Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:5]([F:13])[C:4]=1[F:14])#N.C([O-])(O)=[O:16].[Na+]>[Ni].C(O)=O>[F:13][C:5]1[C:4]([F:14])=[C:3]([CH:1]=[O:16])[CH:12]=[CH:11][C:6]=1[NH:7][C:8](=[O:10])[CH3:9]
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1ccc(C#N)c(F)c1F
Agent: [Ni]
Agent: [Na+]
Solvent: O=CO
Product: CC(=O)Nc1ccc(C=O)c(F)c1F
Yield: 92.5 %

Procedure:
A mixture of 11 g of Raney nickel, 8.2 g of 4'-cyano-2',3'-difluoroacetanilide and 125 mL of 95% HCOOH is stirred and heated 30 minutes at 80°-85° C. The hot solution is filtered through diatomaceous earth and the cake washed with 3×100 mL of CH2CL2. The filtrate and wash are evaporated in vacuo to furnish a white solid. Excess saturated NaHCO3 is added to neutralize the residual HCOOH and the product is extracted with 3×400 mL of CH2Cl2. The CH2Cl2 extract is washed with saturated NaHCO3 and H2O (100 mL each), dried with Na2SO4 and evaporated to furnish 7.7 g (92.5% yield) of 2',3'-difluoro-4'-formylacetanilide, m.p. 154° C. The mass spectrum shows an ion at 200.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13]([C:20]#[N:21])=[CH:14][NH:15]2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C1COCC1.C(Cl)Cl>[C:20]([C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[CH:19][C:11]=2[CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[NH:15][CH:14]=1)#[N:21]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1c[nH]c2cccc(C(CCO)c3ccccc3)c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a 0° C. solution of 4-(3-hydroxy-1-pheny-propyl)-1H-indole-3-carbonitrile LX (377 mg, 1.36 mmol) in THF/DCM (1/1, 22 ml) was added MsCl (105 μl, 1.36 mmol) dropwise. The mixture was stirred at 0° C. for 10 minutes, and TEA (226 μl, 1.62 mmol) was added dropwise. The resulting mixture was stirred at 0° C. for 2.5 hours, poured into ice/water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated affording methanesulfonic acid 3-(3-cyano-1H-indol-4-yl)-3-phenyl-propyl ester(not shown in above scheme) as a yellow oil. A solution of this crude mesylate in MeNH2 (33% in EtOH, 8.5 ml) was placed in a sealed tube and stirred at 100° C. for 45 minutes. The reaction mixture was concentrated, and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified via flash chromatography (DCM/MeOH/NH4OH) affording 4-(3-methylamino-1-pheny-propyl)-1H-indole-3-carbonitrile LXI as a white foamy solid (346 mg). MS (M+H)=290.
Reaction SMILES: CS(C)=O.[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[CH2:13][C:14]=1[OH:15])(=O)[CH2:6][CH3:7].Cl.[CH2:30]([O:32][NH2:33])[CH3:31].C([O-])(=O)C.[Na+]>O>[CH2:30]([O:32][N:33]=[C:5]([C:9]1[C:10](=[O:28])[CH2:11][CH:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=3[CH:27]=2)[CH2:13][C:14]=1[OH:15])[CH2:6][CH3:7])[CH3:31]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)N(C)C(=O)CO3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)N(C)C(=O)CO3)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 20 mL of methyl sulfoxide were added in sequence, 1.0 g (3.0 mmol) of 2-propionyl-3-hydroxy-5-(N-methyl-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one, 0.37 g (3.9 mmol) of ethoxyamine hydrochloride and 0.32 g (3.9 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature for 5 hours, becoming a clear amber solution. The reaction mixture was diluted with 100 mL of water and extracted twice with 30 mL portions of ether. The extracts were combined, washed with water, then aqueous sodium chloride and dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as an oily residue which solidified upon standing. The crude solid was crushed and triturated in ether. The purified above-named product, as a tan solid, was recovered in a yield of 0.9 g (80 percent of theoretical). The title compound melted at 90°-92° C.; 1H NMR(CDCl3): d1.05-1.48 (m, 6H, both --CCH2CH3 's), 2.55-3.62 (m including s at 3.31 for --N--CH3, 1 OH) 4.18 (q, J=7 Hz, 2H,--OCH2CH3), 4.60 (s, 2H, --OCH2C=O), 6.82-7.13 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 3).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:38])[CH2:8][CH2:9][N:10]([CH2:18][C:19]1[CH:37]=[CH:36][C:22]2[N:23]=[C:24]([NH2:35])[N:25]([CH2:26][C:27]3[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]=3)[C:21]=2[CH:20]=1)[C:11]1[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=1)C>O.O1CCCC1>[NH2:35][C:24]1[N:25]([CH2:26][C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[C:29]([CH3:34])[N:28]=2)[C:21]2[CH:20]=[C:19]([CH2:18][N:10]([C:11]3[CH:12]=[C:13]([CH3:17])[CH:14]=[CH:15][CH:16]=3)[CH2:9][CH2:8][C:7]([OH:38])=[O:6])[CH:37]=[CH:36][C:22]=2[N:23]=1
Reactant: CCOC(=O)CCN(Cc1ccc2nc(N)n(Cc3nc(C)ccc3O)c2c1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(N(CCC(=O)O)Cc2ccc3nc(N)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.9 %

