Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl)[CH:13]([CH3:15])[CH3:14].C(OCC)C>C(O)C>[CH2:12]([NH:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][S:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CNc1ccccc1CCl
Reactant: Sc1nc2ncccc2[nH]1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CC(C)CNc1ccccc1CSc1nc2ncccc2[nH]1
Yield: 49.3 %

Procedure:
To a dispersion of 0.96 of 2-mercaptoimidazo[4,5-b]pyridine in 30 ml of ethanol was added at once 1.5 g of 2-(isobutylamino)benzyl chloride hydrochloride at room temperature under stirring. The resulting mixture was further stirred for one hour. To the mixture was added 30 ml of diethyl ether, and the precipitated crystals were collected by filtration and washed with a mixture of ethanol and diethyl ether (1/1 in volume). The obtained powdery product was added portionwise to a mixture of 30 ml o fchloroform and 30 ml of a saturated NaHCO3 solution for neutralization. The organic phase was separated, washed with a saturated aqueous sodium chloride solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was crystallized by addition of diethyl ether and hexane. The crystalline product was collected by filtration, washed with a mixture of diethyl ether and hexane (1/1 in volume) and dried to give 985 mg (yield: 49.3%) of 2-[2-(isobutylamino)benzylthio]imidazo[4,5-b]pyridine as a white crystalline powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=2)=[N:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:14])[CH2:9][C:8]=12)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:35][C:31]1[CH:30]=[C:29]([C:5]2[C:4]([C:1]([NH2:2])=[O:3])=[C:8]3[CH2:9][N:10]([C:13]([NH:15][CH:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]4)=[O:14])[CH2:11][CH2:12][N:7]3[N:6]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)N2CCn3nc(-c4cccc(F)c4)c(C(N)=O)c3C2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(-c2cccc(F)c2)nn2c1CN(C(=O)NC1CCNCC1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of Intermediate 97A (300 mg, 0.617 mmol) in DCM (3 mL) was added TFA (0.238 mL, 3.08 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the resultant residue was basified to pH=8.0 with 10% NaHCO3 solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic layer was washed with water (2×5 mL), brine, dried over Na2SO4, filtered and concentrated to afford Intermediate 97B (200 mg, 80%) as white solid. MS(ES): m/z=387 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.50 (bs, 1H), 7.46 (m, 3H), 7.32 (bs, 1H), 7.21 (m, 1H), 7.11 (bs, 1H), 6.86 (d, J=7.03 Hz, 1H), 4.74 (s, 2H), 4.15 (t, J=5.27 Hz, 2H), 3.86 (t, J=5.27 Hz, 2H), 3.72 (m, 1H), 3.27 (s, 2H), 2.96 (m, 2H), 1.93 (m, 2H), 1.54 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:28].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[CH:34]2.[OH-].[Na+]>>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH2:17][N:14]1[CH2:15][CH2:16][C:11]2([CH2:10][C:9](=[O:28])[C:8]3[C:25](=[CH:26][CH:27]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:2])=[O:29])[CH:7]=3)[O:24]2)[CH2:12][CH2:13]1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccc(F)cc34)CC1)O2
Yield: 63 %

Procedure:
(E)-3-{1′-(5-Fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester was obtained starting from (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (135 mg, 0.45 mmol, Intermediate 1, free base) and 5-fluoro-1H-indole, according to the procedure described in Example 50, Step A (170 mg, 85%). The methyl ester was hydrolyzed with 4 M NaOH following the procedure described in Example 40, Step B, giving (E)-3-{1′-(5-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid (100 mg, 63%). The resulting product was treated with NH2OTHP according to the procedure described in Example 40, Step C, giving (E)-3-{1′-(5-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide. Finally, removal of the THP protecting group following the procedure described in Example 40, Step C gave (E)-3-{1′-(5-fluoro-1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride (76 mg) as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:21])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][S:12][C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>>[OH:21][C:7]1[C:6]([C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5])=[N:11][CH:10]=[C:9]2[S:12][N:13]=[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=12
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2snc(-c3ccccc3)c2c1O
Product: O=C(O)CNC(=O)c1ncc2snc(-c3ccccc3)c2c1O

Procedure:
Prepared in analogy to Example 1 from 4-hydroxy-3-phenyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and glycine; MS (m/z): 330.09 (M+H+).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>[Pt]>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(Sc2c(NCC(C)C)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccc(N)cc1

