Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1-benzyl-3-methyl-4-piperidone (2.0 g, 9.8 mmol) in THF at about −78° C. under argon, was added Lithium diisopropylamide (7.35 mL, 14.7 mmol, 2 M in heptane/THF/ethylbenzene). After stirring for about 1 hour at about −78° C., iodomethane (0.73 mL, 11.8 mmol) was added. The reaction mixture was stirred for about 1 hour at about −78° C., then warmed to room temperature. Stirring was continued overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel, eluting with EtOAc/hexane (3:10) to give a yellow oil of the title compound.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH2:11](Br)[CH2:12][CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([N+:7]([O-:9])=[O:8])=[CH:1][CH:2]=1)[CH2:12][CH2:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of p-nitrophenol (56.0 g. 0.4 mole) in acetone (400 ml.) was added n-butyl bromide (60.0 g., 0.44 mole) and potassium carbonate (anhydrous, 56.0 g., 0.4 mole). The mixture was heated on the steam bath for 48.0 hours. The acetone was removed from the reaction mixture in vacuo. Then, water (400 ml.) was added to the residue, which was extracted twice with benzene (200 ml. portions). The benzene layers were washed thrice with 10% sodium hydroxide solution (150 ml. portions). The washed layers of benzene were then dried over anhydrous potassium carbonate and the solvent was removed in vacuo. The product obtained after evaporation of the solvent was a crude yellow liquid (63.0 g. 79%). This was used in Part B without further purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[C:31]=1[O:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]=[O:9]
Reactant: O=CN1CCC[C@H]1CO
Reactant: Cc1cccc(C)c1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(C)c1OC[C@@H]1CCCN1C=O
Reaction time: 0.17 h

Procedure:
A mixture of (3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-((S)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone (2.0 g; 7.7 mmol), which was prepared as described in example P8, triphenylphosphine (2.1 g; 8.0 mmol) and 2,6-dimethylphenol (0.94 g; 7.7 mmol) in dry THF (30 ml) was cooled in an ice-bath. Diisopropyl azocarboxylate (1.60 g; 8.0 mmol) in dry THF (15 ml) was added dropwise, with stirring under nitrogen atmosphere over 10 minutes. The reaction mixture was stirred at ambient temperature for 6 hours. After removal of the solvent in vacuo, the residue (6.81 g) was purified by flash chromatography using silica gel (eluent: cyclo hexane/ethyl acetate 2:8). 1.31 g (46.8% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)-[(S)-2-(2,6-dimethyl-phenoxymethyl)-pyrrolidin-1-yl]-methanone (compound 1.225) was obtained in form of a white solid m.p. 137-140° C.
Reaction SMILES: [OH-].[Na+].[NH2:3][CH2:4][C@H:5]1[O:9][C@@H:8]([N:10]2[CH:17]=[C:16]([CH2:18][CH3:19])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[OH:20].[C:21]1([CH:27]([CH2:31][CH3:32])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:18]([C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:8]1[O:9][C@H:5]([CH2:4][NH:3][C:28](=[O:29])[CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:31][CH3:32])[C@@H:6]([OH:20])[CH2:7]1)[CH3:19]
Reactant: CCC(C(=O)Cl)c1ccccc1
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(CC)c3ccccc3)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
1.25 ml of 1M sodium hydroxide solution were added to 0.255 g of 5'-amino-2',5'-dideoxy-5-ethyluridine in 5 ml of water and then 0.2 g of 2-phenylbutyryl chloride was added to the mixture. The resulting mixture was shaken for 10 minutes, whereby a white solid was deposited. This solid was collected by filtration, washed three times with 5 ml of water each time, dried at 50° C. in vacuo over phosphorus pentoxide and recrystallized from ethanol to give 0.28 g of 2',5'-dideoxy-5-ethyl-5'-(2-phenylbutyramido)uridine of melting point 235°-236° C.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:47]([N:10]1[C:11]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OCCOc1nn(Cc2ccccc2)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(Cc3ccccc3)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.1 %

