromo-3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.64-8.82 (1H, m), 7.85-7.97 (3H, m), 7.75 (1H, dd, J=9.2, 5.9 Hz), 7.40-7.45 (1H, m), 7.31 (1H, ddd, J=9.3, 8.0, 2.6 Hz), 5.97 (1H, s), 3.71-3.90 (6H, m), 2.77-2.94 (4H, m), 2.38 (3H, s), 1.58 (3H, s), 1.52 (3H, s). Mass Spectrum (ESI) m/e=548.0 [(M+1) (79Br)] and 550.0 [(M+1) (81Br)]
Reaction SMILES: C=[CH:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2(C)[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2(C)[C:11](=CC(=O)[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.N1C=CC=CC=1.[C:31]([O:34]C(=O)C)(=[O:33])[CH3:32]>C(OCC)(=O)C>[C:31]([O:34][C:19]1[CH:20]=[CH:21][C:7]2[C@@H:6]3[C:11]([C@H:16]4[C@@:3]([CH2:4][CH2:5]3)([CH3:24])[CH:2]=[CH:14][CH2:15]4)=[CH:10][CH2:9][C:8]=2[CH:18]=1)(=[O:33])[CH3:32]
Reactant: C=C[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc2c(c1)CC=C1[C@@H]2CC[C@]2(C)C=CC[C@@H]12
Yield: 35.1 %

Procedure:
A solution of estra-1,3,5(10),7,16-pentaen-3-ol (5, 192.1 mg, 0.7612 mmol) in anh. pyridine (2.6 ml, 32 mmol) and acetic anhydride (0.36 ml, 3.8 mmol) was stirred 6 h, after which 30 ml of ethyl acetate were added. The mixture was washed with three 10 ml portions of 1 N hydrochloric acid+10 ml of saturated sodium bicarbonate+10 ml of brine, dried over magnesium sulfate, and filtered through diatomaceous earth. See Example 15. The residue was washed with 10 ml of ethyl acetate and the combined filtrates were concentrated under reduced pressure. Preparative TLC (5% ethyl acetate/hexanes on silica gel GF, 1000μ thickness) and recrystallization from aqueous ethanol gave fine white needles (78.6 mg, 0.267 mmol, 35%), m.p. 77-80° C. TLC (4% ethyl acetate/hexanes on silica gel) showed 2 spots at Rf 0.21 and 0.24.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:12][CH2:13]Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:13][CH2:12][C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:23]=[N-:24]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)(CCCl)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCC(O)(CCN=[N+]=[N-])c1ccccc1

Procedure:
A solution of 1-{[tert-butyl(dimethyl)silyl]oxy}-5-chloro-3-phenylpentan-3-ol ((5.2 g, 15.7 mmol) and NaN3 (7.8 g, 120 mmol) in 50 mL DMF was stirred for 24 h at 65° C. The reaction mixture was then diluted with EtOAc, washed with water, dried, filtered and evaporated in vacuo to provide 1-azido-5-{[tert-butyl(dimethyl)silyl]oxy) 3-phenylpentan-3-ol in quantitative yield as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.40-7.32 (m, 4H), 7.24 (m, 1H), 4.89 (s, 1H), 3.72 (dt, 1H, J=10.3, 3.9 Hz), 3.47-3.36 (m, 2H), 2.97 (ddd, 1H, J=12.3, 10.1, 5.5 Hz), 2.24-2.10 (m, 2H), 2.07-1.93 (m, 2H), 0.86 (s, 9H), −0.02, (s, 3H), −0.09 (s, 3H); ESI-MS 358 (M+Na).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[CH2:7]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)[CH2:8][CH2:9][CH3:10]>O.CO>[CH2:7]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:40][C:39]2[CH:38]=[C:37]([OH:41])[CH:36]=[CH:35][C:34]=2[C@@H:33]2[C@@H:24]1[C@H:25]1[C@@:29]([CH2:31][CH2:32]2)([CH3:30])[C@@H:28]([OH:42])[CH2:27][CH2:26]1)=[O:2])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCSCCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCS(=O)CCCCCCCCCCC[C@@H]1Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Reaction time: 18 h

