Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C@@H:15]([OH:36])[C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([N:19]2[C@@H:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][O:21][C:20]2=[O:31])=[O:18])[CH:10]=1)(C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C@@H:15]([O:36][S:39]([CH3:38])(=[O:41])=[O:40])[C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([N:19]2[C@@H:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][O:21][C:20]2=[O:31])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](OS(C)(=O)=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.2 g of {3-[3-(4 (S)-Benzyl-2-oxooxazolidin-3-yl)-1-(R)-hydroxy-2(S)-isopropoxy-3-oxopropyl]benzyl}-carbamic acid t-butyl ester was dissolved in 100 ml of pyridine, and 4.35 ml of methanesulfonyl chloride was added dropwise under ice-cooling. After stirring was continued for 2 hours under ice-cooling and for 3 hours at room temperature, the reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated, to give methanesulfonic acid 1 (R)-(3-aminomethylphenyl)-3-(4 (S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-isopropoxy-3-oxopropyl ester. This product was dissolved in 500 ml of ethanol, and 10 g of 10% palladium carbon and 5 g of potassium acetate were added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 15.3 g of the title compound as a white solid in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].[NH4+].[Cl-]>C1COCC1>[C:1]([O:5][C:6](=[O:21])[N:7]([CH3:25])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH3:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC1CCCCN1c1ccncc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1CCCCN1c1ccncc1N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
(2-Methyl-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester was dissolved in THF (5 mL) and stirred under argon. NaH (24 mg, 0.98 mmol) was added and after 10 min, iodomethane (61 μL, 0.98 mmol) was added. After stirring for 3 hours, NaH (12 mg, 0.49 mmol) and iodomethane (30 μL, 0.49 mmol) were added again. After 1 h, the reaction mixture was poured into saturated, aqueous NH4Cl solution and extracted three times with EtOAc. The combined organic phases were dried over MgSO4. Filtration followed by removal of volatiles gave crude product. Column chromatography on silica gel (50% EtOAc in n-hexane) gave the desired compound (159 mg, 59% over two steps) that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:22]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) and sodium azide (10.6 g) in dimethyl sulfoxide (350 ml) was stirred at 90° C. overnight and the solution was diluted with ethyl acetate (600 ml). The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-4-azido-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (20.0 g) as a pale brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2SC(C(OC)=O)=CN=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(Cl)c2ccccc2n1
Reactant: COC(=O)c1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)s1
Product: COC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c2ccccc2n1

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 133 starting with methyl 4-chloroquinoline-2-carboxylate (WO 9505378). The product was purified on a silica gel flash column (0→5% MeOH in DCM) followed by recrystallization from EtOAc.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][C:5](=[O:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.CC(C[AlH]CC(C)C)C.CC(C)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1COCC1.CO>[CH3:1][C:2]1([CH3:25])[O:6][CH:5]([OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CC1(C)OC(=O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OC(O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a -50° C. solution of 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone (30 g, 83.3 mmol) in 500 mL of THF was added dropwise a solution of DIBAL (90 mL, 1.5M in toluene) over a period of 15 min. The reaction mixture was allowed to warm to -10° C. over a period of 1 h, then treated with 20 mL of acetone, followed by 50 mL of methanol. The reaction mixture was then warmed to -20° C. and treated with aqueous potassium sodium tartrate (20%, 400 mL). After stirring at r.t. for 1 h, the product was extracted with 500 mL of 2:1 EtOAc/hexane, dried over Na2SO4, filtered and concentrated. The crude product was swished with 2:1 hexane/EtOAc to give 24 g of purified title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([O:5]C)=[O:4].[Li+].[OH-]>CO>[CH3:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)c1ccc(OCc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)c1ccc(OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of methyl (R/S)-α-methyl-4-benzyloxyphenylacetate 45a (2.7 g, 10 mmol) in MeOH (25 mL) was added 1 N LiOH (15 mL). The mixture was stirred for 2 hour and concentrated. EtOAc was added followed by 1 N HCl (10 mL). The organic layer was separated and washed with brine, dried (MgSO4), and concentrated to afford the carboxylic acid (2.3 g, 90%) as a solid. MS (CI—NH3): (M+H+NH3)+=274.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[C:15]2[CH:16]=[CH:17][C:18]([O:20][CH2:21][O:22][CH3:23])=[CH:19][C:14]=2[O:13][CH2:12][C:11]1([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:27][CH:26]=1)[CH3:24].ClCCl.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1.O>N1C=CC=CC=1>[CH3:23][O:22][CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]2[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:44]([C:41]3[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=3)(=[O:46])=[O:45])[C:11]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][O:33][CH3:34])=[CH:29][CH:30]=3)([CH3:24])[CH2:12][O:13][C:14]=2[CH:19]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.2 %

Procedure:
(3RS,4RS)-4-(8-Hydroxyoctyl)-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-2,3-dihydro-4H-benzopyran (80 mg, 0.17 mmol) was dissolved in pyridine (2 ml) and dichloromethane (0.5 ml) and then cooled to 0° C. p-Toluenesulfonylchloride (0.12 g, 0.63 mmol) was added thereto and the mixture was stirred for 6 hours at room temperature. Water was added thereto at 0° C. and the reaction solution was extracted with ethyl acetate, washed with saturated saline and then dried over magnesium sulfate. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 110 mg (yield: ~100%) of the title compound as a colorless oil.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][N:9]([CH:12]2[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]3[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:14]=3[CH2:13]2)[CH2:8][CH2:7]1)(OCC)=O.C(O)CO.[OH-].[K+]>O>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:14]2[CH2:13][CH:12]([N:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:18]3[CH:19]=[C:20]([S:23][CH3:24])[CH:21]=[CH:22][C:17]=3[S:16][C:15]=2[CH:25]=1
Reactant: CCOC(=O)N1CCN(C2Cc3ccc(OC)cc3Sc3ccc(SC)cc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: COc1ccc2c(c1)Sc1ccc(SC)cc1C(N1CCNCC1)C2

Procedure:
61 G. of 1-carbethoxy-4-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine, 600 ml. of ethylene glycol, 25 g. of potassium hydroxide and 2.7 ml. of water are heated at 160° C. for a period of 2 hours. Then, the mixture is poured on to water and extracted with benzene. The organic phase is washed with water, dried over magnesium sulfate and evaporated under reduced pressure, whereby there is obtained 1-(10,11-dihydro-3-methoxy-8-methylthio-dibenzo[b,f]thiepin-10-yl)-piperazine.
Reaction SMILES: [ClH:1].N[C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][N:4]=1.N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:1][C:3]1[N:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][N:4]=1
Reactant: N#Cc1cnc(N)nc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cnc(Cl)nc1
Temperature: 0 °C
Yield: 26.6 %

Procedure:
(Prepared according to: Organic Synthesis, Vol 4, p. 182.) In a 3-necked, round-bottom flask is placed 5.4 mL of concentrated HCl (65 mmol). The solution is cooled to 0° C. and 2-amino-5-cyanopyrimidine (515 mg, 4.28 mmol) is added portion wise with stirring until a homogeneous solution is obtained. The solution is then cooled to −15° C. A 100 mL addition funnel is fitted to the flask and a cold solution of NaNO2 (592 mg, 8.6 mmol) in 5 ml of water is then added dropwise with stirring over period of 20 min. (The temperature is kept at −15 to −10° C.) The solution is stirred an additional hour and the temperature is allowed to rise to −5. At this point, the mixture is carefully neutralized to about pH 7 with a 30% solution of NaOH, taking care that the temperature does not rise above 0° C. The solution is extracted with EtOAc (3×20 ml), dried over MgSO4, filtered and evaporated to give a yellow solid (159 mg, 21.3% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])([CH2:33][O:34][Si](C(C)(C)C)(C)C)[CH2:25][O:26][P:27]([O:31][CH3:32])([O:29][CH3:30])=[O:28])=[C:18]([Cl:50])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([NH:42][C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])([CH2:33][OH:34])[CH2:25][O:26][P:27]([O:29][CH3:30])([O:31][CH3:32])=[O:28])=[C:18]([Cl:50])[CH:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)OCC(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COP(=O)(OC)OCC(CO)(CCc1ccc(Sc2cccc(OCc3ccccc3)c2)cc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a THF solution (30 mL) of the compound of Example 243 (2.70 g), 1 mol/L tetrabutylammonium fluoride in THF (5 mL) was added and the mixture was stirred for 1 hour at room temperature. Following addition of water, the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the desired product as a colorless oil (2.30 g).
Reaction SMILES: II.[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19]I)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2>CN(C=O)C.[Cl-].[Na+].O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([CH2:19][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)[C:15]([O:17][CH3:18])=[O:16])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CI)NC(=O)OCc1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.4 %

