Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:30]=[CH:31][CH:32]=1)[O:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH:20]([NH:22][C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH3:21])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[C:1]1([S:7][N:22]([CH:20]([CH3:21])[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][C:12]3[CH:30]=[CH:31][CH:32]=[C:10]([Cl:9])[CH:11]=3)=[CH:15][CH:16]=2)[C:23](=[O:27])[O:24][CH2:25][CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClSc1ccccc1
Reactant: CCOC(=O)NC(C)COc1ccc(Oc2cccc(Cl)c2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)N(Sc1ccccc1)C(C)COc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
A solution of 4 g of phenylsulfenyl chloride in 10 ml of toluene is added dropwise at 0°-5° C. in the course of 20 minutes to a solution of 9 g of ethyl 2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate in 30 ml of pyridine, with stirring, and the mixture is stirred for a further 15 hours at room temperature. Most of the pyridine and toluene is then distilled off in vacuo at a temperature of lower than 45° C., and the residue is poured into 300 ml of ice-water and extracted repeatedly with ether. The combined ether phases are first washed with cold, dilute hydrochloric acid and then with water, the mixture is dried over sodium sulfate, and the solvent is distilled off completely. The residue is purified further by chromatography on silica gel (eluent: n-hexane/diethyl ether, 19:1), by which process ethyl N-phenylthio-2-[4-(3-chlorophenoxy)phenoxy]-1-methylethylcarbamate is obtained as a colourless oil, nD20 : 1.5810.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[CH:19][C:20]1[O:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[NH:12][C:11]2=O>P(Cl)(Cl)(Cl)=O>[F:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH:18]=[CH:19][C:20]1[O:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=1)[N:12]=[C:11]2[Cl:2]
Reactant: O=c1[nH]c(C=Cc2ccc([N+](=O)[O-])o2)nc2ccc(F)cc12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(C=Cc2nc(Cl)c3cc(F)ccc3n2)o1
Yield: 63.3 %

Procedure:
A 500 ml 3 necked flask fitted with a stirrer, reflux condenser and protected by a calcium chloride trap was charged with 9.0 g of phosphorus pentachloride (0.043 mole) and 70 ml of phosphorus oxychloride and the mixture stirred. To this 11.3 g (0.04 mole) of 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-(3H)quinazolinone was added and rinsed into the flask with 15 ml of phosphorus oxychloride. The mixture was heated under reflux for 4 hours, cooled in an ice bath and diluted with 150 ml of diethyl ether. The 6-fluoro-2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline which precipitated was collected by filtration, washed with 100-150 ml of diethyl ether, slurried in 100 ml of diethyl ether and then refiltered to obtain 8.09 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22].O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:21](=[O:22])[O:23][CH3:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCNc1cccc(Cl)c1
Reactant: COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCNc1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
To a solution of N1-(3-chlorophenyl)propane-1,3-diamine (1 g, 5.4 mmol) in dry CH2Cl2 (10 mL), Et3N (1.65 g, 2.27 mL) was added. The resulting mixture was cooled to 0-5° C., a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (5 mL) was added drop wise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. Upon completion of the reaction, water (15 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×30 mL). The combined organic layers were washed with 10% citric acid (2×10 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product which was purified by preparative HPLC to afford methyl 3-(3-chlorophenylamino)propylcarbamate (1.18 g, yield 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH3:31])[C:22]=1[O:21][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: COc1cccc(CN)c1OC
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1cccc(OC)c1OC
Yield: 91 %

Procedure:
The compound prepared in Example 3 was reacted with 2,3-dimethoxy-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 91%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][Li].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27](Cl)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].[OH-].[Na+]>C(OCC)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([S:27]([N:6]2[CH:7]([CH3:15])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: [Li]C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of phenanthridine (3.58 g, 20 mmol) in anhydrous diethyl ether (20 mL) was cooled to −30° C., and treated drop-wise under nitrogen via syringe with a solution of 1.4 M methyllithium in diethyl ether (14.5 mL, 20.3 mmol). The yellow solution was warmed to room temperature and stirred for 15 minutes. The mixture was cooled to −78° C., and treated with 3,4-dimethoxybenzenesulfonyl chloride (4.73 g, 20 mmol) as a solid in a single aliquot. The reaction mixture was warmed slowly to room temperature over one hour, poured into a 1 N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic phase was washed sequentially with water, 1 N hydrochloric acid, and a saturated, aqueous, sodium chloride solution. After drying over anhydrous sodium sulfate, the organic phase was filtered through a short column of silica gel, and the filtrate evaporated in vacuo to yield a crude yellow solid (5.3 g, 67%). Crystallization of the solid from a mixture of diethyl ether-hexane yielded the title compound (2.93 g) and a second crop (0.8 g) (Total: 3.73 g, 9.43 mmol, 47%) as a homogeneous, off-white, crystalline solid, m.p. 131-133° C.;
Reaction SMILES: F[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:11][C:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:13]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([OH:34])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[F:10][C:9]1[C:2]([O:34][C:31]2[CH:32]=[C:33]3[C:28](=[CH:29][CH:30]=2)[N:27]=[CH:26][N:25]=[C:24]3[NH:11][C:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:13]=2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: Nc1ccn(-c2ccccn2)n1
Reactant: N#Cc1cccc(F)c1F
Reactant: Oc1ccc2ncnc(Cl)c2c1
Product: N#Cc1cccc(F)c1Oc1ccc2ncnc(Nc3ccn(-c4ccccn4)n3)c2c1

