Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][C:45](Cl)=[O:46]>>[N:34]1([CH2:33][CH2:32][CH2:31][O:30][C:26]2[CH:25]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:40]6[S:39][CH:43]=[CH:42][CH:41]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCCC4)c3)n2)c1
Reactant: O=C(Cl)Cc1cccs1
Product: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCN4CCCC4)c3)n2)c1
Yield: 51 %

Procedure:
The title compound was synthesized from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-{[3-(1-pyrrolidinyl)propyl]oxy}phenyl)-2-pyrimidinamine using acylation with 2-thienylacetyl chloride as described in Example 10, Step E to yield a light brown solid in 51% yield. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.6 (s, 4H) 1.8 (s, 2H) 2.4 (s, 4H) 3.9 (s, 2H) 3.9 (d, J=6.2 Hz, 2H) 6.5 (m, 2H) 7.0 (m, 2H) 7.1 (m, 2H) 7.3 (ddd, J=6.3, 1.3, 1.2 Hz, 2H) 7.4 (m, 3H) 7.5 (t, J=2.3 Hz, 1H) 7.7 (m, 1H) 7.9 (d, J=1.8 Hz, 1H) 8.2 (d, J=5.1 Hz, 1H) 8.5 (s, 1H) 8.8 (m, 1H) 9.5 (s, 1H) 10.3 (s, 1H). ES-LC/MS m/z 630 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.CC1(C)COC2=CC3OC[C:33]4(C=3C=C12)[C:41]1[C:36](=[CH:37]C=C[CH:40]=1)[NH:35][C:34]4=O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:40][CH:41]1[CH2:33][CH2:34][NH:35][CH2:37][CH2:36]1)[C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1
Reactant: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Reactant: O=C1Nc2c(F)cccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(CC2CCNCC2)c2c(F)cccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLES 10.18 and 10.19, and making non-critical variations using 7′-fluorospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, 7′-fluoro-1′-(piperidin-4-ylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained and used in the next step.
Reaction SMILES: CCOCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH3:7].[N+:15]([O-])([OH:17])=[O:16]>O>[CH2:6]([C:8]1[C:9]([OH:14])=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=1)[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccccc1O
Solvent: O
Solvent: CCOCC
Product: CCc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 130 ml of ether, 130 ml of water and 10.0 g of 2-ethylphenol was added dropwise 6.7 ml of 61% nitric acid, and the reaction was continued with stirring at room temperature for 4 hours. The reaction mixture was extracted with 300 ml of ethyl acetate and washed with a brine, and then dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting to silica-gel column-chromatography [eluent: chloroform]to give 5.75 g of 6-ethyl-2-nitrophenol.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=[CH:16][C:4]=2[NH:3]1.O=C1C2C=CC(C(O)=O)=CC=2SC2C=CC=CC=2[NH:22]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([NH2:22])=[O:19])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2

Procedure:
In a similar manner, substituting 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-7-carboxylic acid for the 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid in Step A, there is obtained 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-7-carboxamide. Carboxamides of 10,11-dihydrodibenzo[b,f][1,4]thiazepin-3(or 7)-carboxylic acid or dibenzo[b,f][1,4]thiazepin-3(or 7)-carboxylic acid are prepared by the process of Example 33, by substituting the desired 3(or 7) carboxylic acid for the starting material of Step A.
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:52]=[CH:51][C:33]([NH:34][C:35]3[C:40]([NH:41][C:42]([NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:43])=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:45]([NH:44][C:42]([NH:41][C:40]1[C:35]([NH:34][C:33]2[CH:51]=[CH:52][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:53])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:55][CH:54]=3)=[CH:31][CH:32]=2)=[N:36][CH:37]=[CH:38][CH:39]=1)=[O:43])[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCNC(=O)Nc1cccnc1Nc1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Yield: 87.8 %

Procedure:
N-{2-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-3-pyridinyl}-N′-hexylurea (0.15 g, 0.197 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.09 g, 0.173 mmol).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:47])[CH2:31][CH:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[N:38][O:39][CH2:40][C:41](C(C)(C)C)=[O:42])[C:27](=[O:48])[N:9]2[C:10]=1[C:11]([O:13]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12])=[N+:2]=[N-:3].C1([O:55]C)C=CC=CC=1.FC(F)(F)C(O)=O>>[N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[C@H:28]([NH:29][C:30](=[O:47])[CH2:31][CH:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]3=[N:38][O:39][CH2:40][C:41]([OH:42])=[O:55])[C:27](=[O:48])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: COc1ccccc1
Reactant: CC(C)(C)C(=O)CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CN=[N+]=[N-])CS[C@H]12
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CC3C=CC=CC3=NOCC(=O)O)[C@H]2SC1
Reaction time: 0.67 h

