Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13](/[CH:14]=[N:32]/[CH:29]4[CH2:31][CH2:30]4)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1/C=N/C1CC1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 61.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.10 g, 0.26 mmol) in THF (5 ml) was added cyclopropanamine (0.03 g, 0.52 mmol) and NaBH(OAc)3 (0.55 g, 0.26 mmol). The reaction was stirred for 3 hours, quenched with aqueous Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse phase column chromatography (5-35% ACN) to give the title compound (0.068 g, 62%). 1H NMR (400 MHz) δ 11.92 (s, 1H), 9.62 (s, 1H), 8.93 (s, 1H), 8.35 (s, 1H), 7.39 (d, J=7.4 Hz, 1H), 7.31-7.27 (m, 2H), 7.16-7.11 (m, 2H), 6.10 (s, 1H), 5.13-5.10 (m, 1H), 2.96-2.94 (m, 1H), 1.89-1.80 (m, 1H), 1.42 (d, J=6.9 Hz, 3H), 0.98-0.88 (m, 2H), 0.76-0.63 (m, 2H). MS: Calcd.: 422. Found: [M+H]+ 423.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([O:26]CC1C=CC=CC=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>CN(C=O)C.CCO.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([OH:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1CCCNC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c2ccc(O)cc2c1CCCNC(=O)OC(C)(C)C
Yield: 41.8 %

Procedure:
5-Benzyloxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (170 mg, 0.37 mmol, 1.0 equiv) was dissolved in the mixture of DMF (3 mL) and EtOH (18 mL) and 30 mg of 20% Pd(OH)2 on carbon was added. The reaction was subjected to 40 psi of hydrogen gas in Parr apparatus for 10 h. The catalyst was filtered off over diatomaceous earth and the ethanol was removed on the rotovap. The residue was taken up in EtOAc and washed 3×20 ml, of brine. The organic layer was dried (Na2SO4), filtered, and evaporated. The crude product is a mixture of starting material and product. The crude residue was purified by flash chromatography on silica using 0% EtOAc in hexanes graded to 30% EtOAc in hexanes as the mobile phase to yield 5-hydroxy-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (56 mg, 41%). This material was used without further manipulation.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClS([N:17]=[C:18]=O)(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.CC#N>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:18]#[N:17])=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) and CH3CN (243 mL) was added dropwise a solution of ClSO2NCO (5 mL, 57 mmol) in CH3CN (39 mL) at 0° C. After addition, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was poured into ice-water, basified with sat. NaHCO3 solution to pH 7-8 and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give 6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=O.[NH2:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:6]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)(CO)C(=O)O
Product: CCOC(=O)C(NC(=O)C(C)(C)CO)C(=O)OCC
Yield: 88 %

Procedure:
Diethyl N(β-hydroxypivaloyl)aminomalonate was prepared (method B) from β-hydroxy pivalic acid and diethyl aminomalonate in 88% yield. The compound was isolated as an oil. NMR 1.13-1.3 (12H, m), 3.5 (2H, br s), 4.16-4.4 (4H, q), 5.1-5.16 (1H, d), 7.6-7.7 (1H, d).
Reaction SMILES: [CH3:1][C:2]1([C:16]([O:18][CH3:19])=[O:17])[C:7](=[O:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.C(O)(=O)C.C([BH3-])#N.[Na+].O>CO>[OH:8][CH:7]1[CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3][C:2]1([CH3:1])[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COC(=O)C1(C)CN(C(=O)OC(C)(C)C)CCC1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
To an ice-cold solution of O1-tert-butyl O3-methyl 3-methyl-4-oxo-piperidine-1,3-dicarboxylate (0.5 g, 1.85 mmol) in MeOH (10 mL) was added acetic acid (0.5 mL) followed by portion wise addition of sodium cyanoborohydride (0.12 g, 1.85 mmol). The mixture was stirred at rt for 4 h. After completion of reaction (by TLC), water (50 mL) was added and extracted with DCM (3×100 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the product as a viscous liquid (0.5 g). MS: 274.13 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CO[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C1C=CC=CC=1>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OCCCc1ccc(Br)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: c1ccccc1
Product: Brc1ccc(CCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A suspension of sodium hydride (60%, 0.97g), 3-(4-bromophenyl)-1-propanol (1.0 g) and benzyl bromide (0.69 mL) in benzene (24 mL) was stirred for 7 hours under reflux. After cooling to ambient temperature, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (40 mL) and brine (40 mL), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=20/1) to give 4-(3-benzyloxypropyl)bromobenzene (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1.F[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1>>[CH3:1][C:2]1[N:3]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)[CH:4]=[C:5]([C:7]#[C:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[N:6]=1
Reactant: Cc1ccc(F)nc1
Reactant: Cc1nc(C#Cc2cccc(C#N)c2)c[nH]1
Product: Cc1ccc(-n2cc(C#Cc3cccc(C#N)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=299.2 (M+H+), was prepared in accordance with the general method of example 1 from 3-(2-methyl-1H-imidazol-4-ylethynyl)-benzonitrile and 2-fluoro-5-methylpyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[N:15]1([CH2:20][C:21](O)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1.O.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>O.CN(C=O)C>[N:15]1([CH2:20][C:21]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)=[O:22])[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: O=C(O)Cn1cncn1
Reactant: Nc1ccc2sc3ccccc3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1cncn1)Nc1ccc2sc3ccccc3c2c1
Yield: 84.3 %

