Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:39](=[O:41])[CH3:40])[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), acetic anhydride (21 μL) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.24 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[C:30]2[O:31][CH2:32][O:33][C:29]=2[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)=[O:39])=[CH:27][C:26]=1[Cl:46].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:46][C:26]1[CH:27]=[C:28]([C:34]#[C:35][CH2:36][NH:37][C:38]([N:40]2[CH2:41][CH2:42][O:43][CH2:44][CH2:45]2)=[O:39])[C:29]2[O:33][CH2:32][O:31][C:30]=2[C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1c(Cl)cc(C#CCNC(=O)N2CCOCC2)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N4CCOCC4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 72.1 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), N-[3-(7-amino-6-chloro-1,3-benzodioxol-4-yl)prop-2-yn-1-yl]morpholine-4-carboxamide (220 mg, 0.65 mmol) and a solution of sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using 10% methanol in dichloromethane as eluent. There was thus obtained the title compound (272 mg, 72%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.96 (quintet, 2H), 2.39 (m, 4H), 2.47 (t, 2H), 2.50 (m, 4H), 3.55-3.62 (m, 8H), 3.94 (s, 3H), 4.14 (d, 2H), 4.20 (t, 2H), 6.15 (s, 2H), 7.10 (m, 2H), 7.20 (s, 1H), 7.82 (s, 1H), 8.34 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 639/641.
Reaction SMILES: CI.[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[NH:14][C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:23](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:3]([N:10]1[CH2:22][CH2:21][C:13]2[N:14]([CH3:23])[C:15](=[O:20])[N:16]([CH3:19])[C:17](=[O:18])[C:12]=2[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c(=O)[nH]c2c(c1=O)CN(Cc1ccccc1)CC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n(C)c1=O)CN(Cc1ccccc1)CC2
Temperature: 60 °C
Yield: 38.6 %

Procedure:
9.6 ml of methyl iodide were added dropwise at 40° C. over a period of 10 minutes, with stirring, to 40.7 g of 6-benzyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione and 20.7 g of potassium carbonate in 230 ml of dimethylformamide. After heating for 8 hours at 60° C., the mixture was concentrated under reduced pressure, the residue was taken up with water, the pH was adjusted to 8 and the mixture was worked up by extraction with dichloromethane and water. After the combined dichloromethane phases had been concentrated under reduced pressure, the residue was purified by chromatography on silica gel with dichloromethane/ethanol (volume ratio 95:5) to give 16.5 g of 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimi-dine-2,4-dione, from which 6-benzyl-1,3-dimethyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione hydrochloride was obtained as a precipitate in diethyl ether with a solution of hydrochloric acid in ether. The product was recrystallized from methanol/diethyl ether and residual methanol was removed by the addition of water to the precipitate, concentration under reduced pressure and drying of the residue under high vacuum.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 56.3 %

Procedure:
Beginning with 0.30 gm (1.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.165 mL (1.56 mMol) butyryl chloride, 0.22 gm of the title compound were prepared as an ivory foam essentially by the procedure described in Example 4. This residue was crystallized from ethanol:water to provide material for analysis.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[S:11])[CH:7]=[CH:8][N:9]=1.[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1>CCO>[Br:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[N:12]=[C:10]([C:6]3[CH:7]=[CH:8][N:9]=[C:4]([CH2:3][CH2:2][CH3:1])[CH:5]=3)[S:11][CH:19]=2)=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CCCc1cc(C(N)=S)ccn1
Solvent: CCO
Product: CCCc1cc(-c2nc(-c3ccc(Br)cc3)cs2)ccn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
As shown in FIG. 27, in reaction (a) a mixture of prothionamide (9.01 g, 50.0 mmol) and 4-bromophenacyl bromide 6a (13.9 g, 50.0 mmol) in EtOH (400 mL) was stirred at 70° C. for 1 h. After cooled to room temperature, the precipitation was filtered off with EtOAc and washed with EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 4-(4-bromophenyl)-2-(2-propylpyridin-4-yl)thiazole 2 (14.3 g, 79%) as a light-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:5][C:6]=1[CH:7]([OH:9])[CH3:8].[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][C:26]=1[CH3:32].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22](=[O:33])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:9][CH:7]([C:6]2[O:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])=[CH:27][C:26]=1[CH3:32]
Reactant: COC(=O)CCc1ccc(O)cc1C
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OC(C)c2oc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethanol (0.15 g, 0.553 mmol) and 3-(4-Hydroxy-2-methyl-phenyl)-propionic acid methyl ester (0.12 g, 0.610 mmol) are stirred in 10 mL toluene at 0° C. under a nitrogen atmosphere. Tri-n-butylphosphine (0.21 mL, 0.83 mmol) is added followed by 1,1′-(Azodicarbonyl)dipiperidine (0.21 g, 0.83 mmol). The mixture is allowed to stir at room temperature for 20 hr. The resulting slurry is concentrated under reduced pressure. 50 mL of a 1:1 solution of ethyl acetate:hexanes is added, and the slurry is filtered. The resulting solution is concentrated and purified by silica gel chromatography eluting with a mixture of 8:2 hexanes:ethyl acetate yielding 3-(2-Methyl-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-ethoxy}-phenyl)-propionic acid methyl ester as a white solid, 0.176 g (71%). MS (M++1) 446.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:78][CH:79]5[CH2:84][CH2:83][N:82]([CH2:85][CH3:86])[CH2:81][CH2:80]5)=[O:27])=[CH:24][C:23]=4[C:31]([F:32])([F:33])[F:34])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN1CCC(N)CC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(C(F)(F)F)c2)CC1
Reaction time: 0.17 h
Yield: 49.7 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.0880 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0299 g (0.233 mmole) of 4-amino-1-ethylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0459 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-ethyl-piperidin-4-yl)-3-trifluoromethyl-benzamide (I-206) as a white solid.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[C:17]2[NH:16][C:15]([CH3:18])=[N:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[CH2:19]([O:21][C:22]1[CH:36]=[CH:35][C:25]([O:26][C:27]2[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[CH3:20]>O>[Cl:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([O:26][C:25]4[CH:35]=[CH:36][C:22]([O:21][CH2:19][CH3:20])=[CH:23][CH:24]=4)=[CH:28][CH:29]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1nc2cccc(Cl)c2[nH]1
Reactant: CCOc1ccc(Oc2ccc(CCl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc(Cn3c(C)nc4c(Cl)cccc43)cc2)cc1
Reaction time: 1 h
Yield: 34.1 %