Procedure:
The compound of Example 133 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 2,3-difluorobenzonitrile, 3-amino-1-(pyridin-2-yl)-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=O.O>C1(C)C=CC=CC=1.CCCCO.CCCCO.CCCCO.CCCCO.[Ti]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH3:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Ti]
Solvent: O
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: CC(=N[C@@H](C)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Yield: 90.9 %

Procedure:
8 g of tetrabutyl ortho-titanate are added to a solution of 116 g (0.72 mol) of (S)-1-(4-chlorophenyl)-ethylamine (65% ee) and 114.5 g (0.727 mol) of 4-chloroacetophenone in 500 ml of toluene at room temperature with stirring, and the mixture is then refluxed for 6 hours at the water separator. The reaction mixture is filtered, and the filtrate is evaporated under reduced pressure to give 191.3 g (91% of theory) of (S)-[1-(4-chlorophenyl)-ethyl]-[1-(4-chlorophenyl)-ethylidene]-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][CH:21]([F:33])[CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30]([OH:32])=[O:31])=[N:28][CH:29]=1>>[CH:30]([OH:32])=[O:31].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([O:23][CH2:22][CH:21]([F:33])[F:20])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: O=C(O)c1cnc(OCC(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC(F)F)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A10A) and 5-(2,2-difluoro-ethoxy) -pyrazine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as a light yellow solid. MS (ISP): m/z=460.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.S(Cl)([Cl:19])=O>ClCCl>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH:4]([Cl:19])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(C(Cl)c2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
The crude benzhydryl alcohol from above (31.8 g, 107 mmole) was dissolved in 150 ml of dichloromethane and 11.7 ml (1.5 equiv.) of thionyl chloride was added dropwise over ten minutes. The solution was stirred overnight at room temperature and the solvent was removed under vacuum. The crude product was redissolved in 100 ml of toluene and the solvent was again removed under vacuum in order to eliminate excess thionyl chloride, providing crude product as a dark oil. The material was purified by short path distillation (Kugelrohr apparatus, 150° C., 0.5 mm) to give 25.8 g (76%) of (2-bromophenyl)chloro(4-chlorophenyl)methane as a pale yellow oil.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]([OH:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CC(O)C>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][C:19](=[O:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Anhydrous chromium trioxide (16.88 g 169 mmol) is added to a solution of anhydrous pyridine (27.3 ml, 338 mmol) in anhydrous methylene chloride (470 ml). The resulting mixture is stirred at room temperature for 30 minutes and then treated with a solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one (8.92 g, 21.1 mmol) in methylene chloride (80 ml). The reaction mixture is stirred an additional 15 minutes at room temperature and then treated with 2-propanol (6.75 ml). The methylene chloride phase is decanted from the dark, tary residue and evaporated under vacuum. The residue from this operation is triturated with diethyl ether (350 ml) and filtered through a pad of magnesium sulfate which is washed with additional ether (150 ml). The ethereal filtrate is washed with water (200 ml), 5% aqueous sodium bicarbonate (200 ml) and brine, dried with magnesium sulfate, filtered, evaporated under vacuum, and stripped with toluene to afford the crude product (5.99 g) as an amber oil. Chromatigraphy on a silica gel column using 3:2 petroleum ether-ethyl acetate as eluting solvent yields N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)--2-oxopropyl]-azetidin-2-one (5.17 g, 58%) as a pale yellow, viscous oil which solidifies. Trituration with diethyl ether gives the product as small, white crystals: mp 65°-66.5°, IR (CH2Cl2) 1732, 1522, and 1350 cm-1, NMR (CDCl3) δ0.20 (s,3,CH3), 0.23 (s,3,CH3), 0.93 (s,9,C(CH3)3), 2.58 (dd,1,J=2.7 and 15.7, H3β), 2.72 (dd,1, J=9.4 and 18.2, CH2COCH2CO2), 3.19 (dd,1,J=4.0 and 18.2, CH2COCH2CO2), 3.35 (dd,1,J=5.3 and 15.7,H3β), 3.55 (s,2, COCH2CO2), 3.90 (m,1,H4), 5.30 (s,2,CH2Ar), 7.55 and 8.25 (two d, 4,J=8.5, ArH); MS m/e 405 (M+ -15), 363 (M+ -57), 321 (363-42) and 136.
Reaction SMILES: [CH3:1][N:2]([C:4](=[S:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:3].Cl[S:13]([CH2:16][C:17](Cl)=[O:18])(=[O:15])=[O:14].O>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][N:2]([C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[S:11])[NH:3][S:13]([CH2:16][C:17]([NH:3][N:2]([CH3:1])[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[S:11])=[O:18])(=[O:15])=[O:14]
Reactant: CN(N)C(=S)c1ccccc1
Reactant: O=C(Cl)CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CN(NC(=O)CS(=O)(=O)NN(C)C(=S)c1ccccc1)C(=S)c1ccccc1
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a 0° C. solution of N-methylbenzothiohydrazide (10 mmol) in DCM (20 mL) and pyridine (1 mL) was added 2-(chlorosulfonyl)acetyl chloride (5 mmol) dropwise. The mixture was kept at rt for 2 h before it was poured into water (20 ml). The organic layer was separated, dried and evaporated and the resulting residue was purified by column chromatography to give compound 68 as yellowish solids (0.8 g). 1H-NMR (CDCl3) δ 10.5 (m, 1H), 7.4 (m, 10H), 4.4 (m, 1H), 3.4-3.8 (m, 8H) ppm; ESMS calcd for C18H20N4O3S3:436.1; found: 437.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:34][CH3:35])=[N:12][N:13](CC4C=CC=CC=4)[C:14]=3[NH:15][S:16](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:34][CH3:35])=[N:12][NH:13][C:14]=3[NH:15][S:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COc1nn(Cc2ccccc2)c(NS(=O)(=O)/C=C/c2ccccc2)c1-c1ccc2c(c1)OCO2
Reactant: [H][H]
Solvent: CC(=O)O
Product: COc1n[nH]c(NS(=O)(=O)CCc2ccccc2)c1-c1ccc2c(c1)OCO2
Yield: 97.6 %