Procedure:
Lithium hydroxide hydrate (0.00093 mol) was added to a solution of 3-{[2-amino-3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-m-tolylamino}-propionic acid ethyl ester (0.000464 mol) in a mixture of water (10 ml) and tetrahydrofuran (10 ml). The reaction was stirred at room temperature for 12 hours. The tetrahydrofuran was removed under reduced pressure and the solution was acidified to pH 4 with a 1N solution of HCl in water. The precipitate was filtered off, rinsed with water, then with diethyl ether and dried, yielding 0.157 g of 3-{[2-amino-3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-3H-benzoimidazol-5-ylmethyl]-m-tolyl-amino}-propionic acid (76%, compound 161, melting point 165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH2:36]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]2[N:12]=[C:13]3[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]3=[N:15][CH:16]=2)=[N:7]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was stirred for 30 min. Benzyl bromide (63.5 mg, 44.1 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(1-benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 151 μmol, 61.1%) as a pale yellow powder. 1H NMR (CDCl3) δ: 9.29 (s, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.20-7.39 (m, 6H), 5.73 (s, 2H), 5.68 (s, 2H), 4.38-4.55 (m, 1H), 3.52-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.86-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: [CH2:1]([S:6][C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[CH2:1]([S:6]([C:7]1[N:12]=[C:11]([C:13]2[S:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](=[O:19])[N:18]=2)[CH:10]=[CH:9][CH:8]=1)=[O:32])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CCSc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CC(C)CCS(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
2-[6-(Isoamylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.15 g, 0.44 mmol) was dissolved in chloroform (50 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.10 g, 0.46 mmol) in chloroform (10 ml) was added dropwise thereto. The reaction mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from hexane-ethyl acetate to give the titled compound (0.15 g, 96%) as pale yellow amorphous.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][OH:33])=[CH2:2].[OH-].[Na+].[CH3:36]I>>[CH:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:36])=[CH2:2]
Reactant: C=COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: C=COCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A 1-L flask equipped with a stirrer, a dropping funnel, a thermometer, a condenser tube, and a nitrogen gas inlet was charged with 500 parts of decaethylene glycol vinyl ether and 80 parts of sodium hydroxide. The flask was heated to 40° C. with stirring under a nitrogen atmosphere, and then 287 parts of methyl iodide was slowly dropped while the internal temperature was maintained at 40° C. or lower. After completion of the dropping, the mixture was aged for five hours, and distilled under reduced pressure so that unreacted methyl iodide was removed. In order to further remove sodium hydroxide in excess and water and sodium iodide generated after the reaction, adsorption treatment was performed using an adsorbent, and thereby decaethylene glycol methyl vinyl ether was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:18])[S:10][N:9]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:38][C:39]([F:50])([F:49])[C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C1COCC1>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:17]([NH:16][C:11]2[S:10][N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43](=[O:44])[C:42]4[CH:46]=[CH:47][CH:48]=[C:40]([C:39]([F:38])([F:49])[F:50])[CH:41]=4)=[CH:7][CH:6]=3)[C:12]=2[C:13]([NH2:15])=[O:14])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)c1c(-c2ccc(N)cc2)nsc1NC(=O)NCCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1c(-c2ccc(NC(=O)c3cccc(C(F)(F)F)c3)cc2)nsc1NC(=O)NCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of 3-(4-aminophenyl)-5-(3-(3-morpholinopropyl)ureido)isothiazole-4-carboxamide (6 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.0078 mL, 0.045 mmol) in 0.8 mL THF at rt was added 3-(trifluoromethyl)benzoyl chloride (0.0024 mL, 0.017 mmol). The reaction was stirred at rt for 2 hours, then quenched with aqueous Na2CO3 solution, stirred 5 min at rt, and then partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The solid was chromatographed eluting with CHCl3, then gradient 2.5% to 10% MeOH in CHCl3. The resulting solid was subjected to an EtOAc/NaHCO3 work-up to remove the presence of any silica gel impurity. Upon evaporation of the EtOAc layer the title compound was obtained as a white solid (7 mg, 76%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][CH2:4][CH2:5][CH:6]([C:11]1[C:12]([CH3:30])=[N:13][C:14]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO>[F:32][C:2]([F:1])([F:31])[CH2:3][CH2:4][CH2:5][CH:6]([C:11]1[C:12]([CH3:30])=[N:13][C:14]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)C(CCCC(F)(F)F)c1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(N3CCCCC3)nc(C)c2C(CCCC(F)(F)F)C(=O)O)cc1
Yield: 62.7 %