Procedure:
Diphenylmethyl (6R,7R)-3-azidomethyl-7-(2-tertbutylcarbonylmethoxyiminophenylacetamido)-ceph-3-em-4-carboxylate (287 mg) was added to a mixture of anisole (0.3 ml) and trifluoroacetic acid (4 ml). The solution was stirred for 40 min. then evaporated. Benzene (50 ml) was added to the residue and removed by evaporation. The residue was partitioned between ethyl acetate and sodium bicarbonate solution; and the latter was acidified (10 N-HCl) under ethyl acetate, and extracted twice more with ethyl acetate. The organic extracts were washed with water and dried (Na2SO4), then evaporated, leaving an orange foam (183 mg). The foam was dissolved in ethyl acetate (2 ml) and added dropwise to vigorously stirred light petroleum (b.p. 40°-60°, 200 ml). Filtration gave the title-compound (100 mg, 51%), λmax (EtOH) 257.5 nm (ε 15,600), νmax (Nujol) 2100(N3), 1778(β-lactam), 1724(CO2H), 1670 and 1534 cm-1 (CONH), τ(Me2SO d6) values include 0.17(d, J=8 Hz; CONH), 2.2-2.7(Ph), 4.10 (C- 7H), 4.73(C-6H), 5.30(OCH2), 5.58 and 6.04(AB quartet, J=13 Hz, CH2N3), 6.29 and 6.52(AB quartet, J=18 Hz, SCH2).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1.N1C(C)=CC=CC=1C>ClCCl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:32])([CH3:31])[CH3:33])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1)(=[O:8])=[O:9]
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3o2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.74 ml) was added dropwise to an ice-cooled mixture of 2-(5-hydroxy-benzofuran-2-yl)-4-tert-butylthiazole (1.0 g), N,N-dimethylaminopyridine (67 mg) and 2,6-lutidine (0.52 ml, 4.39 mmol) in dry dichloromethane (10 ml) below 10° C. After being stirred at room temperature for 2 hours, the reaction mixture was washed with diluted hydrochloric acid, then dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane-ethyl acetate (4:1) as eluent to give 2-(4-tert-butylthiazol-2-yl)-benzofuran-5-yl trifluoromethanesulfonate as a colorless oil (1.39 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:76])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45]CC2C=CC=CC=2)[CH:27]=[C:26]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][O:68]CC2C=CC=CC=2)[CH:25]=1)([CH3:4])([CH3:3])[CH3:2].[H][H].C(OCC)(=O)C>CO.[OH-].[Pd+2].[OH-]>[C:1]([O:5][C:6](=[O:76])[CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][OH:68])[CH:27]=[C:28]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])[CH:29]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCOCc2ccccc2)cc(OCCOCCOCCOCCOCCOCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)COCCOCCOCCOCCOCCOc1cc(OCCOCCOCCOCCOCCO)cc(OCCOCCOCCOCCOCCO)c1
Reaction time: 6 h

Procedure:
In a nitrogen atmosphere, to a suspension of palladium hydroxide (20% by weight; 90 mg) in methanol (2.7 ml), a solution of Compound 48 (500 mg, 0.462 mmol) in methanol (3.6 ml) was added; after the nitrogen atmosphere was replaced with a hydrogen atmosphere, stirring was conducted at room temperature for about 6 hours. After a nitrogen atmosphere was restored, ethyl acetate (about 20 ml) was added, and the mixture was filtered on silica gel and washed with an ethyl acetate solution containing 10% methanol. Concentration under reduced pressure was conducted to yield a crude product of Compound 49.
Reaction SMILES: [Cl-:1].[CH3:2][N+:3]([CH3:14])([CH2:6][C:7]1([CH3:13])[CH2:11][O:10][C:9](=[O:12])[NH:8]1)[CH2:4][CH3:5].C(O[Cl:20])(C)(C)C>CO>[Cl-:20].[Cl:1][N:8]1[C:7]([CH2:6][N+:3]([CH3:2])([CH3:14])[CH2:4][CH3:5])([CH3:13])[CH2:11][O:10][C:9]1=[O:12]
Reactant: CC(C)(C)OCl
Reactant: CC[N+](C)(C)CC1(C)COC(=O)N1
Agent: [Cl-]
Solvent: CO
Product: CC[N+](C)(C)CC1(C)COC(=O)N1Cl
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a solution of N,N-dimethyl-N-((4-methyl-2-oxooxazolidin-4-yl)methyl)ethanaminium chloride (6.76 mmol) in MeOH (10 ml) was added, dropwise, tert-butylhypochlorite (1.6 ml, 10 mmol). The solution was stirred for 2 h, evaporated, and purified by preparative HPLC (H2O/MeOH) to afford the title compound as a white foam (667 mg, 2.59 mmol, 38% over two steps). 1H NMR (D2O, 400 MHz) δ 1.44 (t, J=7.2 Hz, 3H), 1.65 (s, 3H), 3.22 (s, 3H), 3.25 (s, 3H), 3.57 (q, J=7.2 Hz, 2H), 3.76-3.80 (m, 2H), 4.61 (d, J=9.6 Hz, 1H), 4.90 (d, J=9.6 Hz, 1H). ESI/APCI expected for C9H18ClN2O2+: 221.11. Found: 221.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:31])[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)c3ccncc3)c2c1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.7 %

