Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18]([OH:24])=[N:17][C:16]=2[C:15]([C:25]#[N:26])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:28]1.O>CN(C)C=O>[Cl:9][C:10]1[CH:44]=[CH:43][CH:42]=[CH:41][C:11]=1[CH2:12][N:13]1[C:21]2[C:20](=[O:22])[N:19]([CH3:23])[C:18](=[O:24])[N:17]([CH3:1])[C:16]=2[C:15]([C:25]#[N:26])=[C:14]1[N:27]1[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:39])[CH3:37])[CH2:28]1
Reactant: Cn1c(O)nc2c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n(Cc3ccccc3Cl)c2c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
Potassium carbonate (700 mg) and methyl iodide (0.34 ml) were added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-2-hydroxy-3-methyl-4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (1.3 g) in N,N-dimethylformamide, and the resulting mixture was stirred at 25° C. for 4 hours. After the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (1.1 g) as a white solid.
Reaction SMILES: [I:1]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.O[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[I:1][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: II
Reactant: CC(C)(C)OC(=O)NCCCO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCI
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
Iodine (21.1 g, 83.1 mmol) was added in three portions to a solution of triphenylphosphine (19.83 g, 75.6 mmol) and imidazole (5.15 g, 75.6 mmol) in dichloromethane (300 mL). The resulting reddish-brown solution with a white precipitate was stirred until all of the iodine had dissolved. A solution of tert-butyl 3-hydroxypropylcarbamate (13.25 g, 75.61 mmol) in dichloromethane (150 mL) was added over a period of 45 minutes, and the reaction was stirred for 16 hours at ambient temperature. The reaction mixture was poured into saturated aqueous sodium thiosulfate and stirred until solution became colorless. The organic layer was separated and washed sequentially with saturated aqueous sodium thiosulfate, water, and brine; dried over anhydrous magnesium sulfate; filtered; and concentrated under reduced pressure to a pale yellow oil. The oil was purified by flash column chromatography (eluting with 80:20 hexanes:ethyl acetate) to a pale yellow oil which slowly crystallizes upon standing to afford 16.2 g of tert-butyl 3-iodopropylcarbamate as a yellow solid.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:11]N1C(=O)C2=CC=CC=C2C1=O.S(=O)=O.O=O>[O-][V]([O-])([O-])=O.[Na+].[Na+].[Na+].C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V].C(O)(=O)C>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C1C2CC3CC1CC(C2)C3
Agent: O=[V]
Agent: O=[V]([O-])([O-])[O-]
Agent: CC(=O)/C=C(\C)O
Solvent: CC(=O)O
Product: O=C1C2CC3CC(C2)CC1C3

Procedure:
A mixture of 2 mmol of adamantane, 0.2 mmol of N-hydroxyphthalimide, 0.01 mmol of vanadyl acetylacetonato [VO(acac) 2 ], and 5 ml of acetic acid was stirred at 60° C. in a sulfur dioxide (SO2) (0.5 atm) and oxygen (0.5 atm) atmosphere for 1 hour. A gas chromatographic analysis of a reaction mixture revealed that the conversion rate of adamantane was 91% and that a trace amount of 2-adamantanone was formed. The reaction mixture was extracted with water, was neutralized with an aqueous sodium hydroxide solution, and was adjusted to weak acidity with hydrochloric acid. An aqueous benzyl isothiourea hydrochloride solution in large excess was then added to the mixture to separate S-benzyl thiuronium salt of 1-adamantanesulfonic acid. The yield of this compound was 32%.