Procedure:
This compound was prepared according to general method D from methyl 6,6,6-trifluoro-2-(4-methyl-2-(piperidin-1-yl)-6-p-tolylpyrimidin-5-yl)hexanoate (0.102 g; 0.227 mmol), sodium hydroxide 10N (0.227 mL; 2.27 mmol) in methanol (2.2 mL). Purification by preparative HPLC (HPLC method 1) furnished 0.062 g (60%) of the title compound as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[CH2:9][NH:10][CH:11]([CH3:13])[CH3:12].[N:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[C:18]=[O:19]>ClCCl>[CH3:12][CH:11]([N:10]([CH2:9][C:8]1[CH:14]=[CH:15][CH:16]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[CH:7]=1)[C:18]([NH:17][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:22][CH:21]=1)=[O:19])[CH3:13]
Reactant: CC(C)NCc1cccc(-c2nccs2)c1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)N(Cc1cccc(-c2nccs2)c1)C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 23 °C
Reaction time: 16 h

Procedure:
To a solution of N-[3-(1,3-thiazol-2-yl)benzyl]propan-2-amine (35 mg, 0.15 mmol, 1.0 eq) in dichloromethane (2.5 mL) was added 1-isocyanato-4-(trifluoromethoxy)benzene (30 mg, 0.15 mmol, 1.0 eq) and the reaction was stirred at 23° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by reverse phase liquid chromatography (Gemini-NX C18, 5 μm, 30×100 mm column; 0-100% CH3CN/H2O gradient w/0.10% TFA present) to yield 1-propan-2-yl-1-[3-(1,3-thiazol-2-yl)benzyl]-3-[4-(trifluoromethoxy)phenyl]urea as a white solid. 1H NMR (500 MHz, DMSO): δ 8.58 (s, 1 H); 7.93-7.88 (m, 2 H); 7.80-7.75 (m, 2 H); 7.56 (d, J=8.7 Hz, 2 H); 7.45 (t, J=7.7 Hz, 1 H); 7.38 (d, J=7.7 Hz, 1 H); 7.22 (d, J=8.6 Hz, 2 H); 4.63 (s, 2 H); 4.54-4.48 (m, 1 H); 1.12 (d, J=6.6 Hz, 6 H). LRMS m/z (M+H) 436.1 found, 436.1 required.
Reaction SMILES: [OH:1][C@@:2]1([C:22]#[C:23][CH3:24])[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH2:4][CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:25](OC(=O)C)(=[O:27])[CH3:26]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([O:1][C@@:2]1([C:22]#[C:23][CH3:24])[CH:8]=[CH:7][C@H:6]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH2:4][CH3:5])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC#C[C@]1(OC(C)=O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21CC

