Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[F:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[C:1]([NH:5][S:14]([C:8]1[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=1[F:6])(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(F)c1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)NC(C)(C)C)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice cooled solution of tert-butylamine (12.55 ml) in THF (60 ml) was added a solution of 2-fluoro-4-methylbenzene-1-sulfonyl chloride (5 g) in THF (25 ml), dropwise. After stirring for 15 min at 0° C., the reaction mixture was allowed to warm and stirred at room temperature for 2 hours. The HCl salt was removed by filtration and the filtrate was concentrated to give a yellow residue, which was triturated with Et2O and Hexanes to give 5.10 g N-tert-butyl-2-fluoro-4-methylbenzenesulfonamide as an off-white granular solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:10]([OH:13])=[C:6]([C:7]([OH:9])=O)[CH:5]=1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[NH2:20]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:12]=[CH:11][C:10]([OH:13])=[C:6]([C:7]([NH:20][C:19]2[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=[C:17]([C:16]([F:15])([F:28])[F:29])[CH:18]=2)=[O:9])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 91.5 %

Procedure:
Using 4-hydroxyisophthalic acid 1-methyl ester and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([C:3]1(C)[C:7](=[O:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[BH4-].[Na+]>CCO>[C:1]([CH:3]1[CH:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C)(C#N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(O)C(C#N)C1
Reaction time: 0.5 h

Procedure:
To a solution of 1,1-dimethylethyl 3-cyano-3-methyl-4-oxo-1-pyrrolidinecarboxylate (2.3 g, 10.2 mmol) in EtOH (100 mL) at 0° C. was added NaBH4 (775 mg, 20.5 mmol) portion-wise. After 30 min., the solution was concentrated and the residue partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound as a yellow oil: LCMS (ES) m/e 227 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[CH2:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([CH3:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)[CH:5]=[CH:4][CH:3]=1.O1CCC[CH2:41]1>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>[CH3:19][C:17]1[CH:18]=[C:10]([CH2:9][CH:8]([NH:20][C:21]([N:23]2[CH2:28][CH2:27][CH:26]([N:29]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[NH:31][C:30]3=[O:39])[CH2:25][CH2:24]2)=[O:22])[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:41])[N:7]=2)[CH:11]=[C:12]2[C:16]=1[NH:15][N:14]=[CH:13]2
Reactant: C1CCOC1
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cccc(Br)n2)cc2cn[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cccc(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 110 °C
Yield: 94 %

Procedure:
A microwave tube was charged with (±)-N-(1-(6-bromopyridin-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (11 mg, 0.0187 mmol, 1.0 equiv), Pd(PPh3)4 (2 mg, 0.1 equiv) and anhydrous tetrahydrofuran (0.5 mL) under nitrogen. ZnMeCl (2.0 M in tetrahydrofuran, 0.12 mL, 0.24 mmol) was added via syringe resulting in gas evolution. The vial was sealed and heated by microwave at 110° C. for 4 h. Tetrahydrofuran was removed in vacuo and the residue was partitioned between ethyl acetate and concentrated ammonium hydroxide solution. The organic layer was separated and washed with brine, dried and concentrated. Flash column chromatography (10% methanol/methylene chloride) afforded the desired product (9.2 mg, 94%) as a white powder. MS (ESI) [M+H]+=524. 1H-NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.33 (br., 1H), 7.22-6.80 (m, 7H), 6.65 (d, J=8.0 Hz, 1H), 6.59 (br., 1H), 6.20 (br., 1H), 5.20-5.08 (m, 1H), 4.62-4.48 (m, 1H), 4.22 (s, 2H), 4.20-4.03 (m, 2H), 3.40-3.28 (m, 1H), 3.10-2.97 (m, 1H), 2.97-2.78 (m, 2H), 2.54 (s, 3H), 2.45 (s, 3H), 1.95-1.50 (m, 5H). HPLC tR=1.11 min.
Reaction SMILES: [O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([OH:10])=O)=[CH:5][S:4][CH2:3][CH2:2]1.[NH2:14][CH:15]1[C:33](=[O:34])[N:17]2[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]3[S:25][C:26]([CH3:29])=[N:27][N:28]=3)[CH2:20][S:21][C@H:16]12>>[O:1]1[C:6]([C:7](=[N:11][O:12][CH3:13])[C:8]([NH:14][CH:15]2[C:33](=[O:34])[N:17]3[C:18]([C:30]([OH:32])=[O:31])=[C:19]([CH2:22][S:23][C:24]4[S:25][C:26]([CH3:29])=[N:27][N:28]=4)[CH2:20][S:21][C@H:16]23)=[O:10])=[CH:5][S:4][CH2:3][CH2:2]1
Reactant: CON=C(C(=O)O)C1=CSCCO1
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)s1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)C1=CSCCO1

Procedure:
2-(2,3-Dihydro-1,4-oxathiin-6-yl)-2-methoxyiminoacetic acid (syn isomer, 1 g.) was allowed to react with 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (2 g.) in a similar manner to that of Example 1 to give the captioned compound (2.2 g.), pale yellow powder, mp. 160° to 165° C. (dec.).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][C:5]1[S:9][C:8]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1.[Br:16]Br.CC(OC)(C)C>CC(O)=O>[Br:16][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:8]=2[S:9][C:5]=1[CH2:4][CH2:3][N:2]([CH3:1])[CH3:15]
Reactant: BrBr
Reactant: Cc1ccc2cc(CCN(C)C)sc2c1
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: Cc1ccc2c(Br)c(CCN(C)C)sc2c1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a suspension of dimethyl-[2-(6-methyl-benzo[b]thiophen-2-yl)-ethyl]-amine (1.05 g, 4.78 mmol) in HOAc (5 mL) at 0° C., bromine was added slowly. The mixture was stirred overnight while it was allowed to slowly reach room temperature. MTBE (6 mL) was added and the solid was filtered, washed with MTBE and dried under vacuum. It was taken up in dichloromethane, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give 1.1 g of [2-(3-bromo-6-methyl-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (77% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.[C:15]([CH2:17][C:18]([N-:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])#[N:16]>>[C:23]1([CH2:22][CH2:21][NH:20][C:18](/[C:17](=[CH:8]/[CH:7]=[CH:6]/[C:5]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:15]#[N:16])=[O:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(C=CC=O)cc1OC
Reactant: N#CCC(=O)[N-]CCc1ccccc1
Product: COc1ccc(/C=C/C=C(\C#N)C(=O)NCCc2ccccc2)cc1OC

Procedure:
The compound was prepared as described in Example 3 by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.1 g, 0.52 mmol) to N-(cyanoacetyl)phenylethylamide (Example 20, 0.1 g, 0.52 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.12 g, 63%). The product gave the following analytical data:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[F:8][CH:9]([F:36])[C:10]([NH:12][C@H:13]([CH2:34][F:35])[C@H:14]([OH:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)=[O:11].C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:33][C@H:14]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH2:27][NH:28][S:29]([CH3:32])(=[O:30])=[O:31])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@H:13]([NH:12][C:10](=[O:11])[CH:9]([F:8])[F:36])[CH2:34][F:35])=[O:6]
Reactant: O=C(Cl)CCCBr
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](OC(=O)CCCBr)[C@@H](CF)NC(=O)C(F)F)cc2)cn1
Reaction time: 1 h
Yield: 59.4 %