Procedure:
(E)-N-[4-(1,3-benzodioxol-5-yl)-1-benzyl-3-methoxy-1H-pyrazol-5-yl]-2-phenyl-1-ethenesulfonamide (1.2 g) (Preparation 57) was dissolved in acetic acid (50 ml). Under an atmosphere of nitrogen, Pearlmann's catalyst (JM type 91, 200 mg) was added and the reaction was stirred for 24 h under 2 bars of hydrogen at 50C. The reaction mixture was filtered on a short pad of Celite® and concentrated under reduced pressure. To the oily residue was added water (dichloromethane (200 ml). The phases were separated, the organic phase washed with a 10% aqueous solution of sodium bicarbonate (2×100 ml). The aqueous phase was then extracted with dichloromethane (2×10 ml), the combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure to yield the title compound as a colourless oil (0.96 g).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:38])[CH:10]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.[N:50]([O-])=[O:51].[Na+]>>[CH2:1]([N:8]([N:50]=[O:51])[C:9](=[O:38])[CH:10]([CH:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C:22]1[C:23]([O:30][CH3:31])=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)NCc2ccccc2)C2CCCCC2)c(OC)n1
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C(=O)N(Cc2ccccc2)N=O)C2CCCCC2)c(OC)n1
Temperature: 25 °C

Procedure:
To an ice-cold solution of 15 g (28.81 mmol) N-benzyl-2-cyclohexyl-2-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetamide in 94 ml (1642 mmol) acetic acid and 198 ml (3486 mmol) acetic anhydride were added in 5 portions over 30 min. 9.94 g (144 mmol) sodium nitrite. The resulting solution was allowed to warm to room temperature overnight. The resulting yellow suspension was evaporated and the yellow slurry was taken up in 500 ml saturated aqueous sodium bicarbonate solution and 1500 ml ethyl acetate. The aqueous layer was extracted twice with 1500 ml ethyl acetate and once with 500 ml ethyl acetate. The combined organic layers were washed with water and brine. The remaining unsoluble material was filtered off and the filtrate dried over magnesium sulfate, filtered and evaporated until a suspension has formed. This suspensions was filtered and the filter cake washed twice with 50 ml ice-cold ethyl acetate and dried in high vacuum. Light yellow solid. MS (Turbo Spray): m/z=550.3 [M+H].
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[C:7]([Cl:11])[C:6]=2[C:5]2[CH2:12][N:13]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:14](=[O:22])[C@H:15]([CH2:17][C:18]([O:20]C)=[O:19])[CH2:16][C:4]=2[CH:3]=1.O.O.[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[C:10]2[NH:9][N:8]=[C:7]([Cl:11])[C:6]=2[C:5]2[CH2:12][N:13]([CH2:23][C:24]([F:25])([F:26])[F:27])[C:14](=[O:22])[C@H:15]([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Cl)c3c2CN(CC(F)(F)F)C1=O
Temperature: 50 °C
Reaction time: 5 h

