Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@@H]1CCCN(C(C2C=C(C)C=CC=2C2C=NN(C)C=2)=O)[C@@H]1CNC1C=CC(C(F)(F)F)=CN=1.[NH2:35][CH2:36][C@@H:37]1[C@H:42]([CH3:43])[CH2:41][CH2:40][CH2:39][N:38]1[C:44]([C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[N:53]1[CH:57]=[N:56][C:55]([CH3:58])=[N:54]1)=[O:45].Cl[C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1>>[CH3:43][C@@H:42]1[CH2:41][CH2:40][CH2:39][N:38]([C:44](=[O:45])[C:46]2[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=2[N:53]2[CH:57]=[N:56][C:55]([CH3:58])=[N:54]2)[C@@H:37]1[CH2:36][NH:35][C:60]1[CH:67]=[CH:66][C:63]([C:64]#[N:65])=[CH:62][N:61]=1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Product: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C#N)cn2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 6-chloronicotinonitrile. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: Cl[Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21].CCN(CC)CC.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CCCCCC>[CH3:32][C:31]([NH:35][Si:2]([CH3:23])([CH3:22])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]1[CH3:21])([CH3:34])[CH3:33]
Reactant: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Reactant: CC(C)(C)N
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC1=C(c2ccccc2)c2cc3c(cc2C1[Si](C)(C)NC(C)(C)C)CCC3
Reaction time: 24 h
Yield: 91.3 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-3-phenyl-s-indacen-1-yl)silane (5.3483 g, 0.01578 moles) was stirred in hexane (100 mL) as NEt3 (2.2579 g, 0.02231 moles) and t-butylamine (1.9898 g, 0.02721 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (5.4118 g, 91.3 percent).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([C:30]2([O:36][CH3:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:29]=1)[O:5][C:6]1[O:7][C:8]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].OC1C=C(C2CC(OC)CCO2)C=CC=1>C(OCC)(=O)C>[CH3:37][O:36][C:30]1([C:28]2[CH:27]=[C:4]([CH:3]=[CH:2][CH:29]=2)[O:5][C:6]2[O:7][C:8]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:10]=2)[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1
Reactant: COC1(c2cc(F)cc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Agent: COC1CCOC(c2cccc(O)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1(c2cccc(Oc3nc(-c4ccccc4)c(-c4ccc(S(N)(=O)=O)cc4)o3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.9 %

Procedure:
4-[2-Chloro-4-phenyl-5-oxazolyl]benzenesulfonamide from Example 4, Step 3, (0.6 g, 1.8 mmol), DMF (20 mL), potassium carbonate (0.5 g, 3.6 mmol), and 4 (3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (0.37 g, 1.8 mmol) [prepared as described by G. C. Crawley, et al, J. Med. Chem., 35, 2600-2609 (1992)]were stirred at room temperature for 16.0 hours. The solution was diluted with ethyl acetate (100 mL), washed with 1N HCl, brine and water, dried over MgSO4 and concentrated. The residue was dissolved in ethyl acetate/hexanes (1:1) and filtered through silica. The eluant was concentrated and the residue recrystallized from ethyl acetate/hexanes to give 4-[2-[3-(4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl)phenoxy]-4-phenyl-5-oxazolyl]benzenesulfonamide as a white solid (0.4 g, 44%): mp 145°-147° C. 1H NMR (CDCl3) 300 MHz δ 7.88 (d, J=8.9 Hz, 2H) 7.70 (d, J=8.9 Hz, 2H) 7.6 (m, 2H) 7.36-7.5 (m, 6H) 7.0-7.1 (dt, J=6.4 Hz and J=2.2 Hz, 1H) 4.85 (bs, 2H) 3.7 (m, 4H) 3.05 (s, 3H) 2.0 (m, 4H). Anal. Calc'd. for C27H26N2O6S: C, 64.02; H, 5.17; N, 5.53. Found: C, 63.94; H, 5.17; N, 5.55.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]23[O:25][C:22]([CH2:26]I)([CH2:23][CH2:24]2)[CH2:21][CH2:20]3)=[CH:15][CH:14]=1>CC(N(C)C)=O>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]23[O:25][C:22]([CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])([CH2:23][CH2:24]2)[CH2:21][CH2:20]3)=[CH:15][CH:14]=1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]23[O:25][C:22]([CH2:26][CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])([CH2:23][CH2:24]2)[CH2:21][CH2:20]3)=[CH:15][CH:14]=1
Reactant: Brc1ccc(C23CCC(CI)(CC2)O3)cc1
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)C(CC12CCC(c3ccc(Br)cc3)(CC1)O2)C(=O)OC
Product: COC(=O)CCC12CCC(c3ccc(Br)cc3)(CC1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55 %
Yield: 28 %

Procedure:
To a solution of dimethyl malonate (0.47 mL, 4.1 mmol) in anhydrous dimethyl acetamide (5.6 mL) cooled in an ice-water bath was added NaH (60% dispersion in mineral oil, 163 mg, 4.1 mmol) portion-wise and the reaction was let stir at rt for 30 min until homogeneous. To this was added 1-(4-bromophenyl)-4-(iodomethyl)-7-oxabicyclo[2.2.1]heptane (440 mg, 1.12 mmol) and the reaction was stirred in a microwave reactor at 150° C. for 45 min. The resulting yellow reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford a crude yellow oil. Purification of the crude material by column chromatography (40 g silica gel, 0-30% EtOAc:Hept, monitor 225 nm) afforded 108 mg (28%) of methyl 3-(4-(4-bromophenyl)-7-oxabicyclo[2.2.1]heptan-1-yl)propanoate (decarboxylated material) as a clear yellow film and 245 mg (55%) of the title compound as a clear yellow film. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.54-1.79 (m, 6H), 2.06-2.16 (m, 2H), 2.39 (d, J=7.1 Hz, 2H), 3.66 (s, 6H), 3.73 (t, J=7.1 Hz, 1H), 7.27 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H). ESI-MS m/z: 399.0 [M+H]+, retention time 1.59 min (condition E).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=O)=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.Cl.C([N:43]=C=NCCCN(C)C)C.CN(C)C=O>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]([NH2:43])=[O:28])=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(N)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.30 g), 1-hydroxybenzotriazole ammonia complex (0.17 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.22 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenamide as colorless crystals (0.25 g, yield 83%). Recrystallization from tetrahydrofuran-hexane gave colorless prism crystals. melting point: 187-188° C.
Reaction SMILES: [CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[C:22]([CH3:25])[C:21]=3[CH:26]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([O:15]C)=[O:14])=[CH:8][CH:7]=2.[OH-].[Na+].O>CO.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH:27]([CH3:29])[CH3:28])[C:3]1[C:4]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][CH:23]=[C:22]([CH3:25])[C:21]=3[CH:26]=2)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][CH:7]=2
Reactant: COC(=O)c1ccc2nc(-c3ccc4occ(C)c4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: Cc1coc2ccc(-c3nc4ccc(C(=O)O)cc4nc3N(C)C(C)C)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
To a solution of methyl 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (25 mL) and chloroform (5 mL) was added sodium hydroxide (468 mg, 1.17 mmol) and water (2 mL) with stirring for 3 h at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (15 mL), and adjusted pH to 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylic acid (62 mg, 59%).
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]2[CH:6]=[CH:7][C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[N:10]([C:12](=[O:14])[CH3:13])[CH2:11][C:4]=2[N:3]=1.[C:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)([OH:23])=[O:22].C(N1C2C=CC=CC=2C=CC2N=C(C3C=NC(OC)=CC=3)C(F)=CC=2C1)(=O)C>>[C:12]([N:10]1[C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]=2[CH:7]=[CH:6][C:5]2[CH:19]=[CH:20][C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:21]([OH:23])=[O:22])=[N:3][C:4]=2[CH2:11]1)(=[O:14])[CH3:13]
Reactant: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Reactant: O=C(O)c1ccccc1B(O)O
Agent: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2nc(-c3ccccc3C(=O)O)ccc2C=Cc2ccccc21