Procedure:
To a suspension of zinc (2.53 g, 38.8 mmol) in DMF (20 mL) was added I2 (1.10 g, 4.15 mol) followed by addition of a solution of (R)-methyl 2-(benzyloxycarbonylamino)-3-iodopropanoate (4.70 g, 13.0 mmol) in DMF (20 mL). The mixture was stirred at ambient temperature for 5 min and heated at 35° C. for 40 min. Then a solution of 5-bromo-1H-indole (3.00 g, 15.5 mmol) in DMF (10 mL), Pd2(dba)3 (0.25 g, 0.27 mmol) and S—Phos (0.25 g, 0.60 mmol) were added. The reaction mixture was stirred at 50° C. under nitrogen overnight and then cooled to ambient temperature. Brine (500 mL) was added and the resulting mixture was extracted with EtOAc (200 mL×3). The organics were combined, washed with brine (300 mL) and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=10:1 to 5:1) to afford (S)-methyl 2-(benzyloxycarbonylamino)-3-(1H-indol-5-yl)propanoate as a viscous oil (3.27 g, 60% yield).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29](O)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].CN(C=O)C.S(Cl)(Cl)=O.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][S:49][C:50]2[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=2)[N:43]=1>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:54][C:53]4[CH:55]=[CH:56][C:50]([S:49][CH2:48][C:44]5[N:43]=[N:42][CH:47]=[CH:46][CH:45]=5)=[CH:51][CH:52]=4)=[O:30])=[CH:20][C:19]=3[CH:32]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Reactant: Nc1ccc(SCc2cccnn2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnn4)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.80 g) was dissolved in THF (16 ml), DMF (2 droplets) was added to the mixture, thionyl chloride (0.20 ml) was added to the mixture, and the solution was stirred at room temperature for 1 hour. The solution was added dropwise to a solution of 4-[(3-pyridazinylmethyl)sulfanyl]aniline (0.44 g) and triethylamine (2.55 ml) in THF (13.2 ml) under ice-cooling and the mixture was stirred for 2 hours at room temperature. The reaction solution was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified with silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[(3-pyridazinylmethyl)sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 258) (0.16 g).
Reaction SMILES: [CH3:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH:4]([C:11](Cl)=[O:12])[C:3]2=O.C(N(CC)CC)C.C(O[C:27]([N:29](C)[NH:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39])=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[F:37][C:35]1[CH:34]=[CH:33][C:32]([C:38]([F:39])([F:40])[F:41])=[C:31]([N:30]2[C:11](=[O:12])[C:4]3[C@@H:5]4[C:8]([CH3:10])([CH3:9])[C@@:2]([CH3:1])([CH2:7][CH2:6]4)[C:3]=3[N:29]2[CH3:27])[CH:36]=1
Reactant: CN(Nc1cc(F)ccc1C(F)(F)F)C(=O)OC(C)(C)C
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c2c(c(=O)n1-c1cc(F)ccc1C(F)(F)F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
A solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 349 mg, 1.62 mmol) in 1,2-dichloroethane (9 mL) was added to a cooled (0° C.) solution of triethylamine (320 μL, 2.30 mmol) and N′-(5-fluoro-2-trifluoromethyl-phenyl)-N-methyl-hydrazinecarboxylic acid tert-butyl ester (348 mg, 1.13 mmol) in 1,2-dichloroethane (6 mL) over a period of 1 min. The reaction mixture was stirred for 10 min at room temperature and then in an oil bath at 50° C. for 1 h. A solution of HCl in dioxane (4 M; 8 mL, 32 mmol) was added and the mixture was heated at reflux for 1 h and then allowed to cool to room temperature. Silica gel was added and the solvent was evaporated. The residue was purified using an ISCO40 g column, eluting with 50-100% ethyl acetate/hexanes and then with 10% methanol/ethyl acetate. Fractions homogeneous for the product were evaporated, and the residue was dissolved in dichloromethane (75 mL), and washed with 1:1 water/saturated aqueous sodium thiosulfate (20 mL) and brine (20 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and dried under high vacuum at 95° C. to give (4S,7R)-2-(5-fluoro-2-trifluoromethyl-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (127 mg, 31%) as a white solid. ES(+)-MS (M+H) 369.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH:19]=[C:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8].CCO.[H][H]>[Pd].O1CCOCC1>[CH3:1][C:2]1[C:3](=[O:27])[O:4][C:5]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]4[C:24](=[O:25])[NH:23][C:22](=[O:26])[S:21]4)=[CH:15][C:13]=3[CH:14]=2)=[C:6]([CH3:9])[C:7]=1[OH:8]
Reactant: [H][H]
Reactant: Cc1c(-c2cc3cc(C=C4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1c(-c2cc3cc(CC4SC(=O)NC4=O)ccc3o2)oc(=O)c(C)c1O