Procedure:
To a stirring solution of 2-{[1-benzyl-5-(bis{[4-(tert-butyl)phenyl]sulfonyl)amino)-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 40) (1.01 g) in ethanol (20 ml) was slowly added sodium hydroxide solution (2M, 2 ml). The reaction mixture was left stirring at room temperature overnight. The solvent was removed in vacuo and the residue was taken up in ethyl acetate (30 ml) and washed with water (15 ml) followed by brine (15 ml). It was then dried (MgSO4) and the solvent removed in vacuo to yield the crude material as a yellow oil (ca.1 g). Purification was achieved using the Biotage™ Flash 40 system (silica, 90 g) with a gradient elution of hexane (75% to 65%) and ethyl acetate (25% to 35%) to yield the title product as a yellow solid (250 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH:26][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]3)=[C:4]([O:14][CH3:15])[CH:3]=2)=[N:22]1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2ncn(Cc3cccc(Cl)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 1b) starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole (WO2009076352) and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine from example 7a). The title compound was obtained as a slightly yellow solid (Yield=13%). MS ISP (m/e): 395.2 (100) [(M+H)+].
Reaction SMILES: N1CCCCC1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:9]=1[NH:15][C:16]([CH:18]1[C:26]([CH3:28])([CH3:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]1[C:29](=[O:52])[C@@H:30]([NH:34]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH:31]([CH3:33])[CH3:32])=[O:17]>C(Cl)Cl>[NH2:34][CH:30]([CH:31]([CH3:33])[CH3:32])[C:29]([N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]([CH3:28])([CH3:27])[C@H:18]1[C:16]([NH:15][C:9]1[C:10]([F:14])=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])=[O:17])=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CC(C)C(N)C(=O)N1c2ccccc2C(C)(C)[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
Piperidine (0.1 mL, 1.01 mmol, Eq: 9.86) was added to a solution of (S)-(9H-fluoren-9-yl)methyl 1-(2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (71 mg, 102 μmol, Eq: 1.00) in DCM (2 mL) and the resulting solution was stirred at rt for 3 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give (S)-1-(2-amino-3-methylbutanoyl)-N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (32 mg).
Reaction SMILES: C[Si](C)(C)[O:3][NH2:4].C(=O)([O-])O.[Na+].[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[CH:19][C:20]2[S:25][C@@H:24]([CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C:23](=[O:37])[N:22]([CH2:38][C:39](O)=[O:40])[C:21]=2[CH:42]=1)=[O:16])[CH3:13]>C1COCC1.ClC(OCC(C)C)=O.CN1CCOCC1>[OH:3][NH:4][C:39](=[O:40])[CH2:38][N:22]1[C:21]2[CH:42]=[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])[CH:18]=[CH:19][C:20]=2[S:25][CH:24]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[C:23]1=[O:37]
Reactant: C[Si](C)(C)ON
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)[C@H](CCCc1ccc(OC)cc1)S2
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
In THF (40 ml) was dissolved {(2S)-6-(ethoxycarbonyl)-2-[3-(4-methoxyphenyl)propyl]-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl}acetic acid (the compound of Reference Example 11) (2.06 g), and isobutyl chloroformate (0.72 ml) and N-methylmorpholine (0.51 ml) were added thereto at −20° C. and stirred at −10 to −20° C. for 30 minutes. After O-(trimethylsilyl)hydroxylamine(0.87 ml) was added thereto, the resulting mixture was warmed up to room temperature and stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogencabonate solution and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to obtain (−)-ethyl 4-[2-(hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate (1.69 g, 99.9% e.e.). The optical purity analysis conditions are as follows. [Column: AD-H(CHIRALCEL, DAICEL Chemical Industries Ltd.); detecting wavelength (UV): 254 nm; flow rate: 1.0 ml/min; mobile phase: n-hexane/isopropyl alcohol/TFA=80/20/0.1]
