Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:4].[F:14][C:15]1[CH:16]=[C:17]([N:34]2[CH2:38][C@H:37]([CH2:39][N:40]3[CH:44]=[CH:43][N:42]=[N:41]3)[O:36][C:35]2=[O:45])[CH:18]=[CH:19][C:20]=1[C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH2:31][C@@H:30]([CH2:32]O)[O:29][N:28]=2)=[CH:25][CH:26]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([N:5]([CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:32][C@H:30]1[O:29][N:28]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:20]3[CH:19]=[CH:18][C:17]([N:34]4[CH2:38][C@H:37]([CH2:39][N:40]5[CH:44]=[CH:43][N:42]=[N:41]5)[O:36][C:35]4=[O:45])=[CH:16][C:15]=3[F:14])=[CH:22][N:23]=2)[CH2:31]1)=[O:11])=[O:4]
Reactant: COC(=O)N(C)CCCCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N(C)CCCCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
The carbamate prepared as above (0.175 g, 0.93 mmol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 0.25 g, 0.57 mmol), 4-dimethylaminopyridine (0.01 g, 0.08 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.19 g, 0.99 mmol) were combined in DMF (2 ml). The suspension was allowed to stir for 3.5 hours at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 10% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white powder (0.18 g), melting point: 82° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[S:10]([CH2:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([S:10]([CH2:13][CH:14]([CH3:15])[CH3:16])(=[O:11])=[O:12])[N:8]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: CC(C)CS(=O)(=O)c1nc(C(=O)O)ccc1C1CC1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(S(=O)(=O)CC(C)C)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(isobutylsulfonyl)picolinic acid (Example 351 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials. MS (EI): m/e=410.21 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2ccc(F)cc2)ccc1O
Yield: 56.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-fluorobenzyl bromide (740 mg, 3.92 mmole), 480 mg (44% yield) of 5-(4-fluorobenzyl)aminosalicylic acid was obtained as a white solid.: mp>210° C. (decompose).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[F:11])[CH3:2]
Reactant: CCNc1ccc(F)cc1F
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(C(=O)C(C)(C)C)c1ccc(F)cc1F
Temperature: 0 °C

Procedure:
15.7 g of N-ethyl-2,4-difluoroaniline and 11.0 g of triethylamine are dissolved in 40 ml of toluene. 12.1 g of pivaloyl chloride are added dropwise with cooling, and the mixture is then heated at the boiling point for 1 hour. The mixture is discharged into 100 ml of ice water, and the toluene phase is separated off, washed with 1 N HCl and then with H2O and evaporated in vacuo. 23.7 g of a yellowish oil which crystallizes on standing are obtained. Melting point: 69°-71° (recrystallized from dilute ethanol).
Reaction SMILES: Br[C:2]1[O:6][C:5]2[C:7]([O:13]C(=O)C)=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:17](=[O:30])[C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[CH:32]1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:31]1([C:2]2[O:6][C:5]3[C:7]([OH:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:4]=3[C:3]=2[C:17](=[O:30])[C:18]2[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:35]=[CH:34][N:33]=[CH:32]1
Reactant: COc1cc(C(=O)c2c(Br)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1c[nH]cn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2c(-n3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
A mixture of 2-bromo-7-acetoxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (30 mg, 0.063 mmol) and imidazole (60 mg, 0.88 mmol) in a mixture of toluene:triethylamine (3 mL: 2 drops) was refluxed for 4 hours (tlc). Solvent was distilled under vacuum and the crude residue was purified by PTLC (eluent=ethyl-acetate: 1% triethylamine) to give the title compound as a yellow solid; (8 mg, 30%); 1H NMR (300 MHz, CDCl3) δ 8.24 (bs, 1H), 7.52 (b, 1H), 7.19 (b, 1H), 7.06 (s, 2H, benzoyl Hs), 6.99 (d, 1H, J=8.60 Hz), 6.93 (d, 1H, J=8.66 Hz), 3.96 (s, 3H, OMe), 3.91 (s, 3H, OMe), 3.76 (s, 6H, 2×OMe).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][C:22]=1[C:31]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:32]
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)c1cnc2ccccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCSc1ccncc1)c1cnc2ccccc2n1
Yield: 48.8 %