Procedure:
A solution of sodium metaperiodate (0.016 g.) in water (0.5 ml.) was added to a solution of 7α-11-n-butylthioundecyl)oestra-1,3,5(10)-triene-3,17β-diol (Example 32; 0.035 g.) in methanol (1 ml.) and the mixture was stirred at laboratory temperature for 18 hours, evaporated to dryness and evaporated from toluene to remove the last traces of water. The residue was extracted three times with acetone and the combined extracts were evaporated to dryness. There was thus obtained as an oil 7α-(11-n-butylsulphinylundecyl)oestra-1,3,5(10)-triene-3,17β-diol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=1[Cl:23].C1(C)C=CC=CC=1.C1(N(C)C2CCCCC2)CCCCC1>C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:15][C:16]1[CH:21]=[C:20](/[CH:3]=[CH:2]/[CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])[CH:19]=[CH:18][C:17]=1[Cl:23]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1C(=O)N(C/C=C/c2ccc(Cl)c(Cl)c2)c2ccccc21
Temperature: 80 °C
Yield: 83.9 %

Procedure:
A mixture of 1-allyl-1H-indole-2,3-dione (1.00 g, 5.34 mmol), Pd(P(t-Bu)3)2 (0.0819 g, 0.16 mmol), 1,2-dichloro-4-iodobenzene (1.458 g, 5.34 mmol), dry toluene (10 mL), and N-cyclohexyl-N-methylcyclohexanamine (1.23 mL, 5.86 mmol) in an oven-dried sealed tube under an atmosphere of N2 was heated for 16 h at 80° C. The reaction was cooled, diluted with CH2Cl2, and loaded directly onto a silica gel column that had been packed with CH2Cl2. The column was eluted with a gradient of 100% CH2Cl2 to 95:5 CH2Cl2:EtOAc. The appropriate fractions were combined to provide the title compound as an orange solid (1.489 g, 84%). 1H NMR (600 MHz, CHLOROFORM-D) δ ppm 4.52 (d, J=5.9 Hz, 2H), 6.19 (dt, J=15.9, 5.9 Hz, 1H), 6.56 (d, J=15.6 Hz, 1H), 6.91 (d, J=7.9 Hz, 1H), 7.09-7.20 (m, 2H), 7.37 (d, J=8.2 Hz, 1H), 7.42 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.64 (d, J=7.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[H-].[Na+]>>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: C1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1cnn(C2CCCCO2)c1

Procedure:
To pyrazole (14.3 g, 0.21 mol) was added 3,4-dihydro-2H-pyran (29 ml, 0.315 mol) and, after complete dissolving, trifluoroacetic acid (0.1 ml, 0.0013 mol) was added to the obtained solution. The reaction mixture was refluxed for 5 h, sodium hydride (0.2 g, 0.008 mol) was added, and the mixture was distilled to give 1-(tetrahydro-pyran-2-yl)-1H-pyrazole; b.p. ˜60-65° C./0.5-1 torr.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[C:29]4[N:30]=[C:31](S(C)(=O)=O)[N:32]=[CH:33][C:28]=4[C:27](=[O:38])[C:26]([C:39]([NH2:41])=[O:40])=[CH:25]3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1>>[CH2:15]1[C:23]2[C:18](=[CH:19][C:20]([N:24]3[C:29]4[N:30]=[C:31]([NH:14][C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]6[CH2:6][CH2:5][O:4][CH2:3][CH2:2]6)[CH:9]=5)[N:32]=[CH:33][C:28]=4[C:27](=[O:38])[C:26]([C:39]([NH2:41])=[O:40])=[CH:25]3)=[CH:21][CH:22]=2)[CH2:17][CH2:16]1
Reactant: Nc1cccc(CN2CCOCC2)c1
Reactant: CS(=O)(=O)c1ncc2c(=O)c(C(N)=O)cn(-c3ccc4c(c3)CCC4)c2n1
Product: NC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(Nc3cccc(CN4CCOCC4)c3)ncc2c1=O
Yield: 43.1 %

