Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]2[C:7]([NH:9][CH:3]([CH2:4][CH2:5]2)[CH2:2]1)=O.F[B-](F)(F)F.C([O+](CC)CC)C.C(=O)([O-])[O-].[K+].[K+].C(OC1C2CCC(CC2)C=1)N.Cl.[C:40]1([N:46]([CH2:53][CH2:54][CH2:55][NH2:56])[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.O.C(O)C>[CH:3]12[CH2:4][CH2:5][CH:6]([CH2:1][CH2:2]1)[C:7]([NH:56][CH2:55][CH2:54][CH2:53][N:46]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[N:9]2
Reactant: O=C1NC2CCC1CC2
Reactant: NCCCN(c1ccccc1)c1ccccc1
Agent: CC[O+](CC)CC
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: c1ccc(N(CCCNC2=NC3CCC2CC3)c2ccccc2)cc1
Reaction time: 16 h
Yield: 52.2 %

Procedure:
A mixture of 100 g. (0.80 moles) of 3-isoquinuclidone in methylene chloride is added to a mixture of 190 g. (1.00 moles) of triethyloxonium tetrafluoroborate in methylene chloride. The preparation of 3-isoquinuclidone is described at Organic Synthesis Volume 5, John Wiley and Sons, New York (1973), pages 670-672. The reaction is then stirred for about 16 hours. 276 g. of potassium carbonate is added. 45 ml. of water is then added dropwise over about a 15 minute interval. The reaction mixture is then filtered, and the filtrate is concentrated. The residue is then twice distilled to give 67 g. of 2-aza-3-ethoxy-bicyclo[2,2,2]oct-2-en, bp. 87°-88° C. at 19 mm. A mixture of 3.65 g. (0.0161 moles) of N-[3-(N,N-diphenylamino)propyl]-amine hydrochloride, and 4.94 g. (0.0322 moles) of 2-aza-3-ethoxybicyclo[2,2,2]oct-2-en in 60 ml. of ethanol is heated for about 22 hours on a steambath, allowing solvent to boil away and shielding the reaction mixture from moisture. For about the last six hours, a vacuum is applied to the reaction mixture. The residual reaction product is dissolved in water and washed with ether. The aqueous layer is made basic with caustic. The resulting white crystals are filtered and twice recrystallized from carbon tetrachloride to give 2.8 g of N'-2-azabicyclo[2,2,2]-oct-2-en-3-yl-N,N-diphenyl-1,3-propanediamine, mp. 148.0°-149.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH2:38][CH2:39][NH2:40])[CH:35]=[CH:36][CH:37]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3cccc(Cl)c3)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(3-Chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.85 (m, 1H) 8.15 (m, 4H) 7.6 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:17][F:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([F:26])=[C:4]([Si](CC)(CC)CC)[CH:3]=1.[F-].[K+].C(O)(=O)C.C([O-])(O)=O.[Na+]>O.CN(C=O)C.C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C@:8]([NH:19][S@@:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])([CH2:17][F:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:11])[C:5]([F:26])=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](CF)(CC(=O)OC(C)(C)C)N[S@](=O)C(C)(C)C)c1F
Agent: *CC(*)C
Agent: O=C([O-])O
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C[C@](CF)(N[S@](=O)C(C)(C)C)c1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.5 %

