Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21](O)=[O:22])=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.O[NH:25][C:26]([C:28]1[S:29][C:30]([S:33](=[O:36])(=[O:35])[NH2:34])=[CH:31][CH:32]=1)=[NH:27]>>[CH3:1][C:2]1[C:3]2[N:4]([C:18]([C:21]3[O:22][N:27]=[C:26]([C:28]4[S:29][C:30]([S:33]([NH2:34])(=[O:36])=[O:35])=[CH:31][CH:32]=4)[N:25]=3)=[CH:19][N:20]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C(=O)O)cnc12
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(-c3nc(-c4ccc(S(N)(=O)=O)s4)no3)cnc12

Procedure:
The title compound was prepared from 8-methyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.34) (160 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (diethyl ether/MeOH) as a pink solid (147 mg, 58%). MS (EI) 505.1 [(M)+]; mp 285° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](O)=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([Cl:16])=[C:8]([C:11]#[N:12])[CH:7]=[N:6][N:5]2[CH:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnn2cc(Br)cc2c1O
Product: N#Cc1cnn2cc(Br)cc2c1Cl
Temperature: 75 °C
Yield: 47.7 %

Procedure:
To a 25 mL round bottom flask was added 6-bromo-4-hydroxypyrrolo [1,2-b]pyridazine-3-carbonitrile (16.5 g, 69.47 mmol) and POCl3 (85 mL, 0.88 mol) and the reaction mixture was stirred and heated at 75° C. for 3 hours. The POCl3 was removed under vacuum and the resulting residue was dissolved in CH2Cl2. The solution was cooled to 0° C. and saturated aq. NaHCO3 solution was added and the biphasic mixture was stirred vigorously while allowing to warm to rt. The organic layer was separated and concentrated and the obtained residue was purified by flash silica gel column chromatography to yield 8.5 g (29%) of the title compound as a yellow solid. HPLC (condition P): retention time=16.74 min. 1H NMR (400 MHz, CDCl3) δ ppm: 8.09 (1H, s), 7.94 (1H, d, 2.0 Hz), 7.06 (1H, d, 2.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[CH:15][CH:14]=1)=[CH:9][C:8]([Br:24])=[CH:7][CH:6]=2.C(N(CC)CC)C.Cl[C:33](OC(Cl)(Cl)Cl)=[O:34]>C(Cl)Cl>[Br:24][C:8]1[CH:7]=[CH:6][C:5]2[N:4]=[CH:3][C:2]3[NH:1][C:33](=[O:34])[N:12]([C:13]4[CH:14]=[CH:15][C:16]([C:19]([CH3:22])([CH3:23])[C:20]#[N:21])=[CH:17][CH:18]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reaction time: 0.33 h

Procedure:
A solution of 5 g (13.1 mmol) of 2-[4-(3-amino-6-bromo-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1g) and 1.59 g (15.7 mmol) of triethylamine in 120 ml CH2Cl2 is added over 40 min to a solution of 2.85 g (14.4 mmol) of trichloromethyl chloroformate (Fluka, Buchs, Switzerland) in 80 ml of CH2Cl2 at 0° C. with an ice-bath. The reaction mixture is stirred for 20 min at this temperature then is quenched with sat. aqueous NaHCO3, stirred for 5 min and extracted with CH2Cl2. The organic layer is dried over Na2SO4, filtered and evaporated in vacuo to give crude title compound as a brownish solid. ES-MS: 407, 409 (M+H)+, Br pattern; analytical HPLC: tret=3.05 min (Grad 1).