Procedure:
Using the procedure outlined in Example 23 (a and c), the title compound was prepared from 3-morpholin-4-ylmethyl-phenylamine (5 mg) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid amide (from Example 23 (b), 7 mg). Purification by preparative HPLC (32 mL/min, 5-100% H2O/MeCN (0.01% TFA, v/v) gradient over 10 min) gave the title compound as a white solid (3.9 mg, 35%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.55 (br, 1H), 9.42 (s, 1H), 8.83 (s, 1H), 7.60 (br, 1H), 7.50 (br, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.24 (s, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.13 (br, 2H), 6.23 (br, 1H), 4.00 (br, 4H), 3.32 (br, 2H), 3.08 (t, J=7.3 Hz, 2H), 3.00 (t, J=7.3 Hz, 2H), 2.72 (br, 2H), 2.23 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H28N6O3: 497.22 (M+H), Found: 497.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([C:17]3[N:18]=[C:19]([NH:22][C:34](=[O:41])[C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[S:20][CH:21]=3)=[C:12]([CH3:23])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(OC(C)C)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-(4-isopropoxyphenoxy)-2,6-dimethylphenyl)thiazol-2-amine (16-6, 0.25 g, 0.72 mmol) in CH2Cl2 (5.0 mL) was added triethylamine (0.5 mL, 3.59 mmol) followed by isonicotinoyl chloride hydrochloride (0.35 g, 1.94 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and recrystallized in toluene to give N-{4-(4-(4-isopropoxypherioxy)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (16, 0.26 g) as light yellow solids in 79% yield: 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=5.1 Hz, 2 H), 7.98 (d, J=5.7 Hz, 1 H), 7.16 (s, 1 H), 6.95 (m, 4 H), 6.69 (s, 2 H), 4.55 (t, J=6.0 Hz, 2 H), 2.05 (s, 6 H), 1.27 (s, 3 H), 1.26 (s, 3 H). ESI-MS: m/z 460.1 (M+H)+.
Reaction SMILES: CN([CH:4]=[N:5][C:6]([C:8]1[N:9]=[C:10]2[C:16]3[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12][N:11]2[CH:25]=1)=O)C.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][NH2:35]>>[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[C:6]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[C:18]([C:21]([O:23][CH3:24])=[O:22])[CH:19]=[CH:20][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:25]=2)=[N:5][CH:4]=[N:35]1
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)c1ccc2c(c1)-c1nc(C(=O)N=CN(C)C)cn1CCO2
Agent: Cl
Product: COC(=O)c1ccc2c(c1)-c1nc(-c3ncnn3-c3ccccc3Cl)cn1CCO2
Yield: 59 %