Procedure:
To a mixture of anhydrous N,N-dimethylforamide (10 ml) and sodium hydride (62% oil suspension; 0.071 g), 4-chloro-2-methylbenzimidazole (0.304 g) was added while stirring, and the stirring was continued at room temperature for 1 hour. The resultant mixture was cooled to 5°-10° C., and a solution of 4-(4-ethoxyphenoxy)benzyl chloride (0.400 g) in anhydrous N,N-dimethylformaide (10 ml) was dropwise added thereto in 30 minutes, followed by stirring at room temperature overnight. After completion of the reaction, the reaction mixture was poured into water (100 ml) and extracted with toluene (30 ml) two times. The toluene extract was washed with water, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 4-chloro-1-[4-(4-ethoxyphenoxy)benzyl]-2-methylbenzimidazole (0.204 g) as a colorless liquid. nD26.5 1.6087.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.CC[O-].[Na+].Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19]>CCO>[C:18]([CH2:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)#[N:19]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CCCCOc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 126.8 %

Procedure:
4-Hydroxybenzaldehyde (20 mmol) was dissolved in absolute EtOH (150 mL) and treated with solid NaOEt (24 mmol). After stirring for 15 minutes, 4-bromobutyronitrile (24 mmol) was added and reaction mixture was heated overnight at 90° C. in an oil bath. After letting the reaction cool to room temperature, volatiles were removed, the residue was taken up in ice, adjusted to pH 6 with 1N sulfuric acid, and extracted with methylene chloride. The organic phase was washed with brine, dried over MgSO4 and concentrated. Chromatography over silica gel (eluant, 5% EtOAc in hexanes) gave the 4-(3-cyanopropoxy)benzaldehyde (4.8 g, 58%).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1O)[CH3:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>COCCOC>[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)[CH3:17]
Reactant: CCOc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCOc1ccccc1OC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture at room temperature of (S)-2-hydroxymethyl-morpholine-4-carboxylic acid, tert-butyl ester, 2-ethoxyphenol and triphenylphosphine in DME was added dropwise diisopropyl azodicarboxylate. The solution was stirred at room temperature for 24 h, concentrated (to remove most of the DME), then suspended into hexanes. The solid that formed was filtered. The filtrate was concentrated, redissolved into diethyl ether, then washed with 1 N NaOH (2×), sat. KH2PO4 and brine solutions. The organic extract was dried (MgSO4), filtered, concentrated and chromatographed (MPLC, silica gel, 20% EtOAc in hexanes) to give (S)-2-(2-ethoxy-phenoxymethyl)-morpholine-4-carboxylic acid, tert-butyl ester as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C.N1C=CC=CC=1>[Cl:19][CH2:20][C:21]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:17][C:21](=[O:22])[CH2:20][Cl:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Dissolve 1,8-diaminoanthraquinone (0.476 g, 2.0 mmol) in 20 ml DMF. Add pyridine (0.5 ml) as catalyst in an ice bath. Then add chloroacetyl chloride (0.5 ml, 6 mmol) into the solution, remove the ice bath, introduce nitrogen, protect from light, and stir the solution at room temperature for 24 hours. The reacted solution is poured into ice water (50 ml), filtered to get precipitate. At last, the precipitate is recrystallized to get yellow compound 3.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:14]2.[CH:28]1([SH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH:9]12[CH2:10][CH:11]3[CH2:12][CH:13]([CH2:14][CH:7]([CH2:16]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21]([S:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:15]2
Reactant: SC1CCCCC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1SC1CCCCC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Anhydrous sodium carbonate (2.201 mL, 52.58 mmol) was added in one portion to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.7 g, 17.53 mmol) and cyclohexyl mercaptan (2.14 mL, 17.53 mmol) in DMF (50 mL) under nitrogen. The resulting suspension was stirred at 60° C. for 6 hours.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH:34]=O)[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>ClCCCl>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28]3[CH:29]=[C:30]([CH2:34][NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:31]=[N:32][CH:33]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: O=Cc1cncc(-c2ccc3[nH]ccc3c2)c1
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)CCNCc1cncc(-c2ccc3[nH]ccc3c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.5 %

