Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[N:11](C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1.[C:23](Cl)(=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:1][C:2]1[N:22]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[NH:11][CH:12]=[CH:13][CH:14]=3)[N:4]2[N:3]=1)=[O:32]
Reactant: COc1cccc(C(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc2nc(N)nn12
Product: COc1cccc(C(=O)Nc2nc3cccc(-c4ccc[nH]4)n3n2)c1
Yield: 40.8 %

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from tert-butyl 2-(2-amino[1,2,4]triazolo[1,5-a]pyridin-5-yl)-1H-pyrrole-1-carboxylate ((A6), 50 mg; 0.17 mmol; 1.0 eq.) and m-anisoyl chloride (57 mg; 0.33 mmol; 2.0 eq.). Further treatment with a DCM/TFA solution (2:1) and purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 50:60 to 80:20) gave the title compound as a white solid (23.1 mg, 41%). HPLC, Rt: 3.40 min. (purity 94.7%). LC/MS, M+(ESI): 334.3, M+(ESI): 332.1
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>C(O)C>[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Br:1])=[CH:3][CH:4]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 5 h
Yield: 87.1 %

Procedure:
A mixture of 4-bromoaniline (100 g, 563.9 mmol) and 2-ethoxymethylene-malonic acid diethyl ester (126.9 g, 575 mmol) was heated to 90° C. Then, the resulting brown mixture was stirred for 5 h. After cooling to room temperature, the reaction mixture was diluted with ethanol (˜200 mL) and cooled down in an ice-water bath to afford a hard solid. This mixture was then heated to break down the hard solid and also to remove most of the impurities. After cooling the suspension in the refrigerator, the solids were collected by filtration and washed with cold ethanol. After drying in air, 168 g (87% yield) of 2-[(4-bromo-phenylamino)-methylene]-malonic acid diethyl ester was isolated as a white solid: mp 100-102° C. (lit. 100-101° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[CH:32][C:23]=4[F:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: Fc1cccc2c1CCNC2
Agent: Cl
Product: O=C(c1nc(-c2ccc(F)cc2)nc2ccccc12)N1CCc2c(F)cccc2C1
Yield: 27 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 10 (27.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 2.88 and 3.13 (2t, 2H), 3.64 and 4.24 (2t, 2H), 4.58 and 5.14 (2s, 2H), 6.68-7.33 (m, 5H), 7.65-7.77 (m, 1H), 7.94-8.10 (m, 2H), 8.15-8.20 (m, 1H), 8.57-8.67 (m, 2H); 19F (282 MHz, DMSO-d6) δ −112.0, −121.0; MS (ESI) m/z 402 ([M+H]+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[C:3]1=[O:20]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][N:2]1[CH:6]([C:7]([OH:9])=[O:8])[CH2:5][N:4]([C:14]2[CH:19]=[N:18][CH:17]=[N:16][CH:15]=2)[C:3]1=[O:20]
Reactant: CN1C(=O)N(c2cncnc2)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cncnc2)CC1C(=O)O
Yield: 97.2 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (601 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 5-bromopyrimidine (477 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1466 mg, 4.50 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.7 mg, 0.075 mmol) and the mixture was heated under reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (349 mg, 42%). LC/MS [M+H]+=279. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylate (630 mg, 2.264 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 8 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-(5-pyrimidinyl)-4-imidazolidinecarboxylic acid (assume ˜2.2 mmol) which was used in the next step. LC/MS [M+H]+=223.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:11])=[O:10])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.Cl.[CH2:22]([O:24][C:25](=[O:29])[C@H:26]([CH3:28])[NH2:27])[CH3:23].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:22]([O:24][C:25](=[O:29])[CH:26]([NH:27][C:14](=[O:16])[CH2:13][CH2:12][S:9](=[O:10])(=[O:11])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:17]([F:20])([F:19])[F:18])[CH3:28])[CH3:23]
Reactant: O=C(O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: CCOC(=O)[C@H](C)N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)NC(=O)CCS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
Under the conditions of Example 2(a), 3.152 g (10 mmol) of 3-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]propionic acid, 1.536 g (10 mmol) of L-alanine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is purified by column chromatography on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.[CH3:26][C:27]([N:33]1[CH2:41][C:40]2[C:35](=[CH:36][C:37]([C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-])=O)=[CH:44][CH:43]=3)=[CH:38][CH:39]=2)[C:34]1=[O:51])([CH3:32])[C:28]([O:30][CH3:31])=[O:29]>>[NH2:48][C:45]1[CH:44]=[CH:43][C:42]([C:37]2[CH:36]=[C:35]3[C:40]([CH2:41][N:33]([C:27]([CH3:32])([CH3:26])[C:28]([O:30][CH3:31])=[O:29])[C:34]3=[O:51])=[CH:39][CH:38]=2)=[CH:47][CH:46]=1
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc([N+](=O)[O-])cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Product: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Yield: 78 %