Procedure:
To a solution of ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example 24b, 1.0 g, 3.15 mmol) in dry DMF (20 mL) was added isonicotinic acid (504 mg, 4.10 mmol), followed by EDCI (783 mg, 4.10 mmol), HOBt (554 mg, 4.10 mmol), and triethylamine (414 mg, 4.10 mmol) at room temperature under nitrogen. After it was stirred at room temperature for 12 hrs, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with EtOAc (3×). The aqueous layer was basified with 2N NaOH to pH 8 and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified by chromatography on silica gel eluting with 10% MeOH in dichloromethane to give the title compound as a yellow solid (1.1 g, 83%). 1H NMR (400 MHz, DMSO-d6) δ 1.29 (t, J=4 Hz, 3H), 1.51 (s, 6H), 2.94 (s, 3H), 4.28 (q, J=4 Hz, 2H), 4.42 (s, 2H), 6.93 (dd, J=1, 8 Hz, 1H), 7.24 (dd, J=1, 8 Hz, 2H), 7.52 (t, J=8 Hz, 1H), 7.69 (dd, J=2, 4 Hz, 2H), 8.14 (s, 2H), 8.37 (s, 1H), 8.67 (dd, J=2, 4 Hz, 2H). MS 423 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>CN(C=O)C>[Br:7][CH2:8][CH2:9][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: BrCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a suspention of K2CO3 (4.52 g, 32.7 mmol), 1,2-dibromoethane (10.6 ml, 122.8 mmol) in DMF (12 mL) was added a solution of 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) in DMF (3 mL) at 0° C. The mixture was stirred at room temperature for 18 h., filtered and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc-hexane (increasing percentage of EtOAc from 20 to 25%) to afford the title compound (1.21 g, 64% yield). 1H NMR: (CDCl3) δ (ppm): 9.88 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 4.38 (t, J=6 Hz, 2H), 3.67 (t, J=6 Hz, 2H). LRMS (ESI): (calc.) 227.9, 229.9; (found) 229.1, 231.3 (MH)+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7]1>C(O)(=O)C.C(OC(=O)C)(=O)C>[N+:1]([C:13]1[CH:12]=[CH:11][C:10]2[C:9]([CH3:17])([CH3:16])[CH2:8][CH2:7][C:6]([CH3:18])([CH3:5])[C:15]=2[CH:14]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CCC(C)(C)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 8 h

Procedure:
77.2 ml of glacial acetic acid and 20.8 ml of nitric acid (98% strength) were mixed while cooling and then added dropwise within 2 hours to a solution of 65.8 g (0.35 mol) of 1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in 154 ml of glacial acetic acid and 257 ml of acetic anhydride in a salt/ice bath. After the addition was complete, the reaction mixture was washed to room temperature and stirred overnight. The solution was then poured into water, and the precipitate was filtered off with suction, washed with water and dried. 79.7 g of crude 2-nitro-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene of melting point 46°-50° C. were obtained.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([OH:23])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47]>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:28]2([CH3:29])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:42][C:43]#[C:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:50][CH3:51])[CH2:52][CH3:53])[CH2:46][CH3:47])[CH3:22])[CH2:12][C@@H:11]([O:31][Si:32]([C:35]([CH3:37])([CH3:36])[CH3:38])([CH3:33])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C[C@H](O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(C#CCBr)(CC)O[Si](CC)(CC)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)(CC)O[Si](CC)(CC)CC
Yield: 92.6 %

Procedure:
Under the same conditions as in Example 83, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene (60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol), 15-crown-5(10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) to give the title compound as a colorless oil (79.0 mg, 92%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Cl:24][CH2:25][C:26](Cl)=[O:27]>C(Cl)Cl>[Cl:24][CH2:25][C:26]([NH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:27]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1CNC(=O)CCl
Reaction time: 1 h