Procedure:
Sodium triacetoxyborohydride (855 mg, 4.05 mmol) and then enough acetic acid to bring the pH to 5 were added to a solution of 5-(1H-indol-5-yl)-pyridine-3-carbaldehyde (300 mg, 1.35 mmol) and N,N-dimethylethylene diamine (237 mg, 2.7 mmol) in 15 mL of 1,2-dichloroethane. The mixture was stirred at ambient temperature for 48 h, and then the volatiles were removed in the presence of celite. The product was eluted from the celite through silica gel (elution with methanol/dichloromethane) to give 328 mg of product. LC/MS: Retention time, 0.43 min; (M+H)=295.19.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:27]1[C:28](=O)[C:29]2[C:34]([C:35]=1C1C=CC=CC=1)=CC=[C:31](O)[CH:30]=2.C1(CCO)CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:29]1([CH2:30][CH2:31][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[C:10]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:11]3=[O:19])=[CH:16][CH:15]=2)[CH2:34][CH2:35][CH2:27][CH2:28]1
Reactant: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCC3CCCC3)cc21
Reaction time: 21 h
Yield: 23 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one obtained in Step 1 of Example 64 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-cyclopentylethanol (2.0 eq) instead of 4-(2-hydroxyethyl)morpholine, using 2 equivalents of PPh3 and DIAD, being stirred for 21 h, and being purified by prep. HPLC (20% H2O/CH3CN) to provide the title compound (23%).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:3]1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:32][S:33]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11](=[O:31])[NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=4)=[O:19])[CH2:14]3)[N:10]=2)[CH2:5]1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1coc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(C(=O)N[C@H]3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)co2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
To a solution of 3-hydroxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (680 mg, 1.58 mmol) (obtained as described in Reference Example 76(2)) in methylene chloride (34 ml) were added methanesulfonyl chloride (366 μl, 4.73 mmol) and triethylamine (663 μl, 4.73 mmol) in an ice bath and the mixture was stirred for 10 minutes and at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate→ethyl acetate:methanol (96:4) as the eluant to afford 3-methanesulfonyloxy-1-{4-[(3S)-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-ylcarbamoyl]-1,3-oxazol-2-yl}azetidine (760 mg, yield 95%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]([CH3:22])([CH3:21])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=1.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][N+:8]([CH3:22])([CH3:21])[CH3:7])=[N:13][CH:14]=1
Reactant: C[N+](C)(C)CCOc1ccc([N+](=O)[O-])cn1
Reactant: [H][H]
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: C[N+](C)(C)CCOc1ccc(N)cn1

Procedure:
4.0 g (12 mmol) of the compound from Step 12.2 in 80 mL of water was hydrogenated in the presence of 0.4 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 3 hours the catalyst was filtered off and the water was removed in a rotary evaporator.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH2:6]1)=[O:4].O1CCOCC1.[Cl:28]N1C(=O)CCC1=O>O>[Cl:28][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:7]2[CH2:8][CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:20])[F:21])[CH2:6]2)[NH:15][CH:14]=1
Reactant: O=C(N1CCCC(c2cccc3[nH]ccc23)C1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(N1CCCC(c2cccc3[nH]cc(Cl)c23)C1)C(F)(F)F
Temperature: 20 °C
Reaction time: 20 h
Yield: 98.5 %

Procedure:
A mixture of 10 g of the product of Step A, 300 ml of dioxane and 5 g of N-chlorosuccinimide was stirred at 20° C. for 20 hours and was then diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with water and aqueous sodium chloride solution, was dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 11 g of 3-chloro-4-(1-trifluoroacetyl-piperidin-3-yl)-1H-indole which was used as is for the next step.