Procedure:
The compound of example 515 was prepared analogous to the compound of example 6 by reduction of the compound of example 514.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[H-].[Na+].[CH3:30]COC(C)=O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]([CH3:30])[C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(C)=O
Reactant: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CCC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-methyl 5-(tert-butoxycarbonylamino)-6-(tert-butyldimethylsilyloxy)hexanoate (15 g, 40 mmol) in DMF (100 mL) was added iodomethane (17 g, 120 mmol, 3 equiv.) at 0° C. NaH (60%, 2.4 g, 60 mmol, 1.5 equiv.) was added in 3 portions. The reaction was stirred at RT for 2 h. EtOAc (150 mL) and brine (200 mL) were added to the reaction mixture. The organic layer was washed with brine (200 mL), dried, and concentrated to give (S)-methyl 5-(tert-butoxycarbonyl(methyl)amino)-6-(tert-butyldimethylsilyloxy)hexanoate (15.5 g, quant.) as a colorless oil. LRMS (M-Boc+H+) m/z 290.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C:19]3[NH:20][C:21]([CH3:25])=[C:22]([Cl:24])[CH:23]=3)=[O:18])[C@H:12]([O:26][CH3:27])[CH2:11]2)=[N:7][C:6]=1[C:28]([NH:30]C(C)(C1C=CC=CC=1)C)=[O:29])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:30][C:28]([C:6]1[N:7]=[C:8]([N:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C:19]3[NH:20][C:21]([CH3:25])=[C:22]([Cl:24])[CH:23]=3)=[O:18])[C@H:12]([O:26][CH3:27])[CH2:11]2)[S:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: COC(=O)c1sc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc1C(=O)NC(C)(C)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(N2CC[C@H](NC(=O)c3cc(Cl)c(C)[nH]3)[C@H](OC)C2)nc1C(N)=O
Temperature: 85 °C

Procedure:
Cis(±)methyl-2-(4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-{[(1-methyl-1-phenylethyl)amino]carbonyl}-1,3-thiazole-5-carboxylate (Example 21; 0.058 g, 0.1 mmol) was dissolved in equal volumes of TFA and DCM. The reaction was heated in a sealed tube to an external temperature of 85° C. overnight. The reaction mixture was concentrated to remove the DCM and excess TFA. The residue was partitioned with EtOAc and NaHCO3 and the organic extracts were dried with MgSO4 and concentrated to a yellow solid (0.050 g, 100%). MS (ES) MH+: 456 for C18H22ClN5O5S.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:9].S(Cl)([Cl:13])(=O)=O>C(O)(=O)C>[Cl:13][C:5]1[S:4][C:3]([CH2:2][Cl:1])=[C:7]([CH2:8][Cl:9])[CH:6]=1
Reactant: ClCc1ccsc1CCl
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: ClCc1cc(Cl)sc1CCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
2,3-Bis-chloromethyl-thiophene (500 mg, 2.76 mmol) was dissolved in acetic acid (10 ml). Sulfuryl chloride (372 mg, 2.76 mmol) was added and the mixture was stirred for 1 h at room temperature. The mixture was partitioned between EA, water and an excess of solid sodium hydrogencarbonate and the aqueous phase extracted with EA. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to dryness to give 240 mg of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=C(C(C3N=CC4CCCCC=4C=3)=O)[NH:22]2)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:2]([C:3]([C:5]3[CH:14]=[CH:13][C:8]4[O:9][CH2:10][CH2:11][O:12][C:7]=4[CH:6]=3)=[O:4])[NH:22]2)=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccc2c(c1)OCCO2
Reactant: COC(=O)Cc1c(C(=O)c2cc3c(cn2)CCCC3)[nH]c2cc(Cl)ccc12
Product: COC(=O)Cc1c(C(=O)c2ccc3c(c2)OCCO3)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 6-bromoacetyl-2,3-dihydro-1,4-benzodioxine (J. Med. Chem. 1972, 15, 49) and methyl trans-4-chloro-2-[(phenylsulfonyl)amino]cinnamate (Example 1, step 1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C@H:8]([OH:10])[CH:7]=[CH:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C>C(O)C.[Ni]>[C:1]([O:4][C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:10])[CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1C=C[C@@H](O)C1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)O[C@@H]1CC[C@H](O)C1
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
Dissolve (-)-cis-4-acetoxy-cyclopent-2-enol (11.0 g, 77.4 mmol, prepared in example 19) in ethanol (50 mL) and treat with Raney nