Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[N:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:17]1([SiH3])[CH:22]=[CH:21][CH:20]=[CH:19]C=1.C1C23CC12C3>CC(O)C.ClCCl.CCCCC.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.[Mn]>[C:20]12([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:19][CH:22]([CH2:21]1)[CH2:17]2
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: [SiH3]c1ccccc1
Agent: [Mn]
Agent: C1C23CC12C3
Agent: CC(C)(C)C(=O)/C=C(\O)C(C)(C)C
Solvent: ClCCl
Solvent: CCCCC
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)C12CC(C1)C2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (281 mg, 0.460 mmol) was dissolved in 2-propanol (100 mL) in a 1 L 3-necked flask equipped with addition funnel, gas inlet, and thermometer. The solution was cooled to −15° C. under nitrogen. Di-tert-butyl azodicarboxylate (8.11 g, 34.5 mmol) and phenylsilane (2.9 mL, 23 mmol) were dissolved in dichloromethane (100 mL) and this resulting orange solution was added to the above cooled solution dropwise over 10 minutes, maintaining the internal temperature at approximately −10° C. A solution of [1.1.1]propellane (Journal of the American Chemical Society (2001), 123(15), 3484-3492) (50 mL, 23 mmol, 0.46 M in pentane) was added to the reaction mixture in one portion at −15° C. The reaction was stirred at −15° C. for 30 minutes. The cold bath was removed and the reaction was allowed to warm to room temperature and stir for 4 hours. The reaction was concentrated and purification by flash column chromatography (5-20% ethyl acetate/heptanes) gave the title compound (6.38 g, 93%) as a clear oil which solidified upon standing. −ESI (M−H) 297.4; 1H NMR (400 MHz, CDCl3, δ): 6.26 (br. s., 1H), 2.37 (s, 1H), 2.02 (s, 6H), 1.45 (s, 18H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][C:12]2=[O:24])=[CH:5][CH:4]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]3=[O:24])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CO)cc1
Reactant: C1CCNC1
Product: O=c1cc(OCc2cccs2)ccn1CCc1ccc(CN2CCCC2)cc1

Procedure:
1-[2-(4-Pyrrolidin-1-ylmethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one is prepared as example 2.1b from 45 mg (mg (0.13 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(thiophen-2-ylmethoxy)-1H-pyridin-2-one (example 2.1a) and 22 μL (0.26 mmol) pyrrolidine. The product is purified via reverse HPLC chromatography (Waters X-Bridge; water (0.15% NH4OH)/acetonitrile 95:5 to 10:90 and then Stable bond, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=O.[H-].[Na+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.BrCCBr.[C:25](=S)=[S:26]>O.CCOCC>[S:2]1[CH2:4][CH2:25][S:26][C:1]1=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16]
Reactant: CS(C)=O
Reactant: CC(C)OC(=O)Cc1ccc(F)cc1
Reactant: S=C=S
Agent: [H-]
Agent: [Na+]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: O
Product: CC(C)OC(=O)C(=C1SCCS1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dry dimethyl sulphoxide (180 ml) is added to sodium hydride (9.0 g, 55% dispersion in mineral oil). After 30 minutes, isopropyl 4-fluorophenylacetate (17.7 g) and carbon disulphide (8.2 g) are added. The mixture is stirred for two hours at room temperature. 1,2-Dibromoethane (18.6 g) is then slowly added. The reaction is exothermic and the temperature is maintained below 30°. The mixture is stirred for one hour, and then ether (200 ml) is added. After cooling to 0° water (200 ml) is slowly added. The two phases are separated. The aqueous phase is extracted with ether (2×100 ml) and the combined organic solutions are washed with water (2×50 ml). After drying over magnesium sulphate, the solvent is evaporated in vacuo and the residue is recrystallised from hexane. The product is dried in vacuo to constant weight to yield isopropyl (1,3-dithiolan-2-ylidene)-(4-fluorophenyl)-acetate, m.p. 106°-107°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])(Cl)Cl)=[CH:4][CH:3]=1.C(OC(=O)C)(=[O:14])C.S(=O)(=O)(O)[OH:20]>>[C:2]([Cl:1])(=[O:14])[CH3:7].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([Cl:11])=[O:20])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Cl
Product: O=C(Cl)c1ccc(Cl)cc1
Yield: 91.2 %
Yield: 101 %

Procedure:
To the reaction residue from run 3 was added 230 g of p-chlorobenzotrichloride, 97 g of acetic anhydride and 2 g of sulfuric acid (98%). The reaction was carried as previously described to give 136 g (91.2%) of acetyl chloride and 177 g (101%) of p-chlorobenzoyl chloride. The average yield from runs 1-4 was 92.7% for acetyl chloride and 93% for p-chlorobenzoyl chloride.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Cl:29][C:26]1[S:25][C:24]([CH2:23][N:16]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:15]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3ncccc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(Cn2cc(C3CCNCC3)c3cccnc32)s1
Reaction time: 1 h
Yield: 127.8 %

