Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:44]I.O>C1COCC1>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[O:26][CH3:44])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: CI
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2[C@@H](O)C2CCCCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of (S)-(2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (1.81 g, 3.04 mmol) in THF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 254.4 mg, 6.4 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (1.31 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 5 hours. Water (10 mL) was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with brine, dried with sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound as a colorless oil (1.77 g, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 0.93-1.14(m, 5H) 1.18 (d, J=10.79 Hz, 1H) 1.43-1.54(m, 1H) 1.59-1.65(m, J=4.56 Hz, 2H) 1.68-1.74 (m, J=2.49 Hz, 1H) 1.90 (d, J=12.03 Hz, 1H) 3.06 (s, 3H) 4.08 (d, J=7.05 Hz, 1H) 4.21 (s, 3H) 4.71 (d, J=15.77 Hz, 1H) 4.71 (s, 2H) 4.88 (d, J=16.18 Hz, 1H) 7.35 (s, 1H) 7.49 (d, J=8.30 Hz, 1H) 7.55 (d, J=8.30 Hz, 1H) 7.66 (s, 2H) 7.78 (s, 1H). MS (ES+) Calc: 609.2, Found: 610.5 (M+1). [α]D20=36.49 deg (c=10.05 mg/mL, acetone) Determination of absolute configuration of (S)-(3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxymethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15](S(C)=O)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1.[NH2:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[CH2:33]1.C([O-])([O-])=O.[Na+].[Na+].Cl>C1COCC1.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:31][C@H:32]4[CH2:37][CH2:36][CH2:35][C@@H:34]([N:38]5[CH2:42][CH2:41][CH2:40][C:39]5=[O:43])[CH2:33]4)[C:14]([F:20])=[CH:13][N:12]=3)=[CH:9][N:8]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: N[C@H]1CCC[C@@H](N2CCCC2=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCC[C@@H](N5CCCC5=O)C4)n3)c3cc(Cl)cnc32)cc1

Procedure:
A mixture of 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)-pyrrolo[2,3-b]pyridine, 1a, (0.14 g, 0.29 mmol) and 1-((1R,3S)-3-aminocyclohexyl)pyrrolidin-2-one, 45c, (0.10 g, 0.53 mmol) and Na2CO3 (0.09 g, 0.88 mmol) freshly ground, in THF (2.25 mL) and CH3CN (0.45 mL) and heat to 135° C. for 30 min. The mixture was slowly poured into 15 mL 1M HCl and extracted with EtOAc (5×). The combined organic layers were washed with brine, dried over Na2SO4 and filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-20% MeOH—CH2Cl2 gradient) provided the final product as a sticky residue. Trituration with CH3CN provided an off white powder (105 mg) which was impure, but which was taken directly to the final deprotection step.
Reaction SMILES: [Br:1]C1C2C(=CC(C3SC4C(C5C=CC(Cl)=CC=5)=C([C@H](OC(C)(C)C)C(OCC)=O)C(C)=CC=4N=3)=CC=2)N(C)N=1.N[C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[S:51][C:52]4[C:58]([C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=5)=[C:57]([C@H:66]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])[C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:56]([CH3:77])=[CH:55][C:53]=4[N:54]=3)[CH:48]=2)[N:43]([CH3:78])[N:42]=1>>[Br:1][C:41]1[C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:50]3[S:51][C:52]4[C:58]([C:59]5[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=5)=[C:57]([C@H:66]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])[C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:56]([CH3:77])=[CH:55][C:53]=4[N:54]=3)[CH:48]=2)[N:43]([CH3:78])[N:42]=1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(N)nn4C)sc2c1-c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(Br)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(Br)nn4C)sc2c1-c1ccc(Cl)cc1

Procedure:
prepared in a manner similar to (S)-ethyl 2-(2-(3-bromo-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate except using (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate instead of (S)-ethyl 2-(2-(3-amino-1-methyl-1H-indazol-6-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. LCMS-ESI+: calc'd for C30H29BrClN3O3S: 626.1, 628.1, 630.1 (M+H+); Found; 626.1, 628.1, 630.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:37]2[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2ccc(CCC(=O)O)cc2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 4-(2-carboxyethyl)benzeneboronic acid to give the title compound as a colorless solid. MS (m/e)=548.2 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:16]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[NH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[F-].[Cs+].[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>COCCOC.CO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[NH:13][N:14]=[C:15]([CH:17]3[CH2:19][CH2:18]3)[CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Br)cc1)Nc1cc(C2CC2)[nH]n1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Product: O=C(Cc1ccc(-c2ccccc2)cc1)Nc1cc(C2CC2)n[nH]1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To 40 mg of 2-(4-bromophenyl)-N-(5-cyclopropyl-1H-pyrazol-3-yl)acetamide resin linked 1 ml of a 10.4M solution of CsF in DME:MeOH (3:1), phenylboronic acid (0, 12 mmol) in DME (0.5 ml) and tetrakis triphenylphosphine palladium, (Pd(PPh3)4, 0.008 mmol) in DME (1 ml) were added. The mixture was shaken 18 hrs at 80° C. and then washed with DMF (3×5 ml), MeOH (3×5 ml) and DCM (3×5 ml). To the resin 5 ml of TFA 10% in DCM were added and the mixture was shaken 1 hr at room temperature, the organic phase was filtered off and the resin was washed with DCM (3×5 ml) and DMSO (2×5 ml). The organic fractions were collected and evaporated under reduced pressure and the residue was analyzed by HPLC-MS (area count 90%, 254 nm; M+1=318, 2M+1=365) without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][N:29]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:25][CH3:26])[C:12]=2[N:13]=1)=[O:7].COCCNC.COCCN(CC1C=C(C=CN=1)C(NC1S[C:51]2[C:57]([N:58]3[CH2:63][CH2:62]OCC3)=CC=C(OC)C=2N=1)=O)C>>[O:23]1[CH2:24][CH:18]([C:17]2[C:11]3[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:27]=[CH:28][N:29]=[C:3]([CH2:2][N:58]5[CH2:57][CH2:51][CH2:62][CH2:63]5)[CH:4]=4)=[N:13][C:12]=3[C:14]([O:25][CH3:26])=[CH:15][CH:16]=2)[CH2:19][O:20][CH2:21][CH2:22]1
Reactant: COCCN(C)Cc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CCl)c3)nc12
Agent: CNCCOC
Product: COc1ccc(C2COCCOC2)c2sc(NC(=O)c3ccnc(CN4CCCC4)c3)nc12
Yield: 48 %

Procedure:
2-Chloromethyl-N-(7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide and N-(2-methoxyethyl)-methylamine were reacted as described for 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide in WO03/043636. Usual workup, preparative reversed-phase HPLC and final dry-freezing afforded the tide compound as light yellow solid (48% yield). Mp 108-111° C., MS: m/e=469(M+H+).
Reaction SMILES: O[C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[C:29]([NH2:30])=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:31][CH2:32][CH3:33])[CH:21]=1.C(O)C>CN(C)C=O>[CH2:32]([O:31][C:22]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][C:29]2[C:20]([CH:21]=1)=[N:19][C:11]1[C:2](=[C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]([OH:13])=[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]3=1)[N:30]=2)[CH3:33]
Reactant: CCOc1cc(N)c(N)cc1C(=O)OC
Reactant: CCOC(=O)C1=C(O)C(=O)c2ccccc2C1=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ccccc2c2nc3cc(OCC)c(C(=O)OC)cc3nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 895 mg of ethyl 3-hydroxy-1,4-dihydro1,4-dioxo-2-naphthoate in 10 ml of N,N-dimethylformamide was added 620 mg of N,N'-carbonyldiimidazole, and the mixture was stirred at room temperature for 2 hours. To the mixture was added the crude methyl 4,5-diamino-2-ethoxybenzoate in 10 ml of N,N-dimethyl-formamide under ice cooling, and the mixture was stirred at room temperature overnight. To the reaction solution was added 200 ml of ethanol, and then the resulting precipitate was collected by filtration and recrystallized from chloroform - ethanol to give the title compound, m.p. 270°-273° C., yield of 531 mg.