Reaction SMILES: [C:1]1([C:7]2([C:13]([CH:15]([C:21](OCC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.OS(O)(=O)=O>CCOC(C)=O>[OH:22][C:21]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[C:13](=[O:14])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C1(c2ccccc2)CCOCC1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2ccccc2C2(CCOCC2)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Diethyl 2-(4-phenyl-tetrahydro-2H-pyran-4-carbonyl)malonate (418 mg, 1200 μmol) was dissolved in a minimal amount of EtOAc and then cooled to 0° C. A slurry of P2O5 (681 mg) and H2SO4 (640 μL, 11998 μmol) (also at 0° C.) was added to the mixture via spatula, and the reaction mixture was stirred for 3 hours. The reaction mixture was then poured into a beaker of ice, diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with water, washed with water (2×50 mL), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound which was used without further purification. MS m/e=303 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:14][S:15]([O:18][CH2:19]CN=[N+]=[N-])(=[O:17])=[O:16]>>[CH3:14][S:15]([O:18][CH2:19][CH:4]([N:1]=[N+:2]=[N-:3])[CH2:5][CH3:6])(=[O:17])=[O:16]
Reactant: [N-]=[N+]=NCCCCO
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Product: CCC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 4-azidobutanol (0.80 g, 6.95 mmol) and mesyl chloride (1.48 mL, 10.43 mmol) within 3 h as described for synthesis of 156a gave compound 156c (1.33 g) as a crude colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2[CH:23]=[CH:24][CH:25]=[N:26]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:26][CH:25]1[CH2:23][CH2:24]1)=[O:7]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid (120 mg) in DMF (1 ml) was added a solution of HATU (192 mg) in DMF (1 ml) and a solution of HOBT (69 mg) in DMF (1 ml). To this mixture was added cyclopropylamine (0.04 ml) and DIPEA (0.27 ml). The reaction was stirred at room temperature for 18 hours, before diluting with methanol (5 ml) and filtration through a SPE cartridge (SCX, 2 g). The filtrate was applied to a SPE cartridge (Aminopropyl, 10 g) and washed through with methanol (10 ml). The combined filtrate and washings were reduced to dryness under vacuum to give 3-bromo-4-chloro-N-cyclopropylbenzamide.
Reaction SMILES: I[C:2]1[C:3]([CH3:14])=[N:4][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[CH:6]=1.C1COCC1.C([Mg]Cl)(C)C.CO[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1>>[CH3:14][C:3]1[C:2]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:6][N:5]([C@H:7]2[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]2)[N:4]=1
Reactant: Cc1nn([C@H]2CC[C@H](O)CC2)cc1I
Reactant: COB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1nn([C@H]2CC[C@H](O)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-(4-iodo-3-methyl-1H-pyrazol-1-yl)cyclohexanol (150.0 mg, 0.4900 mmol) in THF (9 mL, 100 mmol) was added 2 M isopropylmagnesium chloride in THF (0.7349 mL, 1.470 mmol) at rt, and the mixture was stirred for 30 min. 2-Methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.3212 mL, 1.960 mmol) was added, and the mixture stirred at rt for 2 h. The reaction was quenched with sat. NH4Cl, and the organic solvent was removed in vacuo. The material was extracted with DCM and water, and the organic layer was concentrated in vacuo to afford the title compound as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7](Cl)(=[O:9])=[O:8].[CH3:12][NH2:13]>C(Cl)(Cl)Cl>[CH3:12][NH:13][S:7]([C:6]1[CH:5]=[C:4]([Cl:11])[S:3][C:2]=1[Cl:1])(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Reactant: CN
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1cc(Cl)sc1Cl

Procedure:
3500 ml. of absolute chloroform are placed in a 4 liter volume flask and 533 g. of 2,5-dichlorothiophene-3-sulfonic acid chloride are dissolved therein. Dry methylamine is passed in at 20° with stirring until the solution gives a basic reaction with moistened indicator paper. The solution is stirred for an additional 11/2 hours at room temperature, then extracted several times with 0.5 N HCl in a separating funnel, dried with anhydrous sodium sulfate, and finally concentrated by evaporation in vacuo. The oil thus obtained is placed in a low temperature container, where it crystallizes. The product thus obtained is purified by recrystallization from 1500 ml. of carbon tetrachloride, is dried in a vacuum drying cabinet at 40° and 2,5-dichlorothiophene-3-sulfonic acid methylamide having a melting point of 59°-61° is obtained.