Procedure:
4-Bromobutanoyl chloride (29.6 μL, 0.255 mmol) is added dropwise to a stirred solution of 2,2-difluoro-N-{(1S,2R)-1-(fluoromethyl)-2-hydroxy-2-[4-(6-{[(methylsulfonyl)amino]methyl}pyridin-3-yl)phenyl]ethyl}acetamide (100.0 mg, 0.232 mmol), N,N-diisopropylethylamine (48.4 μL, 0.278 mmol), and 4-dimethylaminopyridine (11.3 mg, 0.093 mmol) in N,N-dimethylformamide (1.00 mL) at rt. The reaction mixture is stirred for 1 hour before being concentrated. The residue was purified by CombiFlash (4 g column) eluting with 0-100% ethyl acetate to yield the title compound (80.0 mg, 59%) as a yellow foam. MS (ESI+) m/z 581.7 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([CH3:29])[CH:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3-amino-5-methylpyrazole.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:39]C(=O)NCCCCC1N(CCOC2C=CC=CC=2)C2C3C=CC(OCC4C=CC=CC=4)=CC=3N=CC=2N=1)(C)(C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])[C:20]([CH2:31][O:32][CH2:33][CH3:34])=[N:19][C:14]=3[CH:15]=[N+:16]([O-:39])[C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCOc1ccccc1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Product: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NS(C)(=O)=O
Reaction time: 2.5 h

Procedure:
A modification of the general method described in Part B of Example 49 was followed using N-[2-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide (1.71 g, 3.55 mmol) in lieu of tert-butyl{-4-[7-benzyloxy-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-2-yl]butyl}carbamate. The reaction was complete in 2.5 hours and provided 1.75 g of N-[2-(7-benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]methanesulfonamide as a light-brown solid.
Reaction SMILES: N[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O=[C:13]([CH2:17][CH2:18]C(O)=O)[C:14]([OH:16])=[O:15]>C(O)(=O)C.Cl.O>[C:17]1([CH2:13][C:14]([OH:16])=[O:15])[C:10]2=[C:11]3[C:6](=[CH:7][CH:8]=[CH:9]2)[CH2:5][CH2:4][CH2:3][N:2]3[CH:18]=1
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: NN1CCCc2ccccc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cn2c3c(cccc13)CCC2
Yield: 42.9 %

Procedure:
17 g of 1-amino-1,2,3,4-tetrahydroquinoline (preparation see Example 1B) and 20 g of 2-ketoglutaric acid were heated under reflux at a temperature of 80° C. for 2 hours in a mixture of 160 ml of acetic acid and 11.4 ml of concentrated hydrochloric acid. To work up the reaction mixture the solid residue which remained was taken up in water and extracted with ethyl acetate. The organic phase was separated and extracted with 20% strength aqueous sodium hydroxide solution. The alkaline (pH=9) aqueous phase was separated and acidified to pH=4 by addition of aqueous 10% strength hydrochloric acid solution, and a precipitate formed. The solution was extracted with ethyl acetate. The organic phase was evaporated. 10.6 g of crude 5,6-dihydro- 4H-pyrrolo-[3,2,1-ij]quinoline-1-acetic acid were obtained as a solid residue.
Reaction SMILES: [Na].[CH2:2]([O:4][C:5](=[O:12])[CH2:6][C:7]([O:9][CH2:10]C)=[O:8])C.C[O-].[Na+].Cl[CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1>>[CH3:2][O:4][C:5](=[O:12])[CH:6]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: ClCCCCOC1CCCCO1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Product: COC(=O)C(CCCCOC1CCCCO1)C(=O)OC