Reaction SMILES: [CH2:1]([P:12](=[O:21])([O:17][CH2:18][CH:19]=[CH2:20])[O:13][CH2:14][CH:15]=[CH2:16])[P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6].[H-].[Na+].C(Cl)Cl.C[N:28](C=O)C>C1COCC1>[NH2:28][CH:1]([P:2](=[O:11])([O:7][CH2:8][CH:9]=[CH2:10])[O:3][CH2:4][CH:5]=[CH2:6])[P:12](=[O:21])([O:13][CH2:14][CH:15]=[CH2:16])[O:17][CH2:18][CH:19]=[CH2:20]
Reactant: C=CCOP(=O)(CP(=O)(OCC=C)OCC=C)OCC=C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CCOP(=O)(OCC=C)C(N)P(=O)(OCC=C)OCC=C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 59 %

Procedure:
To a solution of bisphosphonate 23 (2.0 g, 5.95 mmol) in DMF (6 mL) was added NaH (60% dispersion in mineral oil, 254 mg, 6.35 mmol) portionwise. The solution was stirred for 45 min at room temperature and added to a solution of O-(diphenylphophinyl)hydroxylamine (1.35 g, 5.77 mmol) in THF (40 mL), cooled in a dry ice/acetone bath. The resulting mixture was stirred for 10 min at the same temperature then 18 h at room temperature. CH2Cl2 (40 mL) was added, the solids were removed by filtration and washed with several portions of CH2Cl2. The combined filtrates were concentrated in vacuo and purified by flash chromatography on silica gel using a gradient of 0-5% MeOH/EtOAc to provide aminobisphosphonate 24 as a clear yellow oil (1.24 g, 3.53 mmol, 59%). 1H NMR (400 MHz, CDCl3) δ 1.69 (bs, 2H), 3.52 (t, J=20.8 Hz, 1H), 4.64-4.67 (m, 8H), 5.24-5.27 (m, 4H), 5.36-5.42 (m, 4H), 5.92-6.02 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH2:22]>CC#N>[C:1]([O:5][C:6]([N:8]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[CH:15]=2)([CH3:13])[CH2:11][O:10][S:9]1(=[O:22])=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)c1
Reactant: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)c2)COS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2-oxide (10.4 g, 28 mmol) in CH3CN (50 mL) at 0° C. was added RuO4 (0.5% in stabilized aq., 50 mg, 0.1% by weight) in H2O (10 mL) and NaIO4 (8.9 g, 41.5 mmol, 1.5 eq) in H2O (35 mL). The mixture was stirred at RT for 2 h. The mixture was partitioned between Et2O (200 mL) and H2O (50 mL). The organic layer was separated and the aqueous layer was extracted with Et2O (3×50 mL). The combined organic layer was dried (Na2SO4), and concentrated to give 10.8 g (100%) of 3-(tert-butoxycarbonyl)-4-(3-bromophenyl)-4-methyl-[1,2,3]-oxathiazolidine-2,2-dioxide (DC4; R6=Me) as a white solid (˜10.8 g, yield: 100%). 1H NMR (CDCl3) 7.56 (t, J=1.8 Hz, 1H), 7.48-7.52 (m, 1H), 7.38-7.44 (m, 1H), 7.30 (t, J=8.0 Hz, 1H), 4.41 (dd, J1=9.3 Hz, J2=20.4 Hz, 2H), 2.01 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)[CH3:13]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1CCC1
Agent: [Rh]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CC(=O)O
Product: CCOC(=O)COC1CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
To a solution of cyclobutanol (720 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 30 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 140° C. to give 1.00 g of the product 469. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.03 (m, 1H), 3.98 (s, 2H), 2.28-2.15 (m, 2H), 2.081.95 (m, 2H), 1.7 (q, 1H), 1.50 (m, 1H), 1.28 (t, 3H)
Reaction SMILES: [F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:21]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:28])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C:18](=[CH:19][CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:21])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: C[C@]12CC=C3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Yield: 71 %

Procedure:
A suspension of 900 mg of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),9(1l)-tetraene in 19 ml of methanol and 1.9 ml of water is refluxed with 900 mg of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed three times with water, once with sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate. After crystallization from hexane, 0.5 g of 17-difluoromethylene-estra-1,3,5(10),9(11)-tetraen-3-ol is obtained as colorless crystals with a melting point of 134-135° C., [α]D22 =+89° (c=0.515% in pyridine).
Reaction SMILES: CC(OC(C)=O)=O.CC([O-])=O.[K+].[NH2:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[C:17]([O:19][CH3:20])=[O:18].C1OCCOCCOCCOCCOCCOC1.C(O[N+:49]([O-])=O)C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl.O.C1COCC1.CO>[CH3:25][C:24]1[C:23]2[C:14](=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[NH:13][N:49]=1
Reactant: CC(C)CO[N+](=O)[O-]