Procedure:
Under nitrogen, 250 mg. of 17β-hydroxy-18-methyl-17α-propinyl-4,15-estradien-3-one in 2.5 ml. of pyridine is agitated at room temperature for 2 hours with 1 ml. of acetic anhydride and 10 mg. of 4-(dimethylamino)-pyridine. After the reaction mixture has been worked up as described in Example 36, and after the crude product has been chromatographed on silica gel with acetone-hexane, 110 mg. of 17β-acetoxy-18-methyl-17α-propin-1-yl-4,15-estradien-3-one is obtained.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:18])([F:17])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:16])([CH3:15])[C:13]#[CH:14])=[CH:8][CH:7]=1.[I:19]I.O>CO>[I:19][C:14]#[C:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][C:4]([F:17])([F:18])[F:3])=[CH:11][CH:10]=1)([OH:16])[CH3:15]
Reactant: II
Reactant: C#CC(C)(O)c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(O)(C#CI)c1ccc(OC(F)(F)F)cc1
Reaction time: 3 h

Procedure:
40 ml of concentrated sodium hydroxide solution were added dropwise to a solution of 23 g (0.1 mol) of 3-(4-trifluoromethoxyphenyl)-but-1-yn-3-ol in 250 ml of methanol at 15°-20° C. in the course of 30 minutes, while stirring, and 25.4 g (0.1 mol) of iodine were simultaneously introduced in portions. After three hours, the reaction mixture was stirred into 1,000 ml of water. The initially oil reaction product crystallized on standing. The solid material was taken up in 200 ml of ethyl acetate, the solution was washed twice with 100 ml of water, and the organic phase was dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The residual oil was dissolved in a small quantity of petroleum ether, the solution was cooled and the precipitated crystals were filtered off under suction. 17.2 g (=48.2% of theory) of colorless crystals of melting point 75°-76° C. were obtained.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[CH:16]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[S:15][CH2:14][C@H:13]([N:25]2[CH2:32][C:31]3[C:27](=[N:28][N:29]([CH2:33][C:34](OC)=[O:35])[CH:30]=3)[CH2:26]2)[CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Cl>CO>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[CH:16]1[C@@H:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:12][C@@H:13]([N:25]2[CH2:32][C:31]3[C:27](=[N:28][N:29]([CH2:33][CH2:34][OH:35])[CH:30]=3)[CH2:26]2)[CH2:14][S:15]1
Reactant: COC(=O)Cn1cc2c(n1)CN([C@H]1CSC(c3cc(F)ccc3F)[C@@H](NC(=O)OC(C)(C)C)C1)C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(CCO)nc3C2)CSC1c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium borohydride (26.4 mg, 0.698 mmol) was added in 3 portions over 4 h to a solution of methyl 2-[5-[(3R,5S)-5-(tert-butoxycarbonylamino)-6-(2,5-difluorophenyl)tetrahydrothiopyran-3-yl]-4,6-dihydropyrrolo[3,4-c]pyrazol-2-yl]acetate (13.2 mg, 0.025 mmol) in methanol (0.25 mL). After an additional 15 min, 2N HCl (0.1 mL, 0.1 mmol) was added and the resulting suspension was stirred at room temperature for 5 min. Filtration of the suspension and purification by reverse-phase HPLC was followed by preparative thin layer plate chromatography (1×500 micron PTLC plate), developed with a 90:10 mixture of methylene chloride/(10:1 EtOH/concentrated ammonium hydroxide). The appropriate uv active band was removed, eluted with a 90:10 mixture of methylene chloride/(10:1 EtOH/concentrated ammonium hydroxide) and evaporated to give the title compound as a white solid. MS: 499.2 [M+1]
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[O:11]=[C:12]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14][CH2:13]1.CI.[CH3:30]C(O)=O>C1COCC1>[CH3:30][C@H:13]1[C:12](=[O:11])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:15]([C:24]([O:26][CH3:27])=[O:25])[CH2:14]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](C)C(=O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 22.3 %

