Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10]Cl)[N:6]=1)([CH3:4])[CH3:3].[F:12][C:13]([F:22])([F:21])[CH2:14][CH2:15][CH:16]([C:19]#[N:20])[C:17]#[N:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:2]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][C:16]([CH2:15][CH2:14][C:13]([F:12])([F:21])[F:22])([C:17]#[N:18])[C:19]#[N:20])[N:6]=1)([CH3:4])[CH3:3]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)c1ncn(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ncn(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 27.3 %

Procedure:
0.78 g of 3-i-propyl-1-(chloromethyl) -1H-1,2,4-triazole hydrochloride and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 12 ml of N,N-dimethylformamide. 1.10 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane-MTBE to obtain 0.31 g of [(3-i-propyl-1H-1,2,4-triazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (28), hereinafter) shown by below formula.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:8]([CH:13]=1)[C:9]([O:11]C)=[O:10])([O-:3])=[O:2].O.O.[OH-].[Li+].Cl>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:14][S:15]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])=[C:8]([CH:13]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1NS(=O)(=O)c1ccccc1
Temperature: 50 °C

Procedure:
A solution of Example 95A (10.9 mg, 0.032 mmol) in methanol (0.9 mL) and distilled water (0.01 mL) was treated with lithium hydroxide monohydrate (4.0 mg, 0.096 mmol), heated to 50° C. for 4 hours, cooled to room temperature, treated with 2N HCl (1 mL), and concentrated. The resulting residue was purified by chromatography to provide the desired product as a white solid. MS (ESI(−)) m/e 321 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.62 (d, 1H), 8.06 (dd, 1H), 7.80 (m, 2H), 7.51 (m, 3H), 7.42 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH:5]1[CH2:8][NH:7][CH2:6]1.C(N(CC)C(C)C)(C)C.[Cl:23][C:24]1[N:29]=[C:28](Cl)[CH:27]=[CH:26][N:25]=1>C(O)(C)C>[Cl:23][C:24]1[N:29]=[C:28]([N:7]2[CH2:8][CH:5]([O:4][C:3]3[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=3[Cl:1])[CH2:6]2)[CH:27]=[CH:26][N:25]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1ccc(OC2CNC2)c(Cl)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc(OC2CN(c3ccnc(Cl)n3)C2)c(Cl)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
To a solution of 3-(2,4-dichlorophenoxy)azetidine (1.0 g, 4.6 mmol) in isopropanol (14 mL) was added N,N-diisopropylethylamine (DIPEA) (1.0 mL, 6.9 mmol) and 2,4-dichloropyrimidine (0.686 g, 4.6 mmol and the reaction mixture was heated at 80° C. for 7 h. The mixture was concentrated under reduced pressure and extracted with EtOAc (2×20 mL) and water (2×20 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-1-yl)pyrimidine (0.600 g, 40%) as a solid. Observed mass (M+1): 330.0
Reaction SMILES: C(O[C:6](=[O:14])[NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(C)(C)C.[CH3:15][C:16]1OC(C(O)=O)=C[CH:17]=1>>[C:6]([NH:7][C:8]1[O:9][C:10]([CH3:13])=[CH:11][CH:12]=1)(=[O:14])[CH:16]([CH3:17])[CH3:15]
Reactant: Cc1ccc(C(=O)O)o1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)o1
Product: Cc1ccc(NC(=O)C(C)C)o1