Reaction SMILES: [OH:1][C:2]1([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][NH:4][CH2:3]1.[F:20][C:21]1[C:22]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:23]([CH:27]=[CH:28][C:29]=1[F:30])[C:24](F)=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:15]([O:14][C:13](=[O:19])[NH:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[C:2]1([OH:1])[CH2:3][N:4]([C:24](=[O:25])[C:23]2[CH:27]=[CH:28][C:29]([F:30])=[C:21]([F:20])[C:22]=2[NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])[CH2:5]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxyazetidin-3-yl)cyclohexylcarbamate (181 mg, 0.669 mmol) and 3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl fluoride (265 mg, 0.669 mmol), prepared using procedures similar to those described in Reference 1, in tetrahydrofuran (2.2 mL) was added N,N-diisopropylethylamine (110 μL) at room temperature. After an hour, the reaction mixture was heated to 50° C. and stirred for 45 minutes, at which time it was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate and 10% citric acid. The organic layer was washed with aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate. This crude material was taken into the next step without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32].C(N(C(C)C)CC)(C)C.[CH3:42][N:43]([CH:45]=[O:46])[CH3:44]>>[CH3:42][N:43]([CH3:44])[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][O:28]2)=[O:24])[C:5]1=[O:32])=[O:46]
Reactant: CN(C)C=O
Reactant: NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)NCCn1c(=O)c(C(=O)NCC2CCCO2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-N-(tetrahydro-2-furanylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.057 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (3 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0055 mL, 0.06 mmol) (40° C. After 2½ h the reaction was cooled, concentrated in vacuo, and the resulting residue treated with 1N NaHSO4, filtered, washed with water, and dried in vacuo to provide the title compound as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.34 (m, 1 H), 1.48-1.67 (m, 1 H), 1.67-2.12 (m, 3 H), 2.70 (s, 6 H), 3.32-3.41 (m, 1 H), 3.57 (d, J=18.81 Hz, 1 H), 3.63-3.71 (m, 1 H), 3.78-3.85 (m, 1 H), 4.00 (d, J=1.97 Hz, 2 H), 4.12 (s, 3 H), 4.26 (t, J=6.04 Hz, 2 H), 6.52-6.57 (m, 1 H), 7.14 (t, J=8.70 Hz, 2 H), 7.35-7.43 (m, 2 H), 8.28 (s, 1 H), 8.53 (s, 1 H), 10.46 (s, 1 H); ES+ MS: 512 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[N:2].[NH3:16]>CO>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([NH2:16])=[O:8])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14])#[N:2]
Reactant: N
Reactant: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Solvent: CO
Product: N#Cc1ccc(C(N)=O)cc1[N+](=O)[O-]
Yield: 32.6 %

Procedure:
2 g (9.71 mmol) Methyl 4-cyano-3-nitrobenzoate (Compound II-8) and 60 ml methanol were added into a reaction flask, stirred, and ammonia gas was passed through for 1 hour, then reacted for 8 hours at room temperature. After the reaction was completed, the mixture was concentrated under reduced pressure to evaporate most of the methanol. Then the mixture was extracted with 100 ml ethyl acetate, and the organic layer was washed with water for three times, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain 1.1 g (5.76 mmol) crude product, which was recrystallized from ethyl acetate-n-hexane to obtain 4-cyano-3-nitrobenzamide (compound I-8), 0.6 g, yield 32.6%.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>N1C=CC=CC=1.CCOCC>[C:16]([O:15][C:13]([NH:12][CH:4]([CH:3]([OH:20])[CH:2]([NH:1][S:34]([C:31]1[CH:32]=[CH:33][C:28]([CH3:38])=[CH:29][CH:30]=1)(=[O:36])=[O:35])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccccc2)C(O)C(Cc2ccccc2)NC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