Reaction SMILES: [OH-].[K+].O.[C:4](=S)=[S:5].[NH2:7][C:8]1[CH:14]=[C:13]([Cl:15])[C:12]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:11][C:9]=1[NH2:10]>C(O)C.CO>[Cl:15][C:13]1[C:12]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:11][C:9]2[NH:10][C:4]([SH:5])=[N:7][C:8]=2[CH:14]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(S(N)(=O)=O)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1cc2[nH]c(S)nc2cc1Cl

Procedure:
To 2.9 g of potassium hydroxide dissolved in 45 ml of ethanol and 9 ml of water was added with stirring 4.0 g of carbon disulfide. This solution was then added dropwise to 300 ml of ethanol containing 11.8 g of 2-amino-4-chloro-5-sulfamylaniline. The reaction was refluxed for 5 hours and then concentrated in vacuo to a dark oil. Treatment with 50° C. water provided a solid which was removed by filtration. The filtrate was cooled with ice and acidified to pH 5.0 with acetic acid to yield a gray solid. Trituration of the solid with boiling methanol provided a solid which upon drying gave 5.6 g of pink crystals, m.p. 341°-343°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:12]([F:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([Br:22])=[CH:19][CH:20]=2)=[C:12]([F:21])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
7-Fluoro-6-phenylamino-3H-benzoimidazole-5-carboxylic acid methyl ester 27a (4.99 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL). N-bromosuccinimide (3.15 g, 17.70 mmol) is added as a solid and the reaction mixture is stirred at room temperature under N2. After 30 minutes, the reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution. The reaction mixture is then poured into a reparatory funnel, diluted with water and ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed three times with water, once with brine and then are dried (Na2SO4) and concentrated under reduced pressure to yield 6.38 g (100%) of the pure desired product as a tan solid. MS ESI (+) m/z 364, 366 (M+ Br pattern) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16].[H][H]>[Pd].O1CCCC1>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])=[C:2]([Cl:1])[CH:7]=1
Reactant: [H][H]
Reactant: O=C1OCCN1c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOC2=O)c(Cl)c1

Procedure:
A mixture of 24.1 g of 1B and 0.5 g of 10% palladium-on-charcoal catalyst in 150 ml of tetrahydrofuran was treated with hydrogen in a Parr shaker. The mixture then was filtered to give 3-(4-amino-2-chlorophenyl)-2-oxazolidinone (1C) in solution in the tetrahydrofuran.
Reaction SMILES: [F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3](Cl)=[O:4].[CH3:14][OH:15]>>[F:1][C@@:2]([C:10]([F:13])([F:12])[F:11])([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:15][CH3:14])=[O:4]
Reactant: CO
Reactant: CCCC[C@](F)(C(=O)Cl)C(F)(F)F
Product: CCCC[C@](F)(C(=O)OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.5 ml of methanol was added 0.17 g of (R)-(-)-2-fluoro-2-(trifluoromethyl)hexanoyl chloride, and this mixture was stirred at room temperature for 30 minutes. The resulting reaction mixture was distilled with Kugelrohr under atomspheric pressure, thereby obtaining 0.15 g of methyl (S)-(-)-2-fluoro-2-(trifluoromethyl)hexanoate having the physical properties as mentioned hereinbefore.