Procedure:
Compound 61A was prepared from 55C (17 mg, 0.060 mmol) and 2-carboxyphenylboronic acid (10 mg, 0.060 mmol) by a route analogous to that used for the preparation of 2B.
Reaction SMILES: C([N:5]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6])(C)(C)C.[C:15]([C:23]([OH:25])=O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:8]([N:6]([C:23]([C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:25])[NH:5][C:7](=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([CH3:13])([CH3:9])[CH3:7]
Reactant: CC(C)(C)N(N)C(=O)c1ccccc1
Reactant: O=C(O)C(=O)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
N'-t-butyl-N'-benzoylhydrazine (1 g), benzoyl formic acid (0.7 g) and methanesulfonyl chloride (0.7 g) were stirred in toluene (30 ml) and saturated sodium bicarbonate (10 ml) at approximately 5° C. Triethylamine was added slowly, dropwise to the reaction mixture and stirred 1 hour at room temperature. After stirring for 1 hour, the reaction mixture was diluted with toluene (25 ml) and washed with water several times. The organic layers were dried over magnesium sulfate, filtered and the toluene rotavapped off to afford a white solid. After column chromatography, the product was obtained as a white solid in approximately 70% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[NH:13]1[CH:17]=[N:16][C:15]([SH:18])=[N:14]1.C(N(CC)CC)C>C(O)C>[NH:13]1[CH:17]=[N:16][C:15]([S:18][CH2:2][CH2:3][O:4][C:5]2[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=2)[C:8]#[N:9])=[N:14]1
Reactant: Sc1nc[nH]n1
Reactant: N#Cc1cccc(OCCCl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: N#Cc1cccc(OCCSc2nc[nH]n2)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
A solution of 3-[(2-chloroethyl)oxy]benzonitrile obtained in Reference Example 1 (11.3 g, 62.3 mmol), 1H-1,2,4-triazole-3-thiol (6.00 g, 59.3 mmol) and triethylamine (8.40 mL, 62.3 mmol) in ethanol (50 mL) was stirred at 80° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a white powder (14.4 g, 98%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:9][N:10]([CH3:22])[CH2:11][C:12]#[C:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].[Cl-].[NH4+]>C(OCC)C>[CH3:22][N:10]([CH3:9])[CH2:11][CH:12]=[C:13]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15]
Reactant: Brc1ccccc1
Reactant: CN(C)CC#CC(O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)CC=C(c1ccccc1)C(O)c1ccccc1
Temperature: 0 °C
Yield: 27.6 %

Procedure:
A solution of bromobenzene (24.8 g) in ethyl ether (120 cc) is added dropwise over approximately 1 hour to a suspension of magnesium turnings (3.85 g) in ethyl ether (100 cc). 4-Dimethylamino-1-phenyl-2-butyn-1-ol (10 g) in ethyl ether (30 cc) is added over approximately 15 minutes to the black solution obtained. The reaction mixture is then refluxed for 3 hours and 30 minutes, and then poured into a mixture of ice (400 g) and a saturated aqueous solution (200 cc) of ammonium chloride. The organic phase is separated; the aqueous phase is extracted with methylene chloride (2×200 cc); the organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residue is purified by "flash" chromatography [eluent: methanol/ethyl acetate (60/40 by volume)], fractions 18 to 39 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After the residue has been recrystallised from isopropyl ether, 4-dimethylamino-1,2-diphenyl-2-buten-1-ol (E) (3.9 g) is obtained in the form of white crystals melting at 113° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]
Reactant: O=Cc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 951.9 %

Procedure:
To a solution of 3-bromo-4-hydroxybenzaldehyde (100 g, 50 mol, 1 eq) in acetone (500 mL) was added potassium carbonate (135 g, 100 mmol, 2 eq) followed by t-butyl 2-bromoacetate (100 g, 50 mmol, 1 eq). After stirring at room temperature for 2 h, the acetone was removed in vacuo and the resultant residue was washed with water to give 150 g (89%) of t-butyl 2-(2-bromo-4-formylphenoxy)acetate (1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[O:25]([CH2:32][C:33](O)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][NH:1][C:33](=[O:34])[CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Reactant: O=C(O)COc1ccccc1
Product: Cl
Product: O=C(COc1ccccc1)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate and 2-phenoxyacetic acid, and in the same manner as in Example 39, the title compound was obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:8][CH:7]=2)[CH2:3]1.CS(Cl)(=O)=O.[F:23][C:24]1[C:29]([F:30])=[C:28]([CH3:31])[CH:27]=[CH:26][C:25]=1O.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CC(N(C)C)=O.O>[F:23][C:24]1[C:29]([F:30])=[C:28]([CH3:31])[CH:27]=[CH:26][C:25]=1[O:1][CH:2]1[CH2:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C@@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])=[CH:10][CH:11]=2)[CH2:5]1
Reactant: CC(=O)N[C@@H](C)c1ccc(N2CC(O)C2)cc1
Reactant: Cc1ccc(O)c(F)c1F
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C)c(F)c3F)C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 0.023 g (0.10 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in 5 mL THF are added 0.017 mL (0.12 mmol) TEA and the mixture is cooled to 0° C. 0.008 mL (0.10 mmol) methanesulfonyl chloride are added dropwise and the mixture is stirred for 2 h at 0° C. Water is added and the aq. phase is extracted with ethyl acetate (2×). The combined organic layers are dried (MgSO4) and concentrated. The residue is taken up in 1.0 mL DMA and is added to a mixture of 0.014 g (0.12 mmol) 2,3-difluoro-4-methylphenol and 0.039 g (0.12 mmol) Cs2CO3 in 1.0 mL DMA. The resulting mixture is stirred for 12 h at 100° C. After cooling the mixture is directly purified by HPLC (MeOH/water (+0.1% NH4OH)) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1N.N([O-])=O.[Na+].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16].[BrH:20]>CC(C)=O.O>[Br:20][CH:15]([CH2:16][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[Cl:1])[C:14]([O:18][CH3:19])=[O:17]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: C=CC(=O)OC
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Br)Cc1cccc(Cl)c1Cl
Temperature: 25 °C