Reaction SMILES: [NH:1]([C:8]1[N:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([OH:23])=O)[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=N[CH2:36][CH2:37][CH2:38][N:39](C)C.C1C=CC2N(O)N=NC=2C=1.C1(N)CC1>C(Cl)Cl>[NH:1]([C:8]1[N:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([S:19][CH2:20][C:21]([NH:39][CH:38]1[CH2:36][CH2:37]1)=[O:23])[N:13]=[C:12]([CH3:24])[CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(c(SCC(=O)O)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Reactant: CCN=C=NCCCN(C)C
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc2c(c(SCC(=O)NC3CC3)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of [(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]acetic acid (20 mg, 0.05 mmol), EDCI (18 mg, 0.10 mmol), HOBT (13 mg, 0.10 mmol) and cyclopropylamine (0.004 mL, 0.06 mmol) in CH2Cl2 (5 mL) was added TEA (0.02 mL, 0.14 mmol). The reaction solution was stirred at room temperature for 24 h before the mixture was diluted with CH2Cl2, washed with 0.5N HCl, saturated aqueous NaHCO3, brine and dried over Na2SO4. Solvents were removed in vacuo and the residue was purified by reverse-phase preparative HPLC (10% CH3CN in water with 0.1% TFA to 95% CH3CN in water, 10 mL/min, 10 min) to provide 2-[(2-anilino-7-methyl-4-oxo-1-phenyl-1,4-dihydro-1,6-naphthyridin-5-yl)sulfanyl]-N-cyclopropylacetaide (13 mg, 59%): LCMS RT: 2.55 min, MH+: 457.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][Cl:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCC1CCCN1Cc1ccccc1
Temperature: 25 °C

Procedure:
Into a 5,000 ml 3-necked roundbottom flask, was placed a solution of (1-benzylpyrrolidin-2-yl)methanol (250. g, 1.30 mol) in chloroform (2,500 ml). This was followed by the dropwise addition of a solution of thionyl chloride (232. g, 1.95 mol) in chloroform (500 ml), while maintaining the internal temperature at room temperature (60 minute addition time). The resulting solution was heated to reflux for 2 hours. After cooling to ambient temperature, the mixture was concentrated, and the resulting residue was dissolved in 3,000 ml of ethyl acetate. Adjustment of the pH to 7 was accomplished by the addition of triethylamine. The resulting mixture was filtered and the filtrate was concentrated and the residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford 1-benzyl-2-(chloromethyl)pyrrolidine.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]([CH3:27])([N:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][C:24]=3[C:14]=2[C:13]1=[O:26])[C:10]#[N:11])([CH3:8])[CH3:7].[OH-].[Na+].CC[O:32]CC>C(Cl)Cl.C(OCC)(=O)C>[CH:6]([C:9]([CH3:27])([N:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][C:24]=3[C:14]=2[C:13]1=[O:26])[C:10]([NH2:11])=[O:32])([CH3:8])[CH3:7]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
Concentrated sulfuric acid (5.50 mL) is added slowly to a solution of 3,6-dihydro-α-isopropyl-α,6-dimethyl-1,3-dioxobenzo[1,2-b:3,4-c']dipyrrole-2(1H)-acetonitrile (5.50 g, 19.0 mmol) in methylene chloride at 10° C. Crushed ice is added. The mixture is stirred for 24 hours at ambient temperature and poured onto crushed ice, treated with 6N sodium hydroxide to pH 2, and extracted with methylene chloride. The organic layer is separated, dried (MgSO4) and concentrated in vacuo to give an orange foamy residue. Flash chromatography (silica gel, ether then ethyl acetate eluents) affords the title product as a yellow foam (1.53 g, 25.7%), mp 159°-168° C.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:42][C:34]4[CH:33]=[N:32][C:41]5[C:36]([CH:35]=4)=[CH:37][CH:38]=[CH:39][CH:40]=5)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1cnc2ccccc2c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4cnc5ccccc5c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added quinoline-3-carboxaldehyde (13 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[H-].