Procedure:
tert-Butyl-5-methyl-2-furylcarbamate, (mp 80° C., 24 g, 0.12 mole) prepared as in Example 1 from 5-methyl-2-furoic acid was reacted as in Example 2 to give 2-isobutanamido-5-methylfuran (13.4 g) mp 78° C. which was then reacted as in Example 4 to give the title compound. b.p. 94° C./0.3 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[Li]C(C)(C)C.[CH3:15][CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17](=[O:18])[CH:16]([CH3:15])[CH2:21][CH2:20][OH:19]
Reactant: CC1CCOC1=O
Reactant: Clc1ccc(Br)c(Cl)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(CCO)C(=O)c1ccc(Cl)cc1Cl
Temperature: -95 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added a solution of 2,4-dichlorobromobenzene (65.5 g, 290.7 mmol) in 1.1 L of THF under nitrogen. The solution is cooled to −95° C. with a MeOH/liquid nitrogen bath. To this solution is added t-BuLi (400 mL, 1.6 M in pentane, 639.5 mmol) slowly via syringe pump followed by the addition of a solution of α-methyl-γ-butyrolactone (43.5 g, 434.8 mmol) in THF (100 mL). The internal temperature is controlled <−80° C. After 1 h stirring <−80° C., the reaction mixture is quenched with saturated NH4Cl solution and warmed to room temperature. Water (2 L) and EtOAc (1 L) are added and separated. The aqueous layer is extracted with EtOAc (2×2 L). The combined organic solutions is dried (MgSO4) and filtered. The filtrate is concentrated in vacuo to dryness to give 80.9 g of 1-(2,4-dichlorophenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil. The residue is used for Swern oxidation. To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added DMSO (104.1 mL, 1465.7 mmol) and CH2Cl2 (1.1 L). The solution is cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution is added oxalyl chloride (63.9 mL, 732.9 mmol) slowly via syringe pump. The mixture is stirred at −80° C. for 15 min followed by the addition of a solution of the above obtained crude 1-(2,4-dichlorophenyl)-4-hydroxy-2-methylbutan-1-one in CH2Cl2 (150 mL) slowly via syringe pump. After stirring <−70° C. for 1 h, to the mixture is added Et3N (456 mL, 3271.7 mmol). The cooling bath is removed after 5 min and the mixture is stirred at room temperature for 1.5 h. The mixture is diluted with hexanes (6 L) and washed with water (6 L). The aqueous layer is extracted with hexanes (6 L). The combined organic solutions is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 36 g (50% for two steps) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.37 (dd, J=2.0, 8.3 Hz, 1H), 3.81–3.76 (m, 1H), 3.18 (dd, J=8.2, 18.6 Hz, 1H), 2.65 (dd, J=5.0, 18.6 Hz, 1H), 1.21 (d, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.1, 202.4, 139.5, 139.2, 134.4, 132.7, 132.4, 129.6, 48.8, 42.0, 18.6; IR (liq.) 2974, 2936, 1996, 1910, 1708, 1585, 1457, 1374, 1228, 1191, 1106, 1064, 978, 828, 810 cm−1; MS (CI) m/z 247 (M+), 245 (M+).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]2[CH2:41][CH2:40][CH2:39][CH:38]([OH:42])[CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1>ClCCl.CCOCC>[CH3:22][O:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH:34]2[CH2:41][CH2:40][CH2:39][C:38](=[O:42])[CH2:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1
Reactant: COCOc1ccc(CCC2CCCC(O)CCC2)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COCOc1ccc(CCC2CCCC(=O)CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
1.65 g of pyridinium dichromate was dissolved in 30 ml of dichloromethane. To the solution was added 0.40 g of 5-[2-(4-methoxymethoxyphenyl)ethyl]-1-cyclooctanol prepared in Reference Example 2. The reaction solution was stirred at room temperature for two hours. To the reaction solution was added another 2.5 g of pyridinium dichromate. The reaction solution was stirred at room temperature overnight. The reaction solution was diluted with 50 ml of ether and purified on Florisil column eluted with ether, to afford 0.37 g of the titled compound as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>CCOCC.O>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:36]
Reactant: CCOC(=O)CCCCBr
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.6 %