The resultant compound of Example 11 (0.05 mmol) in 2 ml of pyridine was cooled to 0° C. and treated with 0.05 mmol of p-toluenesulfonyl chloride. After 2 h, the solution was diluted with ether, washed sequentially with 1N HCl, aqueous NaHCO3, and saturated brine, dried over MgSO4, and concentrated. Silica gel chromatography gave the desired compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[OH-].[K+].S(O[CH2:23][C@H:24]([CH3:33])[NH:25]C(OCCCC)=O)(=O)(=O)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CS(C)=O.O>[NH2:25][C@@H:24]([CH3:33])[CH2:23][N:10]1[CH:9]=[N:8][C:7]2[C:11]1=[N:12][C:13]([NH2:15])=[N:14][C:6]=2[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Reactant: CCCCOC(=O)N[C@@H](C)COS(C)(=O)=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](N)Cn1cnc2c(-c3ccco3)nc(N)nc21
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
A solution of the 6-(2-furyl)-1H-purine-2-amine (0.1 g, 0.5 mmol) in DMSO was treated with freshly ground KOH (112 mg, 2 mmol), shaken for 10 min, treated with N-butoxycarbonyl-L-alaninol mesylate (316 mg, 3 mmol), shaken at 40° C. for a further 17 h, treated with di-tert-butyl dicarbonate (655 mg, 3 mmol), shaken for a further 30 min, diluted with H2O, extracted with EtOAc and the extracts dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; (EtOAc)]. The resulting gelatinous solid was dissolved in MeOH (3 mL), treated with HCl solution (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et2O and filtered to give the title compound (67 mg, 45%) as a yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17].[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[N+:19]([C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([CH2:14][CH2:15][C:16](=[O:18])[CH3:17])=[CH:1][C:13]=3[CH2:12]2)=[CH:7][CH:8]=1)([O-:21])=[O:20]
Reactant: CC(=O)CCc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)CCc1ccc2c(c1)Cc1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
In 50 ml of acetic acid was suspended 5.90 grams of 4-(2-fluorenyl)-butan-2-one and 6.35 ml of concentrated nitric acid was dropped in during 45 minutes with stirring at room temperature. After stirring for 3 hours and 30 minutes, crystals separated out therefrom were collected by filtration, washed with small amount of acetic acid, and washed with water until the washing became neutral. The resulting crystals were dissolved in 250 ml of chloroform, dried over magnesium sulfate, and chloroform was evaporated therefrom in vacuo. The residue was recrystallized from benzene to give 3.83 grams of 4-(7-nitro-2-fluorenyl)-butan-2-one, yellow crystals, m.p. 159°-161.5° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[Cl:32]CCl.ClN1C(=O)CCC1=O.[OH-].[K+]>O>[C:1]([C:5]1[C:9]([Cl:32])=[C:8]([NH:10][C:11]2[C:12]([C:17]([OH:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[N:7]([C:20]2[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:27])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: Cc1cccc(C)c1-n1nc(C(C)(C)C)cc1Nc1cccnc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1-n1nc(C(C)(C)C)c(Cl)c1Nc1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 3-{[3-tert-butyl-1-(2,6-dimethylphenyl)-1H-pyrazol-5-yl]amino}pyridine-2-carboxylic acid (Example 10, 50 mg, 0.14 mmol) in an acetic acid/dichloromethane mixture (1 mL of each) was added N-chlorosuccinimide (18 mg, 0.14 mmol). The solution was stirred at rt for 12 h, and then water (10 mL) was added. The reaction mixture was basified to pH 9 using KOH (1.0 M ice cold solution). The water layer was extracted with dichloromethane (50 mL), and the organic phase was subsequently washed with saturated sodium sulfite, brine, and concentrated to dryness. The crude material was subjected to HPLC purification to give the desired product (42 mg, 76%). 1H NMR (300 MHz, CD2Cl2) δ 10.45 (s, 1H), 9.30 (s, 1H), 8.04 (d, 1H), 7.50 (m, 1H), 7.25 (m, 2H), 7.15 (m, 2H), 2.02 (s, 6H), 1.43 (s, 9H). ES-MS m/z 399.0 (MH+); HPLC RT (min) 3.33.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][N+:9]([O-:11])=[O:10].[OH-].[Na+].Cl>O.CO>[N+:9]([CH:8]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=Cc1cccs1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])C=Cc1cccs1
Temperature: -5 °C