Procedure:
Over a solution of 2.86 g (6.6 mmol) of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-piperidine-1-carboxylic acid tert-butyl ester in 20 ml of dichloromethane, 5.1 ml of trifluoroacetic acid were added. After 1 hour at room temperature, the solvent was removed under reduced pressure. The crude mixture was dissolved in ethyl acetate and washed with saturated solution of potassium carbonate and brine. The organic phase was dried over magnesium sulphate, filtered and removed under reduced pressure affording 2.8 g of a crude mixture which was pure enough for the next synthetic step.
Reaction SMILES: OCCN=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH2:25])[CH3:21].C(O)(=O)C>C(O)C>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24](=[C:5]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH2:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])[NH2:25])[CH3:21]
Reactant: CCOC(CN)OCC
Reactant: Nc1cnccc1C(=NCCO)c1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(OCC)C(N)=C(c1ccncc1N)c1ccccc1Cl
Yield: 54.1 %

Procedure:
A solution of 2-hydroxy-N-[α-(3-amino-4-pyridyl)-2-chlorobenzylidene]-ethylamine (6.28 g, 22 mmol), aminoacetaldehyde diethyl acetal (10 g, 75.1 mmol) and acetic acid (3 ml) in ethanol (150 ml) was refluxed for 30 hours. The mixture was concentrated under reduced pressure, and to the residue was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; methanol: chloroform=1:9) to give the title compound (4.27 g, 11.9 mmol) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:80][C:81]([F:86])([F:85])[C:82]([OH:84])=[O:83]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)[CH:7]=1.[C:82]([OH:84])([C:81]([F:86])([F:85])[F:80])=[O:83]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4CCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (21.94 mg, 0.118 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and a acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then the MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fiber filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.3 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give N-{[5-chloro-3′-(1-piperazinylmethyl)-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (21.9 mg, 49.6%) as a white solid. LC-MS m/z 749 M+; mp 119-122° C.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[C@H:41]1[CH2:46][CH2:45][C@H:44]([NH:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH2:43][CH2:42]1>O.C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([C@H:41]4[CH2:46][CH2:45][C@H:44]([NH:47][CH:48]5[CH2:53][CH2:52][O:51][CH2:50][CH2:49]5)[CH2:43][CH2:42]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](NC3CCOCC3)CC2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](NC3CCOCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C. for 30 min, 4′-({5-oxo-7-propyl-4-[trans-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexyl]-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate/2-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (1.5 mL). N,N′-Carbonyldiimidazole (0.081 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were added, and the mixture was stirred at room temperature for 20 hr. N,N′-Carbonyldiimidazole (0.081 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were further added, and the mixture was stirred at room temperature for 5 hr. N,N′-Carbonyldiimidazole (0.081 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.075 mL) were further added, and the mixture was stirred at room temperature for 20 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 6 with 1 M hydrochloric acid. The precipitate was collected by filtration and washed with methanol to give the title compound as a colorless solid (0.11 g, 41%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH2:28])=[CH:23][CH:22]=2)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[N:20]([CH3:29])[C:21]2[C:26]([CH:27]=1)=[CH:25][C:24]([NH:28][C:12]([C:10]1[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=1)=[O:14])=[CH:23][CH:22]=2)=[O:18]
Reactant: COC(=O)c1cc2cc(N)ccc2n1C
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Product: COC(=O)c1cc2cc(NC(=O)c3ccc(-c4ccccc4)o3)ccc2n1C