Procedure:
The mixture of 3.5 g of 4-(4-acetamidophenylmercapto)-3-isobutylamino-5-sulfamoylbenzoic acid, 35 ml of 2 N aqueous sodium hydroxide and some colloidal platinum is refluxedfor 1 hour under nitrogen, during which time the platinum coagulates. Aftercooling it is filtered, the filtrate acidified with acetic acid to a pH of 4-5, the precipitate formed is filtered off and recrystallized from aqueous ethanol, to yield the 4-(4-aminophenylmercapto)-3-isobutylamino-5-sulfamoylbenzoic acid melting at 250°-252°.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[N:12].[NH2:14][OH:15]>CCO>[CH3:13][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11](=[N:14][OH:15])[NH2:12]
Reactant: NO
Reactant: CN(C)CCOCCOCCC#N
Solvent: CCO
Product: CN(C)CCOCCOCCC(N)=NO
Yield: 90.2 %

Procedure:
A solution of 3-(2-(2-(dimethylamino)ethoxy)ethoxy)propanenitrile (0.5 g, 2.68 mmol) and NH2OH (50% in water, 0.25 cm3, 4 mmol) in EtOH (10 cm3) were stirred at 80° C. for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line for several hours to give give 3-(2-(2-(dimethylamino)ethoxy)ethoxy)-N′-hydroxypropanimidamide (0.53 g, 90.1%) as a light yellow oil.
Reaction SMILES: CCOCC.[CH:6]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16])[CH2:8][CH2:7]1.[CH2:18]([OH:28])[C:19]#[C:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[CH:25]1([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:18]([O:16][CH2:15][C:14]#[C:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:6][CH2:7][CH3:8])=[O:28])[CH2:27][CH2:26]1
Reactant: O=C(Cl)CCCCCCC1CC1
Reactant: CCCCCCCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCC#CCOC(=O)CCCCCCC1CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 60 ml. anhydrous ether and 1.5 g. 7-cyclopropylheptanoyl chloride is added 1.2 g. 2-decyn-1-ol. The mixture is cooled to 0° and 0.8 ml. pyridine is added. The solution is stirred at room temperature for 1 day. The product is worked up using the procedure of Example 1C to yield 2-decynyl 7-cyclopropylheptanoate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])=O)[S:5][CH:6]=1.[NH2:18][NH2:19]>C(O)C>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:9]3[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:11](=[O:12])[NH:19][N:18]=2)[S:5][CH:6]=1
Reactant: Cc1csc(C(=O)c2ccccc2C(=O)O)n1
Reactant: NN
Solvent: CCO
Product: Cc1csc(-c2n[nH]c(=O)c3ccccc23)n1
Temperature: 25 °C

Procedure:
A RBF set up with stirring bar and reflux condenser was charged with 2-(4-methylthiazole-2-carbonyl)benzoic acid (1.9 g, 7.7 mmol), hydrazine (1.3 mL, 226.9 mmol), and ethanol (40 mL, 0.2 M) while kept under nitrogen atmosphere. The reaction mixture was stirred under reflux overnight, then cooled to RT. The resulting precipitate was filtered off and washed with DCM to afford 4-(4-methylthiazol-2-yl)phthalazin-1(2H)-one. MS m/z=244 [M+H]+. Calc'd for C12H9N3OS: 243.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH:17]=O)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21].[NH:22]1[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]1.CC(O)=O.[BH3-]C#N.[Na+]>CO.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([CH:19]=2)[CH2:17][N:22]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23]2)[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:21]
Reactant: O=C(O)C1CNC1
Reactant: CCC(Nc1ccc(C)c(C=O)c1)c1ccc(Cl)c(C)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCC(Nc1ccc(C)c(CN2CC(C(=O)O)C2)c1)c1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of INT 9 (200 mg, 0.66 mmol) and azetidine-3-carboxylic acid (67 mg, 0.66 mmol) in MeOH (6.5 mL) was added HOAc (0.038 mL, 0.66 mmol) followed by NaCNBH3 (42 mg, 0.66 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by preparative HPLC (H2O/CH3CN) to afford the title compound Example 4.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:39]=[C:38]([CH3:40])[C:29]3[NH:30][C:31]([CH:33]4[CH2:37][CH2:36][O:35][CH2:34]4)=[N:32][C:28]=3[CH:27]=2)[CH:20]=1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:40][C:38]1[C:29]2[NH:30][C:31]([CH:33]3[CH2:37][CH2:36][O:35][CH2:34]3)=[N:32][C:28]=2[CH:27]=[C:26]([O:25][C:21]2[N:22]=[CH:23][N:24]=[C:19]([N:14]3[CH2:13][CH2:12][C:5]4([O:4][C:3](=[O:17])[NH:2][C:7]5[N:8]=[CH:9][CH:10]=[CH:11][C:6]4=5)[CH2:16][CH2:15]3)[CH:20]=2)[CH:39]=1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2nc(C3CCOC3)[nH]c12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC4(CC3)OC(=O)Nc3ncccc34)ncn2)cc2nc(C3CCOC3)[nH]c12
Temperature: 0 °C