Procedure:
To a solution of 4.30 g (17.8 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 8.68 ml (62.3 mmol) of triethylamine in 200 ml of methylene chloride, 3.43 g (17.8 mmol) of 2-quinoxaloyl chloride was added with stirring under ice-cooling, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and water, and dried. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) and recrystallization (solvent: ethyl acetate-ether) to give 2.82 g of the desired compound (48.9% yield, white crystals).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[C@H:9]1[C:14]([O:16][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of (2S,3R)-3-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester [186132-96-7] (500 mg, 2.162 mmol; Chem-Impex International, Inc.) in MeOH (9.0 mL), cooled to 0° C., was added with stirring a solution of Cs2CO3 (704 mg, 2.162 mmol) in water (6.0 mL). The mixture was concentrated by rotary evaporation and the residue was suspended in DMF (17.0 mL). The suspension was cooled to 0° C., followed by addition of benzylbromide (0.514 mL, 4.32 mmol) and stirring overnight at RT. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc. The organics were washed with aqueous NaHCO3 (2×) and water (2×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane 2:3) to give the title compound as an oil. MS (LC/MS): 322 [M+H]+, 665 [2M+Na]+; tR (HPLC conditions b): 4.12 min.
Reaction SMILES: [OH:1][CH:2]([C:15]1[CH:19]=[CH:18][O:17][C:16]=1[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NCC1C=C([Si](CC)(CC)CC)OC=1>CN(C)C=O>[C:27]1([NH:33][C:34]([O:1][CH:2]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1ccoc1[Si](CC)(CC)CC
Agent: CC[Si](CC)(CC)c1cc(CN)co1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC(OC(=O)Nc1ccccc1)c1ccoc1[Si](CC)(CC)CC

Procedure:
3-(1-Hydroxytridecyl)-2-triethylsilylfuran is reacted with phenyl isocyanate and copper (2) chloride in dimethylformamide to give 3-(1-phenylcarbamoyloxytridecyl)-2-triethylsilylfuran. Oxidizing the latter intermediate with singlet oxygen and thereafter reduction with sodium borohydride gives 3-(1-phenylcarbamoyloxytridecyl)-2(5H)-furanone. Substituting phenyl isocyanate with diethyl chlorophosphate, gives 3-(1-diethylphosphonooxytridecyl)-2(5H)-furanone. Substituting phenyl isocyanate with ethyl chloroformate, gives 3-(1-ethoxycarbonyloxytridecyl)- 2(5H)-furanone. Substituting phenyl isocyanate with methoxyethyl chloromethyl ether, gives 3-[1-(2-methoxy)ethoxymethoxy]tridecyl-2(5H)-furanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([O:21]C(=O)C)[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1.CO.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C@@H:14]([OH:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:25][CH3:26])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](OC(C)=O)CC[C@H]3[C@H]1CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]1CC2

Procedure:
4.5 g. of rac.-1,3-dimethoxy-17β-acetoxy-8α-estra-1,3,5(10)-triene is saponified under N2 in 100 ml. of methanol with 13 ml. of aqueous potash solution (10%) by heating for 1.5 hours under reflux. After cooling, the mixture is gently neutralized with glacial acetic acid, concentrated to half its volume, precipitated into ice water/NaCl, and worked up, thus obtaining 4.1 g. of crude product. By recrystallization of 500 mg. from methanol, 330 mg. of final product is obtained, m.p. 153/153.5°-154°C.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2[CH2:14][S:15][CH2:16][C:3]1=2.N1C=CC=CC=1.ClN1C(=O)CCC1=O>O>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12
Reactant: CN1C2=C(CSC2)C(=O)Nc2ccccc21
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1c2ccccc2NC(=O)c2cscc21

Procedure:
To a suspension of 3.8 g. of 1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 15 ml. of dry pyridine is added, in portions, a total of 2.18 g. of N-chlorosuccinimide. The resulting solution is heated on a steam bath for 15 minutes, cooled and diluted with water. The solid is collected and recrystallized from methanol, to give a tan solid, m.p. 224°-225° C. (dec.).
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:16][C:17]([NH2:19])=[S:18].C([O-])(=O)C.[Na+].O>C(O)C>[NH2:19][C:17]1[S:18][CH:2]=[C:3]([C:4](=[N:10][O:11][CH:12]([CH3:14])[CH3:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:16]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOC(C)C)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOC(C)C)c1csc(N)n1
Yield: 60.3 %