Procedure:
Carboxylic acid (56)(23 mg, 0.12 mmol) was coupled to 5-amino-1-methyl-1H-indole-2-carboxylic acid methyl ester (25 mg, 0.12 mmol) using Method D to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:61][C:62]([CH3:75])([CH3:74])[CH2:63][NH:64][S:65]([CH2:68][CH2:69][NH:70][CH:71]([CH3:73])[CH3:72])(=[O:67])=[O:66]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH2:69][CH2:68][S:65](=[O:67])(=[O:66])[NH:64][CH2:63][C:62]([CH3:75])([CH3:74])[CH3:61])[CH:71]([CH3:72])[CH3:73])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CC(C)NCCS(=O)(=O)NCC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CCS(=O)(=O)NCC(C)(C)C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.030 g) and HATU® (0.058 g) in DMF (0.4 ml) was added DIPEA (0.040 ml) followed by a solution of 2-isopropylamino-ethanesulfonic acid (2,2-dimethyl-propyl)-amide (0.070 g) in DMF (0.6 ml) after 10 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.042 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([NH:7][CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])=[O:6])[CH3:3].N1C=CC=CC=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C1C=CN=CC=1)C.C1COCC1.CCOC(C)=O>[C:21]([O:13][CH:8]([NH:7][C:5]([O:4][C:2]([CH3:14])([CH3:1])[CH3:3])=[O:6])[C:9]([O:11][CH3:12])=[O:10])(=[O:23])[CH3:22]
Reactant: COC(=O)C(O)NC(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
To a solution of the product of Example 1 (10.0 g, 48.8 mmol), pyridine (7.71 g, 97.6 mmol) and DMAP (300 mg, 2.5 mmol) in THF (50 ML) was added acetic anhydride (5.47 g, 53.6 mmol) slowly at room temperature. After stirring at ambient temperature for 3 hours, the reaction was diluted with EtOAc and washed successively with 1N NaHSO4 and sat'd NaHCO3. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure affording 11.8 g (98%) of product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[Cl:19][Si](C)(C)C>C(#N)C>[Cl:19][CH2:10][C:9](=[O:11])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C[Si](C)(C)Cl
Reactant: CON=C(C(C)=O)C(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CON=C(C(=O)CCl)C(=O)OC
Temperature: -30 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
In 15 ml of acetonitrile was dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate, followed by addition of 2.1 ml of triethylamine. Then, 1.9 ml of chlorotrimethylsilane was added dropwise with ice-cooling and the mixture was stirred at 20°-25° C. for 1 hour for silylation. The reaction mixture was concentrated under reduced pressure and the residue was suspended in 15 ml of tetrahydrofuran. The suspension was filtered in a nitrogen gas stream to remove insolubles. The filtrate was cooled to -30° C. and 0.405 ml of sulfuryl chloride was added dropwise. After the temperature of the system was increased to 20° C., the mixture was concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (1:1, v/v). The eluate was concentrated under reduced pressure to give 813 mg of methyl 4-chloro-2-methoxyimino-3-oxobutyrate as colorless oil. Yield 84.1%.
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:21][CH2:20]2
Reactant: C1COCCN1
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a flask containing a suspension of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.202 g, 0.344 mmol) in 1,4-dioxane (3 mL) was added Hunig's base (0.421 mL, 2.408 mmol) followed by morpholine (0.150 mL, 1.720 mmol). The mixture was heated to 100° C. for 15.5 h then was cooled to rt. The mixture was directly purified by flash chromatography using a 0-40% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-morpholinoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.148 g, 0.219 mmol, 63.7% yield) as a white foam. LCMS: m/e 675.8 (M+H)+, 2.06 min (method 1).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([Br:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>CO>[Br-:17].[CH2:1]([N+:3]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[CH3:2]
Reactant: CCN(CC)CC
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Product: CC[N+](CC)(CC)CC(=O)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A reaction vessel was charged with 10.1 g of triethylamine, 19.9 g of phenacylbromide and 200 g of methanol, and they were stirred at room temperature for 6 hours. By evaporating methanol from this solution, 29.9 g of a white crystalline matter were obtained. This was washed with diethyl ether, then dried under reduced pressure, to obtain 24.9 g of an intermediate triethylphenacyl ammonium bromide (yield: 83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[CH:15]=[C:9]2[NH:8][CH:7]=1)[CH3:2].[H-].[Na+].[CH3:22]I>O1CCCC1.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:11](=[O:12])[N:10]2[N:13]=[C:14]([CH:16]3[CH2:17][CH2:18]3)[CH:15]=[C:9]2[N:8]([CH3:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1c[nH]c2cc(C3CC3)nn2c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cn(C)c2cc(C3CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
To a suspension of (2-cyclopropyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-6-yl)-acetic acid ethyl ester (80 mg, 0.3 mmol, 1 eq) described in example 90 in tetrahydrofuran (2 mL) was added sodium hydride (16 mg, 3.9 mmol, 1.3 eq). The mixture was stirred during 30 min at room temperature and methyl iodide (30 μL, 0.5 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 5 h. The mixture was then diluted with ethyl acetate (5 mL) and water (5 mL) was added. The aqueous layer was extracted with ethyl acetate (2×10 mL) and the aqueous phases were dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography using cyclohexane and ethyl acetate (100/0 to 0/100) to afford the expected compound as white powder (16 mg, 59% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[S:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[OH-].[K+].[CH3:20]C(C)=O>>[CH3:20][S:13][C:9]1[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:3][C:2]([F:1])([F:16])[F:17])[CH:15]=[CH:14][C:7]=2[N:8]=1
Reactant: FC(F)(F)Oc1ccc2c(c1)CCCC(=S)N2
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Product: CSC1=Nc2ccc(OC(F)(F)F)cc2CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7-(trifluoromethoxy)-4,5-dihydro-1H-benzo[b]azepine-2(3H)-thione (22 g, 84.3 mmol) in acetone (1500 ml) was added KOH (7.1 g, 127 mmol) and Mel (18.1 g, 127 mmol) and the mixture was stirred at RT for 1 h. The resulting mixture was concentrated under reduced pressure and the crude product was dissolved in DCM (1000 mL). The mixture was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. The oil was purified by flash column chromatography on neutral aluminium oxide eluting with hexane to give the title compound.