Procedure:
A mixture of 0.7 g (1.95 mmol) of rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester, 0.45 g (2.14 mmol) of ethyl 5-bromovalerate, 0.75 g (5.4 mmol) of anhydrous, granular potassium carbonate, and 8 mL of dimethyl sulfoxide was stirred at room temperature for 24 hr. The resulting mixture was poured into water and worked-up with ether in the usual manner. The crude product was flash chromatographed on silica gel, eluting with 2:1 hexane-ethyl acetate, affording 0.86 g (90%) of rac-(E)-5-[2-(3-methoxy-3-oxo-1-propenyl)-3-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenoxy]pentanoic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13](Cl)[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(COC)OC.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1B(O)O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:31]3[CH:32]=[CH:33][C:34]([CH3:36])=[CH:35][C:30]=3[CH3:29])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nn(Cc2ccccc2)c2cccc(Cl)c2c1=O
Reactant: Cc1ccc(B(O)O)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cccc3c2c(=O)c(C)nn3Cc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
To 0.115 g (0.40 mmol) of 1-benzyl-5-chloro-3-methylcinnolin-4(1H)-one, 0.12 g (0.81 mmol) of cesium fluoride and 0.093 g (0.08 mmol) of tetrakis(triphenylphosphine)palladium(0) was added 4 mL of dimethoxyethane. The dark brown mixture was stirred at room temperature for 15 min. then 0.079 g (0.53 mmol) of 2,4-dimethylphenylboronic acid was added. This mixture was then heated to reflux for 5 h, cooled to room temperature, diluted with ethyl acetate and filtered through a plug of silica gel. The resulting filtrate was concentrated and the residue was purified by flash chromatography eluting with a 17% ethyl acetate/hexanes mixture to give 0.102 g (71%) of the title compound as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([NH:34][C:6]1[C:5]2=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=[CH:11][N:4]2[N:3]=[C:2]([Cl:1])[N:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Clc1nc(Cl)c2c(-c3ccccc3)ccn2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(NCc2ccccc2)c2c(-c3ccccc3)ccn2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
2,4-Dichloro-5-phenylpyrrolo[2,1-f][1,2,4]triazine (0.500 g, 1.89 mmol) was dissolved in THF (10 mL) then was added DIPEA (1.65 mL, 9.47 mmol), followed by benzylamine (0.406 g, 3.79 mmol). Then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to remove THF. To this residue, water (10 mL) was added and the aqueous solution was extracted with CH2Cl2 (25×3 mL). The organic layer was separated and dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 11% EtOAc/hexanes) to afford N-benzyl-2-chloro-5-phenylpyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 63.1%). LCMS Condition B-47: retention time 2.70 min, [M+1]=335.0.
Reaction SMILES: Cl[C:2](=[O:8])[C:3](OCC)=[O:4].[NH2:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])=[C:12]([CH3:22])[CH:11]=1.CCN(CC)CC.[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33][NH2:34]>C1COCC1.CCOC(C)=O>[CH3:30][O:31][CH:32]([O:35][CH3:36])[CH2:33][NH:34][C:2](=[O:8])[C:3]([NH:9][C:10]1[CH:21]=[CH:20][C:13]([O:14][CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])=[C:12]([CH3:22])[CH:11]=1)=[O:4]
Reactant: COC(CN)OC
Reactant: CCOC(=O)C(=O)Cl
Reactant: Cc1cc(N)ccc1OCC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(CNC(=O)C(=O)Nc1ccc(OCC(C)(C)O)c(C)c1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
Slow addition of a solution of ethyl 2-chloro-2-oxoacetate (4.69 g, 34.4 mmol) in THF (30 ml) to a solution of 1-(4-amino-2-methylphenoxy)-2-methylpropan-2-ol (6.10 g, 31.2 mmol) in THF (100 mL) resulted in formation of a precipitate as the reaction stirred at RT for 30 min. At which time a solution of Et3N (13.06 mL, 94 mmol) and 2,2-dimethoxyethanamine (3.94 g, 37.5 mmol) in EtOAc (100 mL) was added prior to heating the mixture at reflux for 25 hours. After cooling and concentration under vacuum, the residue, following dilution with CH2Cl2, was extracted with aqueous 0.5 N HCl (2×150 ml). The CH2Cl2 layer was dried over sodium sulfate and concentrated to yield N1-(2,2-dimethoxyethyl)-N2-(4-(2-hydroxy-2-methylpropoxy)-3-methylphenyl)-oxalamide (11.40 g, 30.6 mmol, 98% yield) as white solid which was carried forward without further purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:15][C:16]1[S:17][CH:18]=[C:19]([CH2:21][N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)[N:20]=1
Reactant: Nc1nc(CCl)cs1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2csc(N)n2)CC1
Yield: 74.8 %

Procedure:
A solution of Boc-piperazine (4.67 g), 2-amino-4-chloromethylthiazole hydrochloride (WO 0190090; 5.1 g) and potassium carbonate (8.4 g) in DMF (100 ml) was mixed at 65° C. for 12 hours. The precipitated insolubles were filtered off, and then the filtrate was concentrated under reduced pressure. The residue was purified with silica gel column to obtain the title compound as a brown solid (5.6 g, 74%).
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N+:31]([O-])=O)=[C:12]([CH:30]=1)[O:13][C:14]1[CH:15]=[C:16]([C@H:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:21])[CH:17]=[CH:18][CH:19]=1.Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+]>[C].[Pd].O.CN(C)C=O>[C:25]([O:24][C:23]([NH:22][C@@H:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[O:13][C:12]1[CH:30]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]=1[NH:31][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:21])=[O:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Reactant: CCOC(=O)CCCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCNc1ccc(Cl)cc1Oc1cccc([C@@H](C)NC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 56.5 %