Procedure:
To 7.85 g (0.07 mol) of 2-thiophenecarboxaldehyde were added 148 ml of MeOH and 12.82 g (0.210 mol) of CH3NO2 ; and 74 ml of 50% aqueous solution of NaOH was added dropwise to the mixture with stirring at -5° C. After being stirred at 10° C. for 1 hr., the reaction solution was poured into a mixture of 296 ml of 36% HCl and 493 ml of water at 0° C. The crystals separating out were collected by filtration and washed with water, whereby 6.65 g (Yield : 61.2%) of the objective compound, 2-(2-nitroethenyl)thiophene (d-1) was obtained as greenish brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][C:3]=1[O:12][CH2:13][O:14][CH3:15].CN(C)CCN(C)C.C([Li])CCC.[CH2:29]1[O:39][C:32]2([CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]2)[O:31][CH2:30]1.Cl>C1COCC1.C(OCC)(=O)C>[CH3:15][O:14][CH2:13][O:12][C:3]1[CH:4]=[C:5]([O:8][CH2:9][O:10][CH3:11])[CH:6]=[CH:7][C:2]=1[C:35]1([OH:38])[CH2:36][CH2:37][C:32]2([O:39][CH2:29][CH2:30][O:31]2)[CH2:33][CH2:34]1
Reactant: COCOc1ccc(Br)c(OCOC)c1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(OCOC)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A round bottomed flask was loaded with 1-bromo-2,4-bis(methoxymethoxy)benzene (2.00 g) and THF (50 mL). N,N,N′,N′-Tetramethylethylene diamine (2.3 ml) was added and the solution was cooled to −78° C. n-Butyl lithium (9.5 ml, 1.6M in hexane) was added. The resulting solution was stirred for 1 hr at −78° C. and 1,4-cyclohexanedione monoethylene ketal (1.35 g) was added as a solution in THF (25 ml). The resulting solution was stirred at −78° C. for 1 hr and then allowed to warm to room temperature overnight. Hydrochloric acid (20 ml, 2M) was added and the reaction mixture stirred vigorously for 15 min. Ethyl acetate (100 ml) was added and the mixture poured into a separating funnel. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×20 ml). The combined organic phases were washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and concentrated affording an orange oil, which was purified by flash column chromatography (SiO2, ethyl acetate/petroleum ether, 45:55, v/v). The title product (1.42 g, 56%) was isolated as a colourless oil. m/z (ES+) 337 (M−H2O+H+); δH (CDCl3) 1.61-1.64(2H, m), 2.00-2.18(6H, m), 3.44(3H, s), 3.48(3H, s), 3.90-3.97(4H, m), 5.11(2H, s), 5.24(2H, s), 6.64(1H, dd), 6.82(1H, d), 7.20(1H, d).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C.COC(=O)[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[F:39].Cl>C1COCC1>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=3[F:39])=[O:18])=[CH:11]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Reactant: COC(=O)c1cccc(F)c1F
Agent: Cl
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccn(S(=O)(=O)c2ccccc2)c1)c1cccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of (1-benzenesulfonyl-1H-pyrrol-3-yl)-acetic acid (1.3 g, 4.90 mmol) in THF was added LiN(TMS)2 (12 mL, 1.0M in THF, 12 mmol) at −78° C. The resulting solution was stirred at this temperature for 1 hour and 0° C. for 1 hour and then was cooled to −78° C. again. To this solution was added 2,3-difluoro-benzoic acid methyl ester (1.1 g, 6.40 mmol) and the reaction was stirred at room temperature for 14 hours. The solution was poured into 2N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The crude product was purified by flash column eluting with 20% of EtOAc in hexanes to afford the title compound as a yellow oil (1.1 g, 58%). 1H NMR (500 MHz, CDCl3) δ7.77 (d, 2H), 7.50 (m, 2H), 7.42 (t, 2H), 7.28 (m, 1H), 7.05 (m, 3H), 6.18 (m, 1H), 3.98 (s, 2H) ppm. MS (ES+): m/e=362.1 (M+H); LC/Method A/3.98 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28]O)[C:21](=[O:27])[NH:22]2>>[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[C:20](=[CH:28][NH:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]3[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[CH:15][CH:14]=1)[C:21](=[O:27])[NH:22]2
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Reactant: Cc1cccc2c1C(=CO)C(=O)N2