Procedure:
2-Aminodibenzthiophene (Bull. Soc. Chim. Fr. (1 996), 133 (6), 597-610; 500 mg, 2.5 mmol) was dissolved DMF (10 ml) and 2-(1,2,4-triazol-1-yl)acetic acid (318 mg, 2.5 mmol) was added in one portion followed by 1-hydroxybenztriazole hydrate (383 mg, 5.0 mmol) and EDAC (960 mg, 5.0 mmol). The resultant mixture was stirred for 16 hours at ambient temperature then poured on to water (100 ml). A fine white solid was collected which was washed extensively with water, methanol (25 ml) and ether (25 ml) to leave a colourless solid (650 mg). NMR: 10.62 (brs, 1H), 8.18 (m, 2H), 8.16 (m, 3H), 7.99 (m,3H), 7.62 (dd, 1H), 7.50 (m, 2H), 5.20 (s, 2H); m/z 309.
Reaction SMILES: O[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: Cc1c(O)c(C(=O)O)nn(C)c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (876 mg, 4.76 mmol) and POCl3 (4.5 mL) was heated for 24 hours at 85° C. POCl3 was removed under reduced pressure. The crude material was quenched with ice. The reaction mixture was stirred for 1 hour at room temperature. After removing solids by filtration, the aqueous filtrate was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give. The recovered material was combined with the solids previously isolated and triturated with ether to afford 577 mg (60%) of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[C:8](=[O:12])[N:7]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]=1[CH2:20][N:21]([CH2:32][C:33]([O:35][CH3:36])=[O:34])S(C1C=CC(C)=CC=1)(=O)=O)=O.C[O-].[Na+].Cl>CO>[CH3:36][O:35][C:33]([C:32]1[C:3]([OH:2])=[C:5]2[C:6](=[CH:20][N:21]=1)[N:7]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:8](=[O:12])[C:9]([Br:11])=[CH:10]2)=[O:34]
Reactant: COC(=O)CN(Cc1c(C(=O)OC)cc(Br)c(=O)n1CC1CCCCC1)S(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2c(cc(Br)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
5-Bromo-1-cyclohexylmethyl-2-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (4.67 g, 8.01 mmol) was dissolved in 150 mL of MeOH and placed in ice bath. NaOMe solution (5.5 mL, 24 mmol, 4.375 M in MeOH) was added and the mixture was stirred for 16 h at r.t. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (4% EtOAc/CH2Cl2) to give 2.41 g of the title compound as an off-white solid. MS: (+) m/z 395.19, 397.21 (M+1, 79/81Br).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].[BH4-].[Na+]>[Co](Cl)Cl.CO>[NH2:18][CH2:17][C:14]1([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH2:8][N:5]2[C:6]([CH3:7])=[C:2]([Cl:1])[C:3]([C:26]([F:27])([F:29])[F:28])=[N:4]2)[CH2:16][CH2:15]1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(CN)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile (0.11 mmol, 1.00 eq), 80 mg cobalt (II) chloride (0.33 mmol, 3.00 eq), 10 mg NaBH4 (0.22 mmol, 2.00 eq) and 500 uL methanol. The mixture was allowed to stir overnight at room temperature and the crude product was purified by reversed phase HPLC (acetonitrile—H2O with 0.1% TFA as the eluent) to yield 1-[4-aminomethyl-4-(4-chloro-phenyl)-piperidin-1-yl]-2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone. MS (ES) M+H expected=448.0, found=448.1
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[Si:18]([C:22]#[CH:23])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:8][C:6]1[N:7]=[C:2]([C:23]#[C:22][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]([NH2:10])=[N:4][C:5]=1[Cl:9]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1nc(Cl)c(Br)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1nc(Br)c(Cl)nc1N
Temperature: -5 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 3,5-dibromo-6-chloro-pyrazin-2-ylamine (5.0 g, 17.42 mmol) in anhydrous THF (40 mL) was added triethylamine (3.52 g, 34.84 mmol) and CuI (0.333 g, 1.74 mmol). The mixture was degassed with bubbling argon for 10 min then evacuated and back-filled with argon. It was purged thoroughly with argon for 20 min and Pd(PPh3)2Cl2 (0.355 g, 0.52 mmol) was added. The reaction mixture was cooled to −5° C., TMS-acetylene (1.90 g, 19.16 mmol) was added very slowly and the temperature was slowly increased to 15° C. during 3 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were concentrated in vacuo then purified by chromatography (silica, 5% ethyl acetate in hexanes) to give 5-bromo-6-chloro-3-trimethylsilanylethynyl-pyrazin-2-ylamine (4.0 g, 75%) as a yellow solid. LC-MS: 304.0 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:5]=[N:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[OH:37]>>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([O:16][CH3:17])[CH:13]=1)[CH2:9][NH:8][C:6]1[N:7]=[C:2]([C:26]2[CH:25]=[CH:24][C:23]([OH:37])=[C:22]([O:21][CH3:20])[CH:27]=2)[CH:3]=[N:4][CH:5]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: COc1cc(CNc2cncc(Cl)n2)cc(OC)c1
Product: COc1cc(CNc2cncc(-c3ccc(O)c(OC)c3)n2)cc(OC)c1
Yield: 88 %