Procedure:
DIPEA (1.34 ml, 7.5 mmol) was added to a solution of 1,1-dimethylethyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate (1 g, 5 mmol) in 50 ml of DCM; then chloroacetyl chloride (0.418 ml, 5.25 mmol) was slowly added and the reaction mixture stirred 1 h before being worked up. DCM was added and the organic phase was washed with a saturated solution of ammonium chloride. The crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate 8/2 affording 1.28 g of the target material.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:8]([O:11][CH2:12][CH2:13][CH2:14]Br)=[CH:9][CH:10]=1)=[O:4].[CH2:26]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([CH:42]=[N:43][OH:44])=[CH:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+]>>[CH2:26]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35](/[CH:42]=[N:43]/[O:44][CH2:14][CH2:13][CH2:12][O:11][C:8]2[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:20][CH:21]=3)=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][CH:9]=2)=[CH:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ON=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1ccc(OCCCBr)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(OCCCO/N=C/c2cn(Cc3ccccc3)c3ccccc23)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 9.9 %

Procedure:
To a solution of 6-(3-bromo-propoxy)-4′-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (0.30 g, 0.72 mmol) and 1-benzyl-1H-indole-3-carbaldehyde oxime (0.18 g, 0.72 mmol) in 10/5/3 tetrahydrofuran/ethanol/water (18 mL) was added 2.5 M sodium hydroxide solution (3 mL). This mixture was heated to reflux for 2.5 hours and then allowed to cool back to room temperature. The mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified to approximately pH 1 using 1 N hydrochloric acid. The layers were then separated. The aqueous layer was extracted with one additional portion of ethyl acetate. The organics were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (20/80 with 1% formic acid) to give 6-[3-({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino }oxy)propoxy]-4′-(trifluoromethyl)-1,1′-biphenyl-3-carboxylic acid (0.041 g, 10%) as a white solid. mp=193-194° C. 1H NMR (400 MHz, DMSO-d6); δ 8.24 (s, 1H), 7.94 (d, 1H), 7.90-7.86 (m, 3H), 7.78-7.74 (m, 5H), 7.40 (d, 1H), 7.25-7.11 (m, 7H), 5.43 (s, 2H), 4.26 (t, 2H), 4.23 (t, 2H), 2.49 (m, 2H). Mass spec; (ES+) m/z 5.73.1 (ES−) m/z 571.5. Elemental analysis; Calculated for C33H27F3N2O4: C, 69.22; H, 4.75; N, 4.89. Found: C, 68.62; H, 4.93; N, 4.81.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18](=O)[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>ClCCCl>[F:1][C:2]1[C:3]([NH:17][C:18](=[S:30])[CH3:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: CC(=O)Nc1nc(OCc2ccc(F)cc2)ncc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Product: CC(=S)Nc1nc(OCc2ccc(F)cc2)ncc1F
Temperature: 100 °C
Yield: 3.2 %

Procedure:
N-(5-Fluoro-2-(4-fluorobenzyloxy)pyrimidin-4-yl)acetamide (50 mg, 0.42 mmol) was stirred in a Biotage Initiator® microwave vessel with 1,2-dichloroethane (3 mL) and Lawesson's reagent (170 mg, 0.42 mmol). The vessel was heated in a Biotage Initiator® microwave to 100° C. for 5 minutes then cooled room temperature, filtered, and diluted with CH2Cl2. The reaction mixture was then washed brine, and the layers were separated. The organic extract was dried onto silica and purified by flash chromatography. The product-containing fractions were then evaporated to dryness and purified again by reverse-phase HPLC to give 4 mg of N-(5-fluoro-2-(4-fluorobenzyl-oxy)pyrimidin-4-yl)ethanethioamide (4%) as a yellow glass: 1H NMR (CDCl3) δ 9.34 (b, 1H), 8.29 (d, J=3 Hz, 1H), 7.41 (m, 2H), 7.06 (m, 2H), 5.33 (s, 2H), 3.13 (s, 3H); HPLC-MS (ESI): m/z 294 (ES−).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=1.[I:22]I>C1COCC1>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[C:11]=1[I:22]
Reactant: II
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(I)c1C(F)(F)F
Temperature: -45 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a freshly prepared solution of LDA (119 mmol) in anhyd THF (250 mL) at −45° C. was added a solution of commercially available 4-fluoro-2-(trifluoromethyl)benzonitrile (21.5 g, 114 mmol) in THF (30 mL), dropwise at a rate such that the internal temperature remained <−40° C. (became dark brown during addition). The mixture was stirred 30 min at −45° C., cooled to −70° C. and iodine (31.7 g, 125 mmol) was added in one portion (−70° C.→−52° C.). The mixture was stirred for 1 h, removed from the cooling bath and quenched by addition of 10% Na2S2O3 (ca. 250 mL) and 1N HCl (ca. 125 mL). The mixture was extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) followed by recrystallization from heptane (30 mL), twice, affording 4-fluoro-3-iodo-2-(trifluoromethyl)benzonitrile (15.79 g, 50.1 mmol, 44.1% yield) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.85 (ddd, J=8.6, 5.1, 0.5 Hz, 1H), 7.36 (ddd, J=8.6, 6.6, 0.5 Hz, 1H); MS (GCMS EI) m/z 315 ([M]+, 100%).