Procedure:
(S)-Methyl 2-(4-bromo-1-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (210 mg, 0.448 mmol) was dissolved in a mixture of tetrahydrofuran (3.0 ml) and methanol (3.0 ml). Water (3.00 ml) was added to the mixture followed by lithium hydroxide hydrate (30 mg, 0.715 mmol). Reaction was warmed to 50° C. and held with stirring for 5 hours. Mixture was cooled to room temperature and allowed to stand for 64 hours. More lithium hydroxide hydrate (24.9 mg, 0.593 mmol) was added to the mixture. Reaction was warned to 50° C. and held for 3 hours. Mixture was cooled to room temperature. Organic solvents were removed from the mixture by roto-vap. Residue was diluted with water. Mixture was neutralized with 1.4 mL 1N hydrochloric acid. Material was extracted twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as off-white solid in quantitative yield. LCMS (M−H)−=453.9.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[F:20][C:21]([F:31])([F:30])[C:22]1[NH:26][N:25]=[C:24]([C:27](O)=[O:28])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:24]3[CH:23]=[C:22]([C:21]([F:31])([F:20])[F:30])[NH:26][N:25]=3)=[O:28])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: O=C(O)c1cc(C(F)(F)F)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3cc(C(F)(F)F)[nH]n3)n2)ccc(C#N)c1Cl
Yield: 41.1 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (0.15 g, 0.546 mmol), 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.108 g, 0.601 mmol), HOBt (0.111 g, 0.819 mmol), DIPEA (0.143 ml, 0.819 mmol) and EDCI (0.157 g, 0.819 mmol) using DCM as solvent using the method of Example 34(d) affording 0.098 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 2.48 (s, 3H), 4.30 (m, 2H), 4.46 (m, 1H), 6.60 (d, 1H), 7.21 (m, 1H), 7.60 (d, 1H), 7.79 (d, 1H), 7.85 (d, 1H), 8.51 (m, 1H), 14.39 (m, 1H).
Reaction SMILES: [C:1]([CH:9]([CH3:13])C(O)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:15][NH2:16].[C:17]([O-:20])(=[O:19])C.[Na+].O>CO>[OH:15][N:16]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:13][C:17]([OH:20])=[O:19]
Reactant: CC(C(=O)O)C(=O)c1ccccc1
Reactant: CC(=O)[O-]
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)CCC(=NO)c1ccccc1
Temperature: 24.5 °C
Reaction time: 4.5 h
Yield: 87.1 %

Procedure:
Benzoylpropionic acid (100 g) was suspended in methanol (300 ml) at room temperature, and hydroxyamine hydrochloride (46.8 g) and sodium acetate (138 g) were added. After stirring the mixture for 4.5 hr at room temperature at 22-27° C., pure water (500 ml) was added under cooling at 24-26° C. Seed crystal was added at 25° C., and the mixture was stirred at room temperature for about 1 hr, then cooled to 10° C. over about 30 min, and stirred at 5-10° C. for about 2 hr. The precipitated solid was collected by filtration, washed with pure water (100 ml×2) and dried under reduced pressure (40° C.) to give 4-(hydroxyimino)-4-phenylbutanoic acid (94.4 g) as a white solid in a yield of 87.1%.
Reaction SMILES: [CH3:1][Mg]I.[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]=[O:14].O.Cl>CCOCC>[Cl:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[CH:12]([CH2:15][CH2:16][CH2:17][CH3:18])[CH:13]([OH:14])[CH3:1]
Reactant: CCCCC(C=O)c1ccc(Cl)cc1Cl
Reactant: C[Mg]I
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCCC(c1ccc(Cl)cc1Cl)C(C)O
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To 14.3 g (0.088 mole) of methylmagnesium iodide in 75 ml of ether is slowly added at less than 10°, 14.5 g (0.059 mole) of the α-(2,4-dichlorophenyl) hexanal. When the addition is complete, the reaction is stirred for 1 hour then heated up to reflux for 2 hours. The reaction is cooled and poured into water. The mixture is acidified with hydrochloric acid and the oil which separates is extracted out with ether. The ether solution is dried and concentrated to give 11.7 g (76%) of the crude product.