Procedure:
In a procedure analogous to Example 22, reaction of 6-chloro-N-(3,5-dimethoxybenzyl)pyrazin-2-amine and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol furnished the product (88%).
Reaction SMILES: [CH2:1]1[CH2:25][O:24][C:3]2([CH:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C@H:18]([OH:21])[CH2:19]3)[C@@H:14]3[C@H:5]([C@H:6]4[C@@:10]([CH2:12][CH2:13]3)([CH3:11])[C@@H:9]([OH:23])[CH2:8][CH2:7]4)[CH2:4]2)[O:2]1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:25]1[CH2:1][O:2][C:3]2([CH:20]3[C@:15]([CH3:22])([CH2:16][CH2:17][C:18](=[O:21])[CH2:19]3)[C@@H:14]3[C@H:5]([C@H:6]4[C@@:10]([CH2:12][CH2:13]3)([CH3:11])[C:9](=[O:23])[CH2:8][CH2:7]4)[CH2:4]2)[O:24]1
Reactant: C[C@]12CC[C@H]3[C@@H](CC4(OCCO4)C4C[C@@H](O)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)CC1C1(C[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)OCCO1
Reaction time: 1 h

Procedure:
To a solution of 6,6-ethylendioxyandrostane-3β,17β-diol (0.216 g) in CH2Cl2 (8.7 mL) under N2, NMNO (0.217 g), TPAP (10.8 mg) and 4 Å molecular sieves (0.30 g) were added. The mixture was stirred for 1 h and then SiO2 was added. The mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc 50/50) to give the title compound II-ag (0.154 g, 72%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.04-3.70 (m, 4H), 2.52-0.82 (m, 20H), 1.18 (s, 3H), 0.88 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][NH2:13])=[CH:4][CH:3]=1.[C:14]([C:19]1[C:20](=[O:32])[CH2:21][CH:22]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][C:24]=1[OH:25])(=O)[CH2:15][CH2:16][CH3:17]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][CH2:10][CH2:11][O:12][N:13]=[C:14]([C:19]2[C:20](=[O:32])[CH2:21][CH:22]([CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH2:23][C:24]=2[OH:25])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:7]=1
Reactant: NOCCC#Cc1ccc(F)cc1
Reactant: CCCC(=O)C1=C(O)CC(C2CCOCC2)CC1=O
Product: CCCC(=NOCCC#Cc1ccc(F)cc1)C1=C(O)CC(C2CCOCC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
2.7 g (15 mmol) of 4-(4-fluorophenyl)-but-3-ynoxyamine were added to a solution of 4 g (15 mmol) of 2-butyryl-3-hydroxy-5-tetrahydropyran-4-ylcyclohex-2-enone in 60 ml of drymethanol. The mixture was stirred for 16 hours at room temperature, after which the methanol was removed under reduced pressure from a water pump. The crude product was purified by chromatography over silica gel (mobile phase: methylene chloride). Yield: 81.2%.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[OH:14].[C:15](=O)([O-])[O-].[K+].[K+].N>O1CCCC1>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[CH:9]=[CH:8][C:7]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Oc1ccnc2ccc(F)cc12