Procedure:
Ethyl 4-chloro-3-oxo-2-iso-propoxyiminobutyrate (syn isomer, 41.5 g.), thiourea (13.4 g.), sodium acetate (14.4 g.), water (110 ml.) and ethanol (110 ml.) were treated in a similar manner to that of Example D-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-iso-propoxyiminoacetate (syn isomer, 27.3 g.), mp. 162° to 164° C.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].OS(O)(=O)=O>N1C=CC=CC=1>[Si:28]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[OH:20])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOCC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
Compound 2a (2.297 g, 7.26 mmol) was dissolved in anhydrous pyridine (20 mL) at RT under argon. Imidazole (1.02 g, 14.52 mmol) in anhydrous pyridine (10 mL) was then added followed by tert-butyl dimethylsilyl chloride (TBDMS-Cl, 2.25 g, 14.52 mmol) in anhydrous pyridine (20 mL). The reaction mixture was stirred at RT for 72 hours, poured into 0.5 M H2SO4 (150 mL) and extracted with diethyl ether (100 mL, 3×). The extract was washed successively with saturated aqueous NaHCO3 (100 mL) and water (100 mL), dried over anhydrous Na2SO4 and the solvent removed under reduced pressure to obtain 3a, an oily material which was dried in a vacuum dessicator for 2 days (3.164 g, 100% yield). 1H NMR (in CDCl3): δ in ppm 0.83-0.89 (15H, m), 1.22 (29H, m), 1.52-1.53 (2H, m), 2.60 (1H, s, D2O exchangeable), 3.40-3.42 (4H, m), 3.59-3.61 (2H, m), 3.64 (1H, m); 13C NMR (in CDCl3): δ in ppm 14.3, 18.2, 18.5, 22.9, 25.8, 26.0, 26.1, 26.3, 29.6, 29.8, 29.9, 32.1, 33.0, 64.2, 70.8, 71.6, 71.9.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13](=O)[CH3:14])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[CH:11][CH:10]=[N:9]1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[CH3:16][C:17]([S@:20]([NH:22][CH:13]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[C:2]([CH3:1])[CH:3]=1)[CH3:14])=[O:21])([CH3:19])[CH3:18]
Reactant: CC(=O)c1cnc(-n2cccn2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cccn1
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (1.11 g, colorless oil) from 1-(5-methyl-6-(1H-pyrazol-1-yl)pyridin-3-yl)ethanone (920 mg, 4.57 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (665 mg, 5.49 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][N:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH3:26]>>[C:2]1([O:1][CH2:8][CH2:9][N:10]2[C:11]3[C:20]4[N:19]=[CH:18][CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:21]=[C:22]2[CH2:23][CH2:24][CH2:25][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: Nc1cnc2cccnc2c1NCCOc1ccccc1
Product: CCCCc1nc2cnc3cccnc3c2n1CCOc1ccccc1
Yield: 73.5 %

Procedure:
Using the general method of Example 73 Part A and Part B, N4-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) was reacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resulting amide intermediate was cyclized to provide 4.0 g of 2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether as a white solid, m.p. 150-150.5° C. Analysis: Calculated for C21H22N4O: % C, 72.81; % H, 6.40; % N, 16.17; Found: % C, 72.78; % H, 6.40; % N, 16.31. 1H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3, 1.7 Hz, 1H), 8.52 (dd, J=8.4, 1.7 Hz, 1H), 7.74 (dd, J=8.4, 4.3 Hz, 1H), 7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t, J=5.2 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H), 1.55-1.43 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS (EI): m/e 346.1794 (346.1793 calc'd for C21H22N4O).
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:27])[CH2:7][CH2:8][N:9]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10](=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.CCO>CCOCC>[CH2:19]([N:9]1[CH2:8][CH2:7][C:6](=[O:27])[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]1=[O:18])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)CCN(CCc1ccccc1)C(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: O=C1CCN(CCc2ccccc2)C(=O)C1c1ccccc1
Yield: 37.1 %

Procedure:
Sodium hydride (1.1 g, 50% in mineral oil) was suspended in ether (40 ml) under argon at RT. 3-(Phenethyl-phenylacetyl-amino)-propionic acid ethyl ester (2.5 g) was added in portions followed by addition of abs. EtOH (0.5 ml). The resulting mixture was refluxed for 2 hours, cooled and poured into water/ice/1 N HCl. The aqueous layer was extracted with ethyl acetate and the organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (ethyl acetate/hexanes 1:1 and then DCM/MeOH 95:5) to give the desired product as a light yellow foam (801 mg). MS (ESI: 294.4 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]#[N:20])=[CH:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>O1CCCC1>[C:19]([C:14]1[NH:15][C:16]2[C:12]([CH:13]=1)=[CH:11][C:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:18][CH:17]=2)#[N:20]
Reactant: N#Cc1cc2cc(C(CO)c3ccccc3)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC(c1ccccc1)c1ccc2[nH]c(C#N)cc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(2-hydroxy-1-phenyl-ethyl)-1H-indole-2-carbonitrile CCLXX (218 mg, 0.789 mmol) in tetrahydrofuran (10 mL) was added at 0° C. methanesulfonyl chloride (73 μL, 0.947 mmol) followed by triethylamine (0.16 mL, 1.183 mmol) and the resulting mixture was stirred at 0° C. for 3 hours. The precipitate which formed was filtered off and the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography to give 240 mg of methanesulfonic acid 2-(2-cyano-1H-indol-5-yl)-2-phenyl-ethyl ester CCLXXI.
Reaction SMILES: [CH2:1]([S:3][C:4]1(SCC)[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@:20]([F:24])([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:25])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2]>C(C1C=CC=CC=1CC)C>[CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@@:20]3([F:24])[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:25])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Temperature: 190 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
A suspension of 1.8 g of 17,17-bis(ethylthio)-9-fluoro-11β-hydroxyandrosta-1,4-dien-3-one in 120 ml of diethylbenzene is stirred at 190° C. (oil bath temperature) for 1 hour. The solution is cooled to 0° C. and the solid that precipitates is filtered. This is redissolved in 1:9 hexane-chloroform and chromatographed on a 60 g-silica gel column. Elution with 1:9 hexane-chloroform gives 1.35 g of a tlc-homogeneous material. Crystallization from chloroform-methanol gives 680 mg of the title compound, melting point 282°-283° C., dec.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1.[F-].[K+].C([Si](CC)(CC)[C:22]([F:25])([F:24])[F:23])C>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu]I>[CH3:16][N:5]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[C:2]([C:22]([F:25])([F:24])[F:23])[CH:3]=[N:4]1
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: COC(=O)c1cc(-c2c(I)cnn2C)cs1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)c1cc(-c2c(C(F)(F)F)cnn2C)cs1
Temperature: 70 °C
Reaction time: 10 h
Yield: 74 %