Procedure:
7.9 g (0.3 mol) of sodium in a stream of nitrogen was placed in a 500-ml 3-necked flash with reflux condenser, drying tube and dropping funnel with pressure equalisation. Next, 250 ml of anhydrous methanol was carefully added dropwise and agitated until the sodium had completely dissolved. A methanolic solution of 95.4 g (0.58 mol) malonic acid diethyl ester was added very slowly dropwise to the still-warm sodium methanolate solution. At the end of the addition process, the mixture was reflux-boiled for a further hour, after which 0.5 mol of 1-chloro-4-tetrahydro-pyranyloxybutane was slowly added dropwise. The mixture was then reflux-boiled overnight.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28](=O)[C:29](OC)=[O:30].CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[OH:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[NH:26][CH:25]=[C:24]2[C:28]1[C:29](=[O:30])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Reactant: COC(=O)C(=O)c1c[nH]c2c(CCCO)cccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCO)cccc45)C(=O)NC3=O)c21
Temperature: 60 °C
Reaction time: 12 h
Yield: 89.2 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)acetamide (105 mg, 0.55 mmol) and methyl 2-(7-hydroxypropyl-1H-indol-3-yl)oxoacetate (146 mg, 0.56 mmol) in DMF (2.0 mL) at 4° C. under N2, was added a 1.0 M solution of potassium tert-butoxide in THF (1.7 mL, 1.7 mmol) dropwise over 25 min. The reaction was heated to 60° C. and stirred for 12 h. The reaction mixture was then cooled to room temperature and quenched with 1.0 N hydrochloric acid (5.0 mL). The mixture was extracted with EtOAc (2×15 mL), washed with saturated NaHCO3 (30 mL), saturated NaCl (30 mL), dried (MgSO4), filtered and concentrated. Flash chromatography (SiO2, 3:47:50 MeOH/EtOAc/CH2Cl2) gave the title compound (196 mg, 87%) as a red solid, mp 183–185° C. 1H NMR (300 MHz, DMSO-d6) 11.81 (s, 1H), 11.12 (s, 1H), 7.87 (m, 1H), 7.61 (m, 1H), 7.28 (m, 1H), 6.98 (m, 3H), 6.50 (m, 2H), 6.29 (m, 1H), 3.68 (s, 3H), 3.41 (m, 2H), 2.78 (m, 2H), 1.76 (m, 2H). MS (electrospray, m/z) 398 [C24H21N3O3−H]−
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.I[CH3:16]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:16])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1
Reactant: CI
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Product: CC(=O)N(C)c1ccc(CCCl)cc1C
Yield: 100 %

Procedure:
N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-N-methyl-acetamide was prepared according to the general method as outlined in Preparation 43 starting from N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-acetamide (0.450 g, 2.126 mmol) and iodomethane (0.176 ml, 2.834 mmol). After chromatographic purification, the product was isolated as a viscous oil (0.480 g, 2.125 mmol). Yield=100%. MS (APCI): 226 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.13(bs, 1H), 7.08 (bd, J=7.57 Hz, 1H), 7.05 (d, J=7.57 Hz, 1H), 3.71 (t, J=7.06 Hz, 1H), 3.15 (s, 3H), 3.04 (t, J=7.06 Hz, 2H), 2.20 (s, 3H), 1.75 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH:23]=[CH2:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:28]([O:30][NH2:31])[CH3:29].C([O-])(=O)C.[Na+]>CS(C)=O.O>[CH2:28]([O:30][N:31]=[C:1]([C:5]1[C:6](=[O:26])[CH2:7][CH:8]([C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH2:19][C:18](=[O:21])[N:17]([CH2:22][CH:23]=[CH2:24])[C:16]=3[CH:25]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:29]
Reactant: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(=O)CC)=C(O)C3)cc21
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCN1C(=O)COc2ccc(C3CC(=O)C(C(CC)=NOCC)=C(O)C3)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 1.3 g (3.7 mmol) of 2-propionyl-3-hydroxy-5-(N-(2-propenyl)-3-oxo-(2H)-1,4-benzoxazin-6-yl)cyclohex-2-en-1-one in 20 mL of methyl sulfoxide was treated with 0.43 g (4.5 mmol) of ethoxyamine hydrochloride and 0.36 g (4.4 mmol) of anhydrous sodium acetate. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for 6 hours. The reaction mixture was diluted with 200 mL of water and extracted thrice with 20 mL portions of diethylether. The extracts were combined, washed with water, then aqueous sodium chloride, dried over MgSO4 and filtered. Evaporation off of the solvent gave the crude product as a yellow oil which solidified upon standing. The resulting glassy solid was dissolved in a warm 1:1 ether-hexane solution. On cooling, the compound oiled out of the solution and again solidified and was isolated by filtration as a light tan solid. The product was recovered in a yield of 1.1 g (75 percent of theoretical) and melted at 79°-83° C.; 1H NMR(CDCl3): d1.12 (t, J=7 Hz, 3H,--CCH2CH3), 1.32 (t, J=7 Hz, 3H,--OCH2CH3), 2.55-3.55 (m, 7H), 4.16 (q, J=7 Hz, 2H,--OCH2CH3), 4.50-4.70 (m including s at 4.60 for OCH2C=O, 4H, --N--CH2), 5.10-5.42 (m, 2H,--OCH=CH3), 4.70 (s, 2H, --OCH2C=O), 4.88 (s, 2H, --NCH2CN), 6.92-7.20 (m, 3H, aromatic H's), 15.10 (broad s, 1H, enol H); (Compound 5).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O.C([O-])(O)=O.[Na+]>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cc1ccc2c(-c3ccc(F)cc3)ccnc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c(-c3ccc(F)cc3)cc(Cl)nc2c1

Procedure:
A solution of 4-(4-fluorophenyl)-7-methylquinoline (3.09 g, 12.2 mmol) in phosphorus oxychloride (8 mL, 85.8 mmol) was stirred 30 min. at 90° C. The mixture was poured slowly into an aqueous saturated solution of NaHCO3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane/hexanes, 1:70:29) gave the title compound. MS (+ESI): 271 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]1[C:12]2[CH:11]=[N:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[Na+]>CC(C)=O>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:1][N:2]=[C:3]2[C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[CH2:6][CH2:5][CH2:4]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: ON=C1CCCc2ccncc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)ON=C2CCCc3ccncc32)cc1
Temperature: 55 °C
Yield: 66.8 %

Procedure:
To a solution of 8-hydroxyimino-5,6,7,8-tetrahydroisoquinoline (960 mg) and p-toluenesulfonyl chloride (1.69 g) in acetone was added 1N sodium hydroxide (8.88 ml) and the mixture was heated at 55° C. for 2 hours. The acetone was evaporated and the aqueous reaction mixture was extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate and concentrated in vacuo to give 8-(4-methylphenylsulfonyl)oxyimino-5,6,7,8-tetrahydroisoquinoline (1.25 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[CH:28]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[C:30]([O:33][CH3:34])=[N:31][CH:32]=1
Reactant: COc1ncc(Cl)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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
Product: COc1ncc(Cl)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)ccc1C
Temperature: 80 °C
Yield: 38.7 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (0.11 g, 0.3 mmol) in 1,2-dimethoxyethane (3 mL) was added 5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.11 g, 0.39 mmol), tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol), and 2 M sodium carbonate (0.3 mL, 0.6 mmol) and the reaction mixture was heated to 80° C. overnight. The crude material was purified by silica gel chromatography (eluting with 0-35% ethyl acetate in hexanes) to yield the product (55 mg, 39%). ESI-MS m/z calc. 473.1. found 474.0 (M+1)+. Retention time 2.33 minutes.
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:32][C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH2:31][C:25]=5[N:24]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:33]([N:29]1[CH2:30][CH2:31][C:25]2[N:24]=[C:23]([C:18]3[C:17]4[C:21](=[CH:22][C:14]([C:7]5[C:6]([CH2:4][CH3:5])=[CH:11][C:10]([OH:12])=[C:9]([F:13])[CH:8]=5)=[CH:15][CH:16]=4)[NH:20][N:19]=3)[NH:32][C:26]=2[CH2:27][CH2:28]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNCC4)n[nH]c2c1
Reactant: BrCc1ccccc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3ccccc3)CC4)n[nH]c2c1
Temperature: 50 °C
Yield: 10.4 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 32, 50 mg, 80 μmol) in DMF (1 mL), was added benzyl bromide (14.4 mg, 10 μL, 85 μmol), and DIPEA (56 μL, 320 μmol). The reaction mixture was heated at 50° C. for 18 hours. The reaction mixture was then cooled to room temperature and partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to furnish a brown oil. The crude material was purified by reverse phase chromatography (Method C) to afford 4 mg of the title compound.