[Na+].Cl[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=1>O>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:9][CH:8]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Fc1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cccnc1OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To an N,N-dimethylformamide (15 mL) solution of (4-bromo-phenyl)-methanol (1.56 g, 8.34 mmol) was added sodium hydride (401 mg, 8.35 mmol, 50% in oil), which was stirred for 5 minutes at room temperature. Then, an N,N-dimethylformamide (5 mL) solution of 2-chloro-3-fluoropyridine (967 mg, 7.35 mmol) was added to this mixture, which was stirred for 1 hour and 10 minutes at room temperature. Water was to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the title compound (2.03 g, 98%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.B(O)(O)[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[S:23][CH:22]=1>>[S:23]1[CH:22]=[C:21]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[CH:18][NH:17][N:16]=3)[N:3]=2)[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3csc4ccccc34)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and thianaphthene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 373(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:2]([CH3:4])[CH3:1])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:12]=2[CH:29]=1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 1 h

Procedure:
A stirred solution of N,N-dimethylhydroxylamine (3.67 g., 0.06 mole) in dry dimethylformamide (50 ml. is cooled in an ice bath, under nitrogen, and treated with a 57% mineral oil suspension of sodium hydride (0.84 g., 0.02 mole). The mixture is kept at ambient temperature for 1 hour (a precipitate formed) and then cooled in an ice bath and treated with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine (6.86 g., 0.02 mole). The mixture is kept at ambient temperature for 2 hours and concentrated in vacuo. Last traces of dimethylformamide are removed from the residue by the successive addition and distillation of xylene, toluene, and benzene. The resulting material is chromatographed on silica gel (250 g.) with methanol. The product thus obtained is crystallized from methanol-ethyl acetate (following activated charcoal treatment) to give 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide, hydrate in three crops: 3.377 g. of melting point 160.5°-162.5° C; 1.145 g. of melting point 160°-162° C.; and 0.785 g. of melting point 160°-162° C. The analytical sample had a melting point of 157.5°-158.5° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].C1COCC1.[CH2:19]([NH2:21])[CH3:20]>ClCCl>[CH2:19]([NH:21][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:20]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CCN
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCNC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Alternatively, 2-chloro-5-nitrobenzoyl chloride (10 g, 45.5 mmol) in anhydrous dichloromethane (250 mL) with Amberlyst A-21 ion-exchange resin (17 g) was treated with a 2M THF solution of ethylamine (45 mL). The mixture was stirred at rt under nitrogen overnight. After filtration, the filtrate was concentrated to give N-ethyl-2-chloro-5-nitrobenzamide (9.0 g, 39 mmol, 86% yield) as a yellow solid.
Reaction SMILES: C(OC([O:11][C:12]1[N:13]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([Cl:21])=[CH:16][CH:15]=2)=O)C1C=CC=CC=1.N.O1CCOCC1>[Cl-].[Na+].O>[Cl:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C:12](=[O:11])[CH2:20]2
Reactant: O=C(OCc1ccccc1)Oc1cc2cc(Cl)ccc2n1C(=O)OCc1ccccc1
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Cc2cc(Cl)ccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 59 %

Procedure:
Benzyl 2-{[(benzyloxy)carbonyl]oxy}-5-chloro-1H-indole-1-carboxylate, intermediate 37 (5.00 g; 11.47 mmol) was treated with a solution of ammonia in dioxane (25.2 ml; 0.50 M; 12.6 mmol) and stirred overnight. Brine was added and the mixture extracted with ethyl acetate. The organic phase was dried (MgSO4) and removed in vacuo, to give a solid residue which was purified by recrystallisation (ethyl acetate), to give the title compound in 59% yield (HPLC purity 88%). MS (ESI+): 302.1; MS (ESI−): 300.1