Procedure:
To a polypropylene vial with cap was added (5)-tert-butyl 3-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutanoate (9.8 g, 17.2 mmol), THF (50 mL) and DMF (50.0 mL). To the solution was added potassium fluoride (Aldrich; 2.75 g, 47.3 mmol) and acetic acid (2.71 mL, 47.3 mmol). The solution was stirred at rt for 17 h. The mixture was poured into sat NaHCO3 (200 mL) and then diluted with water (200 mL). The solution was extracted with EtOAc (3×100 mL) and the combined extracts were washed with water (3×100 mL) and brine (100 mL) and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 40% EtOAc/hexane, 120 g Silicycle column) afforded (5)-tert-butyl 3-(6-bromo-3-fluoropyridin-2-yl)-3-((R)-1,1-dimethylethylsulfinamido)-4-fluorobutanoate (6.93 g, 15.22 mmol, 88% yield) as a yellow oil. MS m/z=455.0 [M+H]+. Calculated for C17H25BrF2N2O3S: 454.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=O)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1.CSC>C1COCC1>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[C:18]([F:21])([F:19])[F:20])[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCN1CCN(C(=O)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: CSC
Product: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a mixture of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 66.4 mmol) in THF (500 mL) was added BH3.DMS (19.91 mL, 199 mmol) dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixture was quenched by adding MeOH and then concentrated. The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35) to give a white solid of 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288 (M+H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[C:1]1([CH2:7][CH2:8][C:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Dissolve 3-phenylpropionic acid (1.5 g, 10 mmol) in dimethylformamide (5 mL) and add t-butyldimethylsilyl chloride (7.5 g, 50 mmol) and imidazole (6.8 g, 0.1 mol). Stir for 48 hours at room temperature, pour into ethyl ether and water and separate the organic phase. Dry (MgSO4) and evaporate the solvent in vacuo to give 3-phenylpropionic acid, t-butyldimethylsilyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([OH:19])=O.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:1][N:2]1[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=2)[CH:4]=[C:3]1[C:17]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:17]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[C:6]([O:15][CH3:16])[C:7]([O:13][CH3:14])=[C:8]([O:11][CH3:12])[CH:9]=3)=[O:19])[CH2:22][CH2:21]1)=[O:19]
Reactant: C1CNCCNC1
Reactant: COc1cc2c(cc(C(=O)O)n2C)c(OC)c1OC
Product: COc1cc2c(cc(C(=O)N3CCCN(C(=O)c4cc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
N-Methyl-4,5,6-trimethoxyindole-2-carboxylic acid (130 mg) and homopiperazine (24 mg) were reacted in the same manner as in Preparation Example 37 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:5]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:15])[CH2:13]I)[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:38][O:39][C:40]1[C:47]([O:48][CH3:49])=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([S:19]([N:5]([C@H:6]([C:16]([OH:18])=[O:17])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([CH2:13][NH:43][CH2:42][C:41]2[CH:44]=[CH:45][CH:46]=[C:47]([O:48][CH3:49])[C:40]=2[O:39][CH3:38])=[O:15])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: COc1cccc(CN)c1OC
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)CI)C(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CNCC(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)c1OC

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-iodoacetyl-L-lysine (150 mg, 0.29 mmol, example 105, step B) by following the indications of general procedure H using DIEA (0.14 mL, 0.81 mmol) and 2,3-dimethoxybenzylamine (0.12 mL, 0.81 mmol). The crude material was purified by preparative HPLC. The product was isolated as a solid (25 mg, 16% yield).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[C:9](=[O:14])[CH2:8][CH2:7]2>CO>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:13])[CH:9]([OH:14])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCc2cc(Cl)c(Cl)cc21
Reaction time: 1 h

Procedure:
4.85 g of sodium borohydride were added at 0° C. to a solution of 4 g of the product of Step A in 285 ml of methanol and after stirring for one hour, the methanol was evaporated. The residue was diluted with water and excess hydride was eliminated by addition of hydrochloric acid. The mixture was extracted with ethyl acetate and the organic phase was evaporated to dryness under reduced pressure to obtain the desired product melting at 84° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:4]([CH:15]([O:18]C)OC)[CH:3]=1.C([Li])CCC.[C:25](=[O:27])=[O:26].[OH-].[Na+]>O1CCCC1.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([S:7][C:5]2[S:6][C:2]([C:25]([OH:27])=[O:26])=[CH:3][C:4]=2[CH:15]=[O:18])=[CH:13][CH:12]=1
Reactant: O=C=O
Reactant: COC(OC)c1cc(Br)sc1Sc1ccc(Cl)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cc(C(=O)O)sc1Sc1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 53.4 %