Procedure:
138 mg (0.54 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 180 mg (0.54 mmol) 5-(6-chloropyrimidin-4-yloxy)-7-methyl-2-(tetrahydrofuran-3-yl)-1H-benzo[d]imidazole and 280 μL (1.62 mmol) DIPEA in 5.0 mL DMF were stirred overnight at 60° C. The reaction mixture was combined with ice water. The precipitate formed was suction filtered and purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with an aqueous NaHCO3 solution and extracted with ethyl acetate. The organic phase was dried and evaporated down i.vac.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17]N1C(=O)CCC1=O>C(#N)C>[Br:17][C:10]1[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH:11]=1
Reactant: CCOC(=O)c1nccn1CCCCOC
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)cn1CCCCOC
Temperature: 60 °C
Reaction time: 14 h
Yield: 23.5 %

Procedure:
Ethyl 1-(4-methoxybutyl)-1H-imidazole-2-carboxylate (2.18 g) was dissolved in acetonitrile (30 ml), N-bromosuccinimide (1.71 g) was added and the mixture was stirred at 60° C. for 14 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-70:30) was concentrated under reduced pressure to give the object product (689 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CCC(C)=O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([NH:18][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:16][CH:17]=2)[N:6]=1
Reactant: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1nc(NS(C)(=O)=O)ccc1Oc1nc(OC)cc(OC)n1
Yield: 19.7 %

Procedure:
3.1 g (10 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-aminopicolinate, 2.4 g (21 mmol) of methanesulfonyl chloride and 1.5 g (11 mmol) of potassium carbonate were added to 10 ml of MEK, and the mixture was stirred and refluxed for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residual oily product was purified by column chromatography and then crystallized from diisopropyl ether to obtain the desired product as a slightly yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>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.O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(-c4ccccc4)c23)C1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
Intermediate 1 (228 mg) obtained in Example 1, Step A is added with phenylboronic acid (122 mg, Aldrich), tetrakis(triphenylphosphine)palladium(0) (116 mg), 1,2-dimethoxyethane (5 ml) and 2 N aqueous sodium carbonate (2 ml), and the mixture is refluxed by heating for 5 hours under a nitrogen gas atmosphere. The reaction mixture is cooled to room temperature, then added with water (25 ml), and extracted 3 times with ethyl acetate (20 ml for each time), and the combined organic layer is washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (158 mg (predictive yield)).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)CCc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33 %

Procedure:
To a solution of methyl 3-(1H-indol-2-yl)propanoate (800 mg, 3.94 mmol) in dry DMF (10 mL) was added NaH (300 mg, 7.50 mmol) at 0° C. After 15 min, MeI (0.40 mL, 6.40 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (50 mL×3). The combined organic phase was dried over sodium sulfate, filtered, and concentrated. Purification via flash chromatography then afforded the title compound (332 mg, 1.299 mmol, 85% purity, 33% yield). LCMS: rt=3.17 min, [M+H+]=218.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCOCC>C1(C)C=CC=CC=1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]2[O:4][C:3](=[O:5])[C@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[O:1]2)=[CH:13][CH:12]=1
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)C[C@@H]1OC(c2ccc(Br)cc2)OC1=O
Reaction time: 1 h

Procedure:
(2S)-2-hydroxy-4-methylpentanoic acid (46.4 g, 351 mmol) and 4-bromobenzaldehyde (50 g, 270.2 mmol) were dissolved in 400 ml toluene and pyridinium 4-methylbenzenesulfonate (340 mg, 1.35 mmol) was added. The mixture was refluxed in a Dean-Stark for 24 hours. The mixture was cooled, poured into 500 ml NaHCO3(sat) and 500 ether, the phases were separated and the organic phase washed with 500 ml NaHCO3(sat.) and brine. The organic phase was dried with Na2SO4 and the solvent striped. 400 ml Hexane was added to the resulting solid and the mixture was stirred 1 hour in salt ice bath. The solution was filtered thru Celite, and the solvent removed. (5S)-2-(4-bromophenyl)-5-isobutyl-1,3-dioxolan-4-one (3:2 mixture of cis/trans) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:33])([CH3:32])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:35]=[CH:34][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][Si:13]([CH3:33])([CH3:32])[O:14][Si:15]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[CH:27][CH:28]=2)([CH3:16])[CH3:17])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: C[Si](C)(CCCCOc1ccc([N+](=O)[O-])cc1)O[Si](C)(C)CCCCOc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: C[Si](C)(CCCCOc1ccc(N)cc1)O[Si](C)(C)CCCCOc1ccc(N)cc1

Procedure:
1,3-bis[4-(4-nitrophenoxy)butyl]-1,1,3,3-tetramethyldisiloxane (2a) (1.35 g; 3.38 mmol) and 10 mL of a 10 wt % Pd/C (0.0393 g) ethyl acetate solution were mixed, and stirred for 2 days in a hydrogen atmosphere at room temperature. The solution was filtrated by Celite and then concentrated to obtain a colorless oily material (1.18 g, 98% of yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]#[N:9].[S:10]([O-])([O-:12])=[O:11].[Na+:14].[Na+]>CCO.O>[Na+:14].[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:10]([O-:12])=[O:11])#[N:9]
Reactant: N#CCCCCCCBr
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCCCCCCS(=O)[O-]
Yield: 36 %

Procedure:
In a three necked flask, fitted with a water condenser, a mechanical stirrer and a dropping funnel was placed a solution of 1-bromo-6-cyanohexane (8.04 g, 42.3 mmol) in 75 mL of 95% EtOH was prepared. The mixture was heated to reflux and to it was slowly added a solution of sodium sulfite (8.00 g, 63.5 mmol) in 50 mL of H2O over a period of 30 min. The mixture was heated for 2 h and then concentrated under reduced pressure. The residue was dissolved in 95% EtOH (200 ml), heated to boiling and filtered. The filtrate was concentrated and cooled in an ice bath. The precipitate was collectedby filtration and dried to give 3.00 g of a white solid. The mother liquor on further concentration, produced another batch of 2.2 g of the product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[C:22]([CH2:23][N:24]3C(=O)C4=CC=CC=C4C3=O)=[N:21][N:20]=[C:19]2[CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[C:6]([CH:17]=1)[C:7]([C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[F:16])=O.O.NN>C(O)C>[CH3:39][N:37]([CH3:38])[CH2:36][CH2:35][C:19]1[N:18]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[C:7]([C:9]3[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=3[F:15])=[N:24][CH2:23][C:22]2=[N:21][N:20]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1c(F)cccc1F
Agent: NN
Solvent: CCO
Solvent: O
Product: CN(C)CCc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 1C, 5-chloro-2',6'-difluoro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine hydrate to give 1-[2-(dimethylamino)ethyl]-8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine. This compound is converted to its hydrochloride by treating it with ethereal hydrogen chloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:5][CH:4]([CH3:6])[CH2:3][CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CC(C)CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.3 %

Procedure:
1-Bromo-3-methylbutane (7.07 g, 5.60 mL, 46.8 mmol) was added in one portion to a stirred suspension of 4-nitrophenol (5.00 g, 35.9 mmol) and potassium carbonate (5.46 g, 49.5 mmol) in dimethylformamide (50 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h then the volatiles were evaporated. The residue was partitioned between diethyl ether (50 mL) and water (50 mL) and the phases separated. The aqueous phase was extracted with ether (2×50 mL) then the organic extracts were combined and dried (magnesium sulfate). The solvent was evaporated and the residue chromatographed on silica gel (10% diethyl ether:cyclohexane) to give the title compound as a pale yellow oil (6.63 g, 88%). LC/MS: 3.69 min. 1H NMR (400 MHz; CDCl3): 0.95 (6H), 1.75 (2H), 1.85 (1H), 4.05 (2H), 6.95 (2H), 8.20 (2H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([NH:20][C@@H:21]([CH3:37])[CH2:22][N:23]2[CH:27]=[CH:26][C:25]([C:28]3[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=3)=[N:24]2)=[O:11])[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: CC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-acetyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (300 mg, 1.05 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzo-nitrile (273 mg, 1.05 mmol). The product was purified with flash-chromatography. Yield 366 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.09 (s, 9H), 0.81 (t, 2H), 1.15 (d, 3H), 2.6 (s, 3H), 3.49 (t, 2H), 4.31-4.47 (m, 3H), 5.66 (s, 2H), 6.95 (s, 1H), 7.85 (d, 1H), 7.92-7.97 (m, 2H), 8.06 (s, 2H), 8.17 (d, 1H).