Procedure:
Following the procedure in Example 22, methyl 2-((dimethylamino)methylenecarbamoyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate was coupled with 2-chlorophenylhydrazine hydrochloride to give methyl 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-10-carboxylate. Yield 59%. MS(ESI+): 422.1
Reaction SMILES: [CH:1]1([C:4]2[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:17])([CH3:16])[C:8]=3[CH:7]=[C:6]([C:18]#[CH:19])[CH:5]=2)[CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=1)[CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I.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>[CH3:20][O:21][C:22](=[O:32])[CH:23]([C:25]1[CH:26]=[CH:27][C:28]([C:19]#[C:18][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:15]3[O:14][C:11]4([CH2:13][CH2:12]4)[CH2:10][C:9]([CH3:16])([CH3:17])[C:8]=3[CH:7]=2)=[CH:29][CH:30]=1)[CH3:24]
Reactant: COC(=O)C(C)c1ccc(I)cc1
Reactant: C#Cc1cc(C2CC2)c2c(c1)C(C)(C)CC1(CC1)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C(C)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 8-cyclopropyl-6-ethynyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (described in U.S. Pat. No. 6,252,090; 0.068 g, 0.27 mmol), and methyl-2-(4-iodo phenyl)propionate (Reagent 1, 0.086 g, 0.3 mmol) in triethyl amine (3 mL), was treated with copper(I)iodide (0.028 g, 0.15 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (0.057 g, 0.08 mmol) was added and the reaction mixture was stirred overnight at room temperature. It was diluted with diethyl ether and filtered over a bed of celite. The filtrate was evaporated in vacuo to brown oil that was subjected to flash column chromatography over silica gel (230–400 mesh) to afford the title compound as an oil (0.072 g, 56%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[Br:9].[OH-].[K+].[CH3:12]OS(OC)(=O)=O>CC(C)=O>[Br:9][C:3]1[C:2]([NH2:1])=[N:7][C:6]([O:8][CH3:12])=[CH:5][CH:4]=1
Reactant: Nc1nc(O)ccc1Br
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1ccc(Br)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.9 %

Procedure:
A suspension of 11.58 g (61 mmol) 6-amino-5-bromo-pyridin-2-ol in 200 ml acetone was treated with 10.3 g (184 mmol) KOH pellets and 10 g (80 mmol) dimethylsulfate. The mixture was stirred for 4 h at room temperature and evaporated to dryness. 400 ml water was added and the mixture was extracted four times with 300 ml ethyl acetate. The combined organic phases were dried with MgSO4 and evaporated. The residue was purified by flash column chromatography on silica eluting with hexane/ ethyl acetate 1:1 to yield 3.455 g (28%) of the title compound as orange oil.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:35])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Cl:33][C:27]1[C:26]([CH3:34])=[C:25]([NH:24][C@@H:10]([C:11]2[O:12][C:13]([C:16]3[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=3)=[N:14][N:15]=2)[C@@H:9]([OH:8])[CH3:35])[CH:32]=[CH:31][C:28]=1[C:29]#[N:30]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Temperature: -40 °C

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added 4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (9.98 g, 19.6 mmol), followed by anhydrous THF (245 mL) under an atmosphere of nitrogen. The reaction mixture was cooled to −40° C. via a CO2/acetone bath. To this was added tetrabutylammonium fluoride as a 1M solution in THF (22.54 mL, 22.54 mmol) producing an instant color change to yellow. This was allowed to warm to room temperature for a period of 4 h. The solvent was then removed under reduced pressure to yield a black residue. This residue was taken up in EtOAc (200 mL) and washed with water (2×250 mL), brine (1×200 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid. This was purified via silica gel chromatography eluted with hexanes-EtOAc (20:80) the title compound as a white solid (5.23 g, 68%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.10 (d, J=8.4 Hz, 2H), 7.80 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 1H), 6.65 (d, J=8.4 Hz, 1H), 5.27 (d, J=8.0 Hz, 1H), 4.80 (dd, J=2.8, 8.4 Hz, 1H), 4.62-4.65 (m, 1H), 2.91 (br s, 1H), 2.37 (s, 3H), 1.46 (d, J=6.4 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([Cl:17])=[C:11]([F:18])[C:7]=1[C:8](O)=[O:9]>CN(C)C=O>[Cl:5][C:6]1[C:14]([F:15])=[C:13]([F:16])[C:12]([Cl:17])=[C:11]([F:18])[C:7]=1[C:8]([Cl:3])=[O:9]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)c(Cl)c(F)c(F)c1Cl

Procedure:
160 ml of thionyl chloride are initially introduced into the reaction vessel at room temperature. 36.8 g (0.15 mol) of 2,5-dichloro-3,4,6-trifluorobenzoic acid are added in portions, while stirring. After addition of 0.5 ml of dimethylformamide, the mixture is slowly heated to 80°-90° C. and is stirred at this temperature for 5 hours. It is then concentrated and the residue is distilled under a high vacuum.