Procedure:
5% carbon-palladium (1.I g) was added to an ethyl acetate (50 ml) solution of tert-butyl(1R)-(-)-1-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (3.5 g, 8.9 mmols). The resulting mixture was hydrogenated at room temperature under atmospheric pressure for 1 hour. The catalyst was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was stirred with ethyl 4-bromobutyrate (7 g, 36 mmols), potassium carbonate (3.7 g, 27 mmols) and N,N-dimethylformamide (50 ml) at 80° C. for 72 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[N-[2-[3-[(1R)-1-tert-butoxycarbonylaminoethyl]phenoxy]-4-chlorophenyl]]aminobutyrate (2.4 g, 56%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[CH:5]([CH3:7])[NH2:6].C(N(CC)CC)C.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26])([O-:18])=[O:17]>ClCCl>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([NH:6][CH:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:27])=[O:26])([O-:18])=[O:17]
Reactant: COC(=O)C(C)N
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 87.8 %

Procedure:
DL-Alanine methyl ester hydrochloride (13.96 g; 0.1 mol) is dissolved in 800 ml of dichloromethane and placed at 0° C. Triethylamine (2.3 eq.; 230 mmol; 32 ml) is added dropwise, along with portionwise addition of 2-nitrobenzenesulfonyl chloride (1 eq.; 100 mmol; 22.16 g), and the reaction medium is allowed to return to room temperature overnight. The reaction medium is washed with water and then dried over sodium sulfate, filtered through silica and evaporated to dryness to give 25.3 g of solid corresponding to the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([C@@:15]1([CH2:29][CH2:30][OH:31])[CH2:19][C:18](=[O:20])[N:17]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:8]([O:12][C:13]([C@@:15]1([CH2:29][CH2:30][O:31][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:19][C:18](=[O:20])[N:17]([C@@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)CC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 87.5 %

Procedure:
Triethylamine (3.0 mL, 21.8 mmol) was added to a solution of (3S)-3-(2-hydroxyethyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (2.42 g, 7.25 mmol) in dichloromethane (70 mL), and the mixture was cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (2.50 mL, 10.9 mmol) was added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. After addition of an ice piece and stirring, the reaction solution was poured into a mixture of ethyl acetate (50 mL) and saturated sodium bicarbonate (50 mL), followed by extraction with ethyl acetate (200 mL, 100 mL). The organic layers were combined and washed with brine (50 mL). After drying over anhydrous sodium sulfate and filtration, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1→2:1) to give 2.84 g (88%) of the title compound as a white solid.
Reaction SMILES: C([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[C:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]1=[O:26])(=O)C1C=CC=CC=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[C:31]([O:33][CH2:34][CH3:35])=[O:32].[OH-].[Na+]>C1COCC1.CO>[CH2:34]([O:33][C:31]([C:30]1[CH:29]=[C:28]([NH:27]/[C:18](=[C:11]2\[C:10](=[O:26])[NH:9][C:17]3[C:12]\2=[CH:13][CH:14]=[CH:15][CH:16]=3)/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:38]=[CH:37][CH:36]=1)=[O:32])[CH3:35]
Reactant: O=C1C(=C(Cl)c2ccccc2)c2ccccc2N1C(=O)c1ccccc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 9c and 8 from 1-benzoyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and ethyl 3-aminobenzoate in THF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][Si:25]([CH3:33])([CH3:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:24][Si:25]([CH3:33])([CH3:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C[Si](C)(CCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(SC[Si](C)(C)c2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.4 g, 10 mmol), chloromethyldimethylphenylsilane (1.9 g, 10 mmol) and dimethylformamide (50 mL) and stir overnight at room temperature under argon atmosphere. Dilute the mixture with ice-water and extract with ethyl ether. Wash the ethereal layer with water, then brine, filter through flourosil-Na2SO4, and evaporate to an orange oil (3.5 g). Purify the product by first distilling (bp 160-170° C. @ 0.1 mm Hg), then subjecting to silica gel chromatography (CCl4 :CHCl3 /1:1) to obtain the title compound as a light yellow oil which slowly crystallizes to a white waxy solid (2.3 g, 59%). Anal. Calcd for C23H34OSSi: C, 71.44; H, 8.86; S, 8.29; Found: C, 71.14; H, 8.86; S, 7.98.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cccc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
A solution 3-tert-butyl-trimethylsilanylethynyl benzene (Intermediate 102, 0.47 g, 2.04 mmol) in methanol (20 mL) was treated with potassium carbonate (2.8 g, 20.2 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230–400 mesh) using 10% ethyl acetate in hexane as the eluent afforded the title compound as a light yellow oil (0.125 g, 39%).