Procedure:
8.1 g of 2,3-Dichloroaniline (0.05 mole) in acetone (100 ml.) and concentrated hydrobromic acid (16 ml.) was stirred at -5° C. and treated with a solution of 4.2 g. of sodium nitrite (0.06 mole) in water (10 ml.). Methyl acrylate (0.5 mole) (43 g.) and cuprous bromide (100 mg.) were then added at 0° C. The reaction temperature was kept below 15° C. until nitrogen evolution ceased and then stirred at 25° C. for thirty minutes. The reaction mixture was poured into water and extracted with benzene which was dried over sodium sulfate and evaporated to give methyl 2-bromo-3-(2,3-dichlorophenyl)propionate. The propionate, 156 g. (0.5 mole) was dissolved in glacial acetic acid (1 l.) and stirred. Zinc dust 65 g. (1 mole) was added in portions and the mixture was stirred for one hour, filtered and evaporated to give methyl 3-(2,3-dichlorophenyl)propionate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH:24](S)([SH:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:25]1[O:23][C:13]2([CH2:14][C@H:15]([CH3:22])[C@@:16]3([CH2:17][OH:18])[C:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:19]3[CH2:20][CH2:21][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])=[CH:12]2)[S:26][CH2:24]1
Reactant: CC(S)S
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Reaction time: 4 h

Procedure:
17β,19-Dihydroxy-1α-methyl-4-androsten-3-one in acetic acid is treated with ethanedithiol and p-toluenesulfonic acid. After 4 hours at room temperature, the solution is poured onto water and the mixture extracted with methylenechloride. The methylenechloride extracts are washed well with water, sodium hydroxide solution, water, dried over sodium sulfate and evaporated under reduced pressure to leave 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal which is recrystallized once from a solution of acetone-hexane.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:29]1[N:28]=[C:27]([C:20]2[C:21]3[C:22](=[N:23][CH:24]=[CH:25][CH:26]=3)[NH:18][CH:19]=2)[CH:32]=[CH:31][N:30]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Reactant: Nc1ccccc1F
Product: Fc1ccccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 54.7 %

Procedure:
Using the procedure of example 1, 2-fluoroaniline (90 mg) was reacted with compound 1f (100 mg) to provide compound 31 (45 mg, 55%). 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=8.0 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H), 8.26 (m, 1H), 8.24 (s, 1H), 8.04 (t, J=8.0 Hz, 1H), 7.25 (d, J=5.6 Hz, 1H), 7.22-7.14 (m, 4H). MS (ESI) m/z: 306 (M+H)+.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[CH2:13]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([OH:34])=O)[N:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[CH3:35][O:36][C:37]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH3:47])[C:38]=1[NH2:39].Cl.C(N(CC)CC)C>C1COCC1>[CH2:13]([C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([NH:39][C:38]2[C:40]([O:46][CH3:47])=[CH:41][C:42]([O:44][CH3:45])=[CH:43][C:37]=2[O:36][CH3:35])=[O:34])[N:30]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCCc1nc(CC(=O)O)cs1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCc1nc(CC(=O)Nc2c(OC)cc(OC)cc2OC)cs1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
Carbonyl dimidazole (0.38 g, 2.35 mmol) was added to a solution of 2-tridecyl-4-thiazole acetic acid (0.71 g, 2.28 mmol) in dry THF (50 mL), and the resulting mixture was stirred at room temperature for 1.5 hours, then 2,4,6-trimethoxyaniline made in situ [2,4,6-trimethoxyaniline.HCl (0.05 g, 2.28 mmol) and triethylamine (0.32 mL, 2.28 mmol) were stirred together at room temperature for 0.5 hour] was added and the solution stirred for 3 days at room temperature, then filtered, and the filtrate stirred with 3:1 chloroform/water (200 mL) for 1 hour. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, concentrated, and triturated with hexanes to yield a grey solid (0.93 g, 82%) which was air dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:23]4[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN2CCc3c(c(=O)oc4cc(OC)ccc34)C2)cc1
Yield: 54 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-methoxybenzaldehyde. Yield 54%; mp 101°-103° C.