Reaction SMILES: O1CCCC1.[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([C:23](=O)[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>O>[C:6]([O:10][C:11]([NH:13][C@:14]12[CH2:22][CH:21]1[CH2:20][C@H:19]1[C@@H:15]2[CH2:16][N:17]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COc1ccc(C(=O)N2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@H]3CC4C[C@]4(NC(=O)OC(C)(C)C)[C@H]3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
A 1M tetrahydrofuran solution (7.0 ml) of a borane-tetrahydrofuran complex (7.0 mmol) was added dropwise to a tetrahydrofuran (20 ml) solution of (1R,2R,6S)-1-t-butoxycarbonylamino-4-p-anisoyl-4-azatricyclo[6.1.0.02,6]nonane (970 ml, 2.60 mmol) while cooling with ice, and the mixture was stirred at room temperature for 1 hour. While cooling with ice, water was added to the reaction mixture to decompose the excess borane-tetrahydrofuran complex. A 1N sodium hydroxide aqueous solution (10 ml) was added thereto, followed by refluxing for 6 hours. After cooling to room temperature, the reaction mixture was extracted with diethyl ether. The extract was dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give 453 mg (1.26 mmol, 48%) of the title compound as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:5][CH:6]=[CH:7][CH:8]=1.Br.[NH+]1C=CC=CC=1.O.C(O)(=O)C.C(OCC)C.B(Br)(Br)[Br:34]>ClCCl>[Br:34][C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:3]([OH:2])=[CH:8][CH:7]=1
Reactant: COc1ccccc1-c1ccc(F)cc1
Reactant: BrB(Br)Br
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4′-fluoro[1,1′-biphenyl]-2-yl methyl ether (107 g), pyridinium hydrobromide perbromide (34.0 g) and water-acetic acid-diethyl ether mixed solution (1:4:5, 500 ml) was stirred for 18 h at room temperature. Hypowater was added to the reaction mixture and the mixture was concentrated. The resulting crystals were collected by filtration to give a crude product (15.2 g) of 5-bromo-4′-fluoro[1,1′-biphenyl]-2-yl methyl ether as a yellow solid. To a solution of this product (14.1 g) in dichloromethane (150 ml) was added dropwise a solution of boron tribromide (5.69 ml) in dichloromethane (40 ml) at −78° C., and the mixture was stirred at room temperature ifor 18 h. The reaction mixture was poured into ice and the organic layer was separated, neutralized with aqueous sodium hydrogen carbonate, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chomatography (eluent;hexane→hexane:ethyl acetate=5:1) to give the title compound (13.2 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([CH3:19])[C:3]=1[CH:20]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([Si](C(C)C)(C(C)C)C(C)C)[CH:26]=[C:25]2[CH:41]([CH3:43])[CH3:42])O.CC(O)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O.O>[CH3:19][C:4]1[CH:5]=[C:6]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:11])[CH3:12])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:20][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH:41]([CH3:43])[CH3:42]
Reactant: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1C(O)c1ccc2c(c1)c(C(C)C)cn2[Si](C(C)C)(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(C)c1Cc1ccc2[nH]cc(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a solution of (2,6-dimethyl-4-triisopropylsilanyloxyphenyl)-(3-isopropyl-1-triisopropylsilyl-1H-indol-5-yl)-methanol (1.86 g, 3.0 mmol) in CH2Cl2 (20 ml) was added tiethylsilane (1.74 g, 15.0 mmol), followed by AcOH (1.11 ml), then TFA (1.11 ml, 15.0 mmol). The reaction was stirred at r.t. for 1 hr, the reaction mixture was diluted with EtOAc and water and the layers were separated. The EtOAc layer was collected and the water layer was further extracted with EtOAc once. The combined organic layers was washed with Sat. NaHCO3, water and brine, dried over MgSO4, filtrated and concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (1:49) to afford 5-(2,6-dimethyl-4-triisopropylsilyloxybenzyl)-3-isopropyl-1H-indole (1.0 g, 74.6%): 1H NMR (200 MHz, CDCl3): δ 7.59 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.97 (s, 1H), 6.70 (s, 1H), 6.63 (d, J=8.2 Hz, 1H), 3.89 (s, 2H), 2.88 (m, 1H), 2.01 (s, 6H), 1.2 (m, 3H), 1.05 (d, J=6.6 Hz, 6H), 0.99 (d, J=6.2 Hz, 18H). TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:49); Rf=0.70.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]#[N:6].S(=O)(=O)(O)[OH:15]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[C:5]([NH2:6])=[O:15]