Procedure:
In an argon atmosphere, 5-bromo-2-(4-chlorophenylthio)-3-(dimethoxymethyl)thiophene (1.04 g, 2.75 mmol) was dissolved in tetrahydrofuran (15 mL) and the mixture was cooled to −78° C. n-Butyl lithium (1.6 mol/L hexane solution; 2.5 mL, 4.1 mmol) was added thereto, followed by stirring for 5 minutes. Dry ice (about 1 g) was added thereto, followed by stirring for 10 minutes. Water and 1 mol/L sodium hydroxide aqueous solution was added to the reaction liquid so that pH becomes 10, and the mixture was washed with ether. 1 mol/L Hydrochloric acid was added to the aqueous layer so that pH becomes 3, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). 1 mol/L hydrochloric acid (2 mL) was added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid and the product was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with isopropyl ether to give 2-(4-chlorophenylthio)-3-formyl-5-thiophenecarboxylic acid (439 mg, 54%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][OH:5])[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: CNCCO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCO)c1ncccc1[N+](=O)[O-]
Reaction time: 2.5 h

Procedure:
2-(Methylamino)ethanol (3.04 ml) is added to a mixture of 2-chloro-3-nitropyridine (3.00 g) and of potassium carbonate (5.22 g) in acetonitrile (90 ml) at 0°. The mixture is stirred for 2.5 hr at 20°-25° and additional 2-(methylamino)ethanol (1.5 ml) is added. The mixture is stirred for 1.5 hr, concentrated to a gum and diluted with methylene chloride (85 ml) and water (20 ml). The layers are separated and the organic phase is washed in water and dried over magnesium sulfate. Removal of solvent under reduced pressure gives the title compound, NMR (CDCl3) 8.27, 8.14, 6.76, 4.38, 3.88 and 2.87 δ.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])=[N:7][N:6]=[CH:5]2.[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B3OC(C)(C)C(C)(C)O3)[CH:26]=2)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CO.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].O>[CH:20]1([NH:23][C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=3[CH3:19])=[N:7][N:6]=[CH:5]4)[CH:26]=2)[CH2:21][CH2:22]1
Reactant: Cc1ccc(-c2nncc3cc(Cl)ccc23)c(C)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(-c2nncc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc23)c(C)c1
Temperature: 25 °C

Procedure:
A mixture of 6-chloro-1-(2,4-dimethylphenyl)phthalazine (150 mg, 558 μmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (437 mg, 1450 μmol), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (18.3 mg, 50.2 μmol, Strem), Pd2(dba)3 (15.3 mg, 16.7 μmol, Strem), and potassium carbonate (231 mg, 1674 μmol) in Dioxane:H2O=4:1 (5 mL) was heated to 80° C. for 18 h. After cooling to room temperature, the mixture was diluted with MeOH and concentrated over SiO2. The residue was purified with column chromatography (MeOH/CH2Cl2=0-4%). The residue was purified with reverse-phase chromatography (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 min gradient). Yield: 113 mg (50%). MS (ESI, pos. ion) m/z: 408 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[C:13]([N:14]=[CH:15][N:16]=3)=[C:12](SC)[N:11]3[CH2:20][CH2:21][N:22]=[C:10]23)=[CH:4][CH:3]=1.[NH3:23]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:12](=[NH:23])[N:11]3[CH2:20][CH2:21][N:22]=[C:10]23)=[CH:4][CH:3]=1
Reactant: N
Reactant: CSC1=C2N=CN=C2N(Cc2ccc(Cl)cc2)C2=NCCN21
Solvent: CCO
Product: N=C1c2nc[nH]c2N(Cc2ccc(Cl)cc2)C2=NCCN12
Temperature: 25 °C

Procedure:
The product of Procedure 76, 2.26 g. is suspended in a solution of about 6 g. of ammonia in 100 ml. of ethanol. Further anhydrous ammonia was added to yield a substantially saturated solution. The mixture was then placed in a pressure apparatus and heated at 100° overnight with agitation. The container was cooled to room temperature, opened, and the supernatent liquid decanted from the yellow solid. The precipitated solid and the residue obtained on evaporation of the supernatant liquid proved to be identical by infrared and thin-layer chromatography. They were combined and recrystallized from DMF, recovered as the hydrate containing 1/4 mole water of hydration, m.p. 296°-299°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8](O)[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C[C@H](O)c1cccc(Cl)c1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a mixture of (R)-tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)(methyl)carbamate (2.0 g, 7.00 mmol) in THF (23.33 mL) was added phthalimide (1.339 g, 9.10 mmol) and PPh3 (3 mmol of PPh3/1 g of resin, 2.34 g, 7.02 mmol). Then DTBAD (1.660 g, 7.21 mmol) in THF was slowly added at room temperature, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite® and washed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with sat. Na2CO3, water and brine, dried over sodium sulfate, filtered off, and concentrated. The crude product was purified by flash chromatography to afford (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)(methyl)carbamate (1.96 g, 4.72 mmol, 67.5%). LCMS (m/z): 315.1 (MH+-100), 1.19 min.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([CH3:21])=O>>[CH:19]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(=NOC(C)C)C(C)=O