Reactant: CCc1ccc(C(=O)OC)cc1N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C)n[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Ac2O (0.579 ml, 6.14 mmol) was added to a stirred mixture of KOAc (361 mg, 3.68 mmol) and methyl 3-amino-4-ethylbenzoate (550mg, 3.07 mmol) in CHCl3 (5 ml) and the mixture was stirred at 90° C. for 2 h. KOAc (361 mg, 3.68 mmol), 18-crown-6 ether (81 mg, 0.307 mmol) and isobutylnitrate (719 mg, 6.14 mmol) were added thereto at room temperature and the mixture was further stirred at 90° C. for 2 h. The reaction mixtuer was diluted with chloroform and H2O, the organic layer was washed with water, brine, and dried over MgSO4. After filteration and evaporation, the residue was diluted with THF (5.00 ml) and MeOH (5.00 ml), and K2CO3 (848 mg, 6.14 mmol) was added thereto at room temperature. After the mixture was stirred for 2 h. at room temperature, CHCl3 and H2O was added thereto. The organic layer was washed with H2O, brine, and dried over MgSO4. After filteration and evaporation, the reside was puritied by silicagel column chromatography (hexane/EtOAc) to give intended compound as a pale brown solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].Cl[C:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]=1>C(Cl)(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18](=[O:25])(=[O:26])[N:17]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)c3ccccc32)o1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a refluxing solution of 2.14 g (10 mmol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine in 150 ml of chloroform is added incrementally 2.02 g (10 mmol) of 3-chlorobenzisothiazole 1,1-dioxide. The reaction mixture is refluxed for an additional 30 minutes, is cooled to room temperature and then solvent is removed on a rotoevaporator. The resulting oil is subjected to preparative column chromatography on silica gel. Elution with methylene chloride followed by methylene chloride: methanol (95:5) yields 420 mg (12%) of a white solid. The solid is suspended in ethyl ether, separated by suction filtration and dried in vacuo to give 270 mg (7%) of the title compound: m.p. 91-94.C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:4]=1[CH2:5][S:6][C:7](=[NH:20])[C:8]([C:18]#[N:19])=[C:9]([SH:17])[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1.II.[ClH:37]>C(OCC)(=O)C>[ClH:37].[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([NH:10][C:9]2[S:17][N:20]=[C:7]([S:6][CH2:5][C:4]3[C:21]([O:27][CH3:28])=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=3[O:2][CH3:1])[C:8]=2[C:18]#[N:19])[CH:12]=1
Reactant: COc1cc(OC)c(CSC(=N)C(C#N)=C(S)Nc2cccnc2)c(OC)c1
Agent: Cl
Agent: II
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(OC)c(CSc2nsc(Nc3cccnc3)c2C#N)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To compound 12 (5.88 g, 14.1 mmol) in ethyl acetate (127 mL) is added pyridine (2.3 mL, 28.3 mmol) at 0° C. A solution of iodine (3.6 g, 14.1 mmol) in ethyl acetate (178 mL) is then added over 2 hours to the reaction. The reaction is then stirred for an additional 3 hours at 0° C. 1N HCl (101.5 mL) is then added and stirred for 5 min. The suspension is then filtered and washed with water to provide 13 (2.53 g, 40%). The mother liquor is basified with saturated aqueous sodium bicarbonate and more ethyl acetate is added (200 mL). The layers are separated and the organic layer is filtered and the mother liquor is concentrated in vacuo. To the resulting solids are added ethyl acetate (183 mL) and 1N HCl (61 mL) and the suspension is stirred for 5 minutes. Filtration provides additional 13 (1.21 g, 19%). 1H NMR (d6 DMSO): δ 11.27 (1H, br. s), 8.72 (1H, d, J=2.1 Hz), 8.49 (1H, dd, J=4.9, 1 Hz), 8.05 (1H, dd, J=8.4, 2.1 Hz), 7.74 (1H, dd, J=8.4, 4.9 Hz), 6.23 (2H, s), 4.35 (2H, s), 3.76 (9H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[CH:43]=[CH:42][N:41]=[C:40]([CH3:44])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)ccn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS 335255-65-7] (302 mg, 1.0 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (311 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (480 mg, 89%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]([Cl:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1Cl

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3-chloro-4-methoxy-phenylboronic acid, 5-(3-chloro-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=66%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].[OH:11][C:12]1[CH:17]=[C:16]([CH3:18])[O:15][C:14](=O)[CH:13]=1>ClC1C=CC=CC=1Cl>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][OH:10])=[CH:3][C:2]=1[N:1]1[C:16]([CH3:18])=[CH:17][C:12]([OH:11])=[CH:13][C:14]1=[O:15]
Reactant: Nc1cc(CO)ccc1F
Reactant: Cc1cc(O)cc(=O)o1
Solvent: Clc1ccccc1Cl
Product: Cc1cc(O)cc(=O)n1-c1cc(CO)ccc1F
Reaction time: 0.17 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar, Dean-Stark trap and reflux condenser was charged with (3-amino-4-fluorophenyl)methanol (4.5 g, 31.9 mmol), 4-hydroxy-6-methyl-2-pyrone (4 g, 31.9 mmol) and o-dichlorobenzene (5 mL). The system was immersed in a 170 C oil bath for 10 minutes. The solvent was removed in vacuo and the residue was chromatographed on reverse phase (75:25 water:acetonitrile with 0.05% TFA). The product contained some starting materials after purification and was used without further purification (1.27 g, 15%). 1H NMR (400 MHz, dmso-d6) δ 7.39 (m, 1H), 7.20 (dd, J=2.2 and 7.6 Hz, 1H), 6.74 (dd, J=2.7 and 9.6 Hz, 1H), 5.93 (dd, J=1.2 and 2.2 Hz, 1H), 5.22 (dd, J=0.4 and 2.2 Hz, 1H), 2.12 (s, 3H) ppm. ES-HRMS m/z 250.0862 (M+H calcd for C13H13FNO3 requires 250.0874).