Product: Cc1cccc2c1C(=CNc1ccc(OCC3CCCN(C)C3)cc1)C(=O)N2
Yield: 51 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (603 mg, 1.2 equiv.) and 4-methyl-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.28 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (439 mg, 51%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:22]=[O:23])C.[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:22]=[O:23])=[C:11]([CH3:13])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1cn(-c2ccc(F)cc2)nn1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1C=O
Temperature: -75 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-methyl-1H-[1,2,3]triazole (3.67 g, 21 mmol) in THF (110 mL) was added n-BuLi (1.6 M in hexane, 15.53 mL, 25 mmol) dropwise at −75° C. under Argon. The resulting solution was stirred at −75° C. for 1 h, then DMF (2.1 mL, 27 mmol) was added dropwise at −75° C. and the reaction mixture was allowed to warm up to room temperature over 1 h. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (3.85 g, 91%) as a white solid. MS: m/e=206.2 [M]+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7]1.[C:15](=O)(O)[O-:16].[Na+]>CN(C=O)C>[NH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([CH:15]=[O:16])=[CH:7]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ncccc12
Temperature: 5 °C

Procedure:
Phosphorus oxychloride (36.5 mL) was added dropwise to cooled solution of DMF (40 mL) while maintaining the temperature below 10° C. The resulting solution was further cooled to 5° C. and a solution of 7-azaindole in DMF (40 mL) was added slowly over 30–40 min, maintaining the temperature below 25° C. The mixture was heated at 95° C. for 48 h then cooled to 35° C. and added cautiously with stirring over an hour to a cooled solution of saturated aqueous sodium bicarbonate solution (800 mL). The mixture was extracted with ethyl acetate (4×500 mL) and the combined extracts washed with water (500 mL) and brine (500 mL), then dried (MgSO4), filtered and concentrated in vacuo to afford a dark brown semi-solid. This crude product was purified using column chromatography eluting with a 50:50 mixture of ethyl acetate:hexane, gradually increasing to 90:10 mixture. 1H-NMR (400 MHz/D6-DMSO): δ=7.25 (m, 1H), 8.38 (m, 2H), 8.42 (s, 1H), 9.92 (s, 1H), 12.62 (br.s, 1H). MS (ES+): 147 [MH+].
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][C:22]=3[F:36])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]=3[F:36])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)OC(C)(C)C)cc3F)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CC(=O)O)cc3F)CC2)CC1
Yield: 91.6 %

Procedure:
4-[1-(4-tert-Butoxycarbonylmethyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 75a (368 mg) was dissolved in DCM (5 mL) and TFA (3 mL) and stirred at r.t. for 4 h. The solvent was removed in vacuo, DCM and water were added and the organic phase was dried over MgSO4 and concentrated to give 4-[1-(4-carboxymethyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 75b (300 mg).
Reaction SMILES: N[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[ClH:16].N([O-])=O.[Na+].[OH-].[Na+]>O>[Cl:16][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: Nc1c(C(F)(F)F)ccc2ccncc12
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)c1ccc2ccncc2c1Cl
Reaction time: 8 h

Procedure:
8-Amino-7-trifluoromethylisoquinoline (0.7 g.) in 2 ml. of concentrated hydrochloric acid and 10 ml. of water is diazotized at 0° C. with 0.25 g. of sodium nitrite in 5 ml. of water. The resulting solution is added to a solution of 2 g. of cuprous chloride in 20 ml. of concentrated hydrochloric acid previously warmed to 70° C. After standing overnight, the reaction mixture is basified with 10% aqueous sodium hydroxide solution and extracted with ether. The ether extracts are washed with water, dried over sodium sulfate and evaporated to give 8-chloro-7-trifluoromethylisoquinoline as the residue. This isoquinoline is converted to the hydrochloride and recrystallized from ethanol and ether.