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-propyl iodode (32.5 g.), potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that of Example D-(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[N:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(C(C)=O)CC1
Temperature: 95 °C
Yield: 62.7 %

Procedure:
A solution of 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-chloro-6-methoxyquinazoline (0.285 g, 0.753 mmol), 5-hydroxy-7-azaindole (0.111 g, 0.828 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (0.114 g, 0.828 mmol) in DMF (1.6 ml) was stirred and heated at 95° C. under nitrogen for 3 hours. The mixture was cooled and filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methylene chloride and methanol (saturated with ammonia). The fractions containing the expected product were combined and evaporated and the residue was triturated under diethyl ether, filtered and dried under vacuum to give 7-(3-(4-acetylpiperazin-1-yl)propoxy)-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (0.225 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]2[C:15]#[C:16][Si](C)(C)C.[F-].[K+]>CO>[C:15]([C:6]1[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH3:14])[CH:7]=1)#[CH:16]
Reactant: COc1cc2c(C#C[Si](C)(C)C)cn(C)c2cc1OC
Agent: [F-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cn(C)c2cc(OC)c(OC)cc12
Yield: 78.1 %

Procedure:
But using 1.71 g of 5,6-dimethoxy-1-methyl-3-trimethylsilanylethynyl-1H-indole and 1.04 g of potassium fluoride in 70 ml of methanol. 1 g of 3-ethynyl-5,6-dimethoxy-1-methyl-1H-indole is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[O:21]=[C:22]1[O:26][CH2:25][S:24][CH2:23]1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1)=[O:29].Cl>O1CCCC1>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][C:28]([CH:23]2[C:22](=[O:21])[O:26][CH2:25][S:24]2)=[O:29])=[CH:33][CH:34]=1
Reactant: COc1ccc(COC(=O)Cl)cc1
Reactant: O=C1CSCO1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc(COC(=O)C2SCOC2=O)cc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium diisopropylamide prepared from diisopropylamine (3.1 ml), n-butyllithium (14 ml as 1.6M hexane solution) and tetrahydrofuran (40 ml) is cooled at -70° C., mixed with 5-oxo-1,3-oxathiolane (1.04 g) and p-methoxybenzyl chloroformate. After 30 minutes, the mixture is acidified with hydrochloric acid, concentrated, and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated to give 5-oxo-1,3-oxathiolane-4-carboxylic acid p-methoxybenzyl ester (265 mg).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@:7]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[O:20][CH:21]2O)[C:16]([Cl:31])=[CH:15]3)[CH2:12][CH2:11]1)[C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4].C(=O)([O-])O.[Na+].Cl>O.CO>[C:3]([O:6][C@:7]1([C@:27]2([CH3:28])[C@H:13]([C@H:14]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:17](=[CH:18][C:19](=[O:30])[O:20][CH2:21]2)[C:16]([Cl:31])=[CH:15]3)[CH2:12][CH2:11]1)[C:8](=[O:10])[CH3:9])(=[O:5])[CH3:4]
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC(O)[C@]4(C)[C@H]3CC[C@@]21C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)OC[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
Sodium borohydride (72 mg) was added to a mixture of 200 mg of 17α-acetoxy-6-chloro-1ξ-hydroxy-2-oxapregna-4,6-diene-3,20-dione, 80 mg of sodium hydrogen carbonate, 20 ml of methanol and 10 ml of water, and the mixture was stirred at room temperature for 30 minutes. Concentrated hydrochloric acid (about 0.4 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by TLC [developing solvent: chloroform)] to give 120 mg of 17α-acetoxy-6-chloro-2-oxapregna-4,6-diene-3,20-dione.