Reactant: N#Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=S(=O)(O)O
Product: NC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A total of 7.2 g of 3,4-dihydroxy-5-nitro-benzonitrile are introduced portionwise into 130 ml of conc. sulfuric acid while stirring within 10 minutes, whereupon the mixture is stirred at 50° for 4 hours. The reaction mixture is poured into 800 ml of ice-water. The separated precipitate is filtered under suction, washed with water and taken up in ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. After recrystallization from acetone/ethyl acetate there is obtained 3,4-dihydroxy-5-nitrobenzamide in the form of orange crystals of m.p. 235°-236°.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[CH3:17])[N:13]=[CH:12][NH:11][C:10]2=O>>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([N+:18]([O-:20])=[O:19])[C:16]=1[CH3:17])[N:13]=[CH:12][N:11]=[C:10]2[Cl:3]
Reactant: Cc1c(Br)cc2c(=O)[nH]cnc2c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Br)cc2c(Cl)ncnc2c1[N+](=O)[O-]
Temperature: 130 °C
Yield: 70 %

Procedure:
A mixture of phosphorous oxychloride (5 mL) and 6-bromo-7-methyl-8-nitroquinazolin-4(3H)-one (800 mg, 2.82 mmol) was refluxed at 130° C. for 4 h. On cooling, POCl3 was removed under reduced pressure. The resulting crude product residue was diluted with ice-water and extracted out of the aqueous layer with DCM (3×20 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give 6-bromo-4-chloro-7-methyl-8-nitroquinazoline (595 mg, 70% yield) as an amorphous light yellow solid. MS (ESI, pos. ion) m/z: 302 [M+H]+
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH:7]C(OCC1C=CC=CC=1)=O)[CH2:2][CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([NH:4][C:5](=[O:19])[C@@H:6]([CH3:18])[NH2:7])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCNC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCNC(=O)[C@@H](C)N

Procedure:
35.0 Parts of benzyloxycarbonyl-D-alanine n-propylamide is dissolved in ethanol. Then, palladium black catalyst is added and the mixture is shaken at about 60 psi at room temperature for several hours or until one molecular equivalent of hydrogen has been absorbed. The catalyst is removed by filtration, and the resulting solution is decolorized with charcoal. Removal of the solvents under reduced pressure affords, as an oil, D-alanine n-propylamide.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])=[CH:11][C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[C:32](Cl)(=[O:36])[CH2:33][CH2:34][CH3:35]>O1CCCC1.O>[CH2:25]([O:24][C:10]1[CH:11]=[C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH3:20])[CH2:21][CH2:22][CH3:23])[CH:13]=[CH:14][C:9]=1[NH:8][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCCC(=O)Cl
Reactant: CCCN(CCC)CCc1ccc(N)c(OCc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1ccc(CCN(CCC)CCC)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.3 ml of triethylamine is added to 0.65 g of N-[2-(4-amino-3-benzyloxyphenyl)ethyl]-N,N-dipropylamine in 10 ml of tetrahydrofuran, and then 0.23 ml of butyryl chloride is added dropwise thereto. The reaction mixture is stirred for one hour at room temperature, diluted with water, and the product extracted by shaking with methylene chloride, isolating 770 mg of N-[2-benzyloxy-4-(2-dipropylaminoethyl)phenyl]butyramide as an oil from the methylene chloride solution.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:19][CH3:20].[Cl:21][C:22]1[N:23]=[C:24]([C:29](O)=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:21][C:22]1[N:23]=[C:24]([C:29]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:19][CH3:20])=[O:30])[NH:25][C:26]=1[CH2:27][CH3:28]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1cccc(N2CC[C@H](N)[C@H](OC)C2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3cccc(C(=O)OC)c3F)C[C@H]2OC)nc1Cl
Yield: 36.5 %

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-2-fluorobenzoate obtained in Example (263b) (about 0.06 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (9 mg, 0.05 mmol), WSC hydrochloride (34 mg, 0.18 mmol), HOBT (12 mg, 0.09 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 8 mg of the title compound as a colorless oily substance (33%).