Procedure:
This compound is prepared as described by Gu et al, Tetrahedron Lett., 2003, 44, 3203-3205. Lithium hexamethyldisilazide in THF (1.0 M; 8.47 mL, 8.47 mmol) was added dropwise over 30 min. to a solution of 1-tert-butyl 2-methyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (2.0 g, 8.2 mmol) in THF (20 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h. Methyl iodide (1.30 mL, 20.9 mmol) was then added dropwise over 10 min. After stirring at −78° C. for 2 h, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. The reaction was then quenched by the addition of AcOH (1.00 mL, 17.6 mmol), and the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (100 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound (0.47 g, 22%). LCMS calc. for C12H19NNaO5 (M+Na)+: m/z=280.1. found 280.1. 1H NMR (CDCl3, 400 MHz) δ 4.57 (1H, dd, J=1.6 and 9.6 Hz), 3.77 (3H, s), 2.68 (1H, m), 2.27 (1H, m), 1.93 (1H, m), 1.49 (9H, s), 1.21 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[N:7]=1.[F:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:28]=1[NH:27][N:26]=[C:25]2[NH2:29]>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:7]=[C:2]([NH:29][C:25]2[C:24]3[C:28](=[C:20]([F:19])[CH:21]=[CH:22][CH:23]=3)[NH:27][N:26]=2)[C:3]2[CH:18]=[CH:17][CH:16]=[N:15][C:4]=2[N:5]=1
Reactant: Clc1ccccc1-c1nc(Cl)c2cccnc2n1
Reactant: Nc1n[nH]c2c(F)cccc12
Product: Fc1cccc2c(Nc3nc(-c4ccccc4Cl)nc4ncccc34)n[nH]c12

Procedure:
Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-d]pyrimidine (100 mg, 0.36 mmol) and 7-Fluoro-1H-indazol-3-ylamine (108 mg, 0.72 mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, Rt 3.04 min; 1H NMR (DMSO, 500 MHz): δ13.67 (1H, s), 11.40-11.25 (1H, bs), 9.35-9.25 (2H, m), 7.95 (1H, m), 7.80-7.47 (5H, m), 7.35(1H, m), 7.15 (1H, m); MS (m/z), MH+391.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:20]([S:22]Cl)=[O:21].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:10]=1[C:11]1[O:12][C:20](=[O:21])[S:22][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Cl)cc1OCc1ccccc1
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1oc(-c2ccc(Cl)cc2OCc2ccccc2)ns1
Temperature: 90 °C
Yield: 98.8 %

Procedure:
To a solution of 2-(benzyloxy)-4-chlorobenzamide (0.103 g, 0.38 mmol) in toluene (5 ml) was added chlorocarbonylsulfenyl chloride (63 μL, 0.76 mmol) under nitrogen atmosphere and the resulting reaction mixture was refluxed at 90° C. for 2 h. After the completion of the reaction (TLC monitoring) water was added followed by extraction with ether (3×25 ml). The combined organics was then sequentially washed with water, 10% NaHCO3 (aqueous solution) and finally again with water. The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated to get desired product (0.12 g, 94%) that was carried forward as such without further purification. MS: 320.21 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13][C:12]2=[O:20])=[CH:7][CH:6]=1)=[O:3].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=1>>[CH3:18][C:14]1([CH3:19])[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:24]4[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=4)[CH2:30][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)[C:12](=[O:20])[CH2:13]1
Reactant: CC1(C)CC(=O)N(c2ccc(OC(=O)Cl)cc2)C(=O)C1
Reactant: c1cncc(CN2CCNCC2)c1
Agent: Cl
Product: CC1(C)CC(=O)N(c2ccc(OC(=O)N3CCN(Cc4cccnc4)CC3)cc2)C(=O)C1

Procedure:
The title compound was prepared from 4-(4,4-dimethyl-2,6-dioxo-piperidin-1-yl)-phenyl chloroformate and 1-pyridin-3-ylmethyl-piperazine, hydrochloride, preparative HPLC (Method C) (75%, colourless oil). HPLC-MS m/z=437.2 (M+1), Rt: 1.70 min.