Procedure:
To 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinylidene) methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one (350 mg) in a mixed solvent of EtOH (10 ml) and 1,4-dioxane (10 ml) there was added 10% Pd/C (70 mg), and the mixture was stirred for one day in a hydrogen gas atmosphere. The reaction solution was filtered, the mother liquor was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (CH2Cl2/MeOH=5/1) to obtain 3,5-dimethyl-6-(5-((3,5-dioxo-2,4-thiazolidinyl)methyl)benzofuran-2-yl)-4-hydroxy-2H-pyran-2-one.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].BrC1C=C2C(C(Cl)=NNC2=O)=CC=1.[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH2:48][NH2:49])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH2:48][NH:49][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][N:6]=[C:5]3[Cl:13])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(CN)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(CNc2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Temperature: 90 °C
Yield: 18 %

Procedure:
A mixture of 6-bromo-4-chloro-2H-phthalazin-1-one and 7-bromo-4-chloro-2H-phthalazin-1-one (300 mg, 1.16 mmol), 4-(2-aminomethyl-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (338 mg, 1.05 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), BINAP (217 mg, 0.35 mmol) and NaOt-Bu (327 mg, 3.48 mmol) in DMA (10 mL) was purged with nitrogen for 10 min. The mixture was heated at 90° C. for 1.5 h. The mixture was allowed to cool and diluted with ethyl acetate (30 mL) and washed with ammonium chloride (25 mL). The organic layer was dried and concentrated. Chromatography on silica yielded the title compound (102 mg, 18%) m/z (M+H)=500.32.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=[O:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(CCO)cc1Br
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#Cc1ccc(CC=O)cc1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-Bromo-4-(2-hydroxyethyl)benzonitrile (220 mg, 1.0 mmol) in DCM (15 mL) was added Dess-Martin reagent (1.2 g, 2.8 mmol) and the mixture was stirred at RT for 4 hours. The mixture was washed with water, dried over Na2SO4, and concentrated in vacuo to give the title product. 1H NMR (400 MHz, CDCl3) δ 9.77 (t, J=1.6 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (d, J=1.6 Hz, 1H), 7.25 (dd, J=7.8, 1.6 Hz, 1H), 3.78 (d, J=1.6 Hz, 2H).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Cl[C:16]1[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1>>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[N:21]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: NC1CCN(c2nccc(C(F)(F)F)n2)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-4-trifluoromethyl-pyrimidine using the procedure outlined for Descriptions D11 and D12.