Procedure:
To a solution of methyl 4-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (470 mg, 1.35 mmol), copper (I) iodide (256 mg, 1.35 mmol) and potassium fluoride (78 mg, 1.35 mmol) in anhydrous DMF/HMPA (2 ml/2 mL) was added triethyl(trifluoromethyl)silane (745 mg, 4.04 mmol). The mixture was heated to 70° C. under N2 in a sealed tube. After 10 h, the reaction was quenched with NH4Cl (sat'd) (2 mL), extracted with ether (5 mL×5) and washed with distilled water (5 mL×5). The combined organic phase was dried over Mg2SO4 and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (0.29 g, 74%) as a yellow syrup: LC-MS (ES) m/z 291 (M+H)+.
Reaction SMILES: Cl[C:2]([F:28])([F:27])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:4]=1[C:23]([O:25][CH3:26])=[O:24].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[CH2:21]([N:18]([CH2:19][CH3:20])[C:5]1[C:4]([C:23]([O:25][CH3:26])=[O:24])=[C:3]([CH:2]([F:27])[F:28])[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1N(CC)CC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1N(CC)CC
Yield: 68.2 %

Procedure:
A mixture of 2.5 g (0.006 mol) of product of Example 53, 0.61 g (0.006 mol) of triethylamine and 0.12 g of Pd/C (10%) in 35 ml of ethanol was hydrogenated at 50° C. under 480 kPa of hydrogen pressure for 45 minutes. Reaction mixture was filtered through Celite and concentrated in vacuo. The residue was dissolved in ether, washed with 10% HCl and the aqueous 10% HCl layer was extracted with chloroform. The combined organic layers were dried (MgSO4) and concentrated in vacuo to 1.91 g. Crude was kugelrohr distilled at 109 Pa, pot temperature 99° C., affording 1.63 g (68.2%) of this product as a yellow oil, nD25 1.4682.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH2:64])[N:59]=2)[CH2:57][CH2:56]1>CN(C)C=O>[CH:55]1([C:58]2[O:62][N:61]=[C:60]([CH2:63][NH:64][C:20]([C:10]3[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH:9]=3)=[O:21])[N:59]=2)[CH2:57][CH2:56]1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: NCc1noc(C2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCc1noc(C2CC2)n1)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Yield: 66.8 %

Procedure:
To a stirred solution of 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M, 100 mg, 0.300 mmol) in dimethylformamide (4 mL, dried), was added 4-methylmorpholine (CAS No. 109-02-4, 0.09 mL 0.901 mmol), HBTU (CAS No. 94790-37-1, 171 mg, 0.450 mmol), 5-cyclopropyl-[1,2,4]oxadiazol-3-methanamine hydrochloride (Chembridge, MFCD09864586, 52 mg, 0.300 mmol) at rt and this mixture was stirred for 12 h at rt. Volatile were removed under reduced pressure and the residue was extracted with ethyl acetate. The combined organic layer was washed with aq. NaHCO3 soln, brine and concentrated to afford the crude residue which was purified by column chromatography (100-200 silica gel, elution with ethyl acetate/hexane). The title compound (91 mg, 66.0% yield) was obtained as a white solid; LC-MS (UV peak area/ESI) 96.8%, 454.6 (M+H)+.