Agent: N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1ccc(=O)c2cc(F)ccc21
Reaction time: 18 h

Procedure:
Iodomethane (6.9 ml) was added to a stirred suspension of 6-fluoro-4-hydroxyquinoline (16.3 g) and anhydrous potassium carbonate (15.2 g) in dry tetrahydrofuran (100 ml) at ambient temperature and stirring was continued for 18 hours. More iodomethane (1.8 ml) and anhydrous potassium carbonate (3.8 g) were added and stirring was continued for 4 hours at ambient temperature. Concentrated aqueous ammonia (specific gravity 0.88; 100 ml) was added and the mixture was evaporated to dryness. The residue was treated with water (200 ml) and extracted with dichloromethane (2×400 ml). The extract was dried and evaporated to dryness. The residue was crystallised from ethyl acetate to give the novel compound 6-fluoro-1-methyl-4-quinolone, m.p. 88°-89°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:23])=[C:4]([N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:9][C:10]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2cccc(Cl)c2C)cc1
Reactant: COc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
707 mg of N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine was dissolved in 8.00 mL of DMF, and 302 mg of 4-methoxybenzylamine, 324 mg of HOBt, and 460 mg of WSC were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 881 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)-N2-[(4-methylphenyl)sulfonyl] glycinamide.
Reaction SMILES: [C:1]([NH:4][NH:5][CH:6]1[CH:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:8]2=[N:7]1)(=O)[CH3:2].C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:2][C:1]1[N:7]2[C:8]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1
Reactant: CC(=O)NNC1C=NC(c2ccccc2)=c2cc(Cl)ccc2=N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 92.5 °C
Reaction time: 4.5 h
Yield: 80 %

Procedure:
2-(2-acetyl hydrazino)-7-chloro-5-phenyl-2H-1,4 benzodiazepine (117.5 g; 0.36 mole) and toluene (11.75 mole.) were added to a RB flask. 0.94 mole of toluene was distilled out at 110-112° C. The reaction mixture was cooled to 90-95° C. and charged with p-toluene sulphonic acid (0.0012 mole). The reaction mixture was then refluxed at 105-110° C. for 10-12 hrs with a Dean-Stark apparatus for water removal. At the end of the reaction (as indicated by TLC), reaction mixture was cooled to 25-30° C. The reaction mass was then further cooled to 10-15° C. and stirred at same temperature for 4-5 hrs. The solids precipitated were filtered and washed with cold toluene to obtain crude 8-chloro-1-methyl-6-phenyl-4H-s-trizolo[4 3-I][1,4] benzodiazepine (alprazolam). The crude alprazolam was purified from isopropanol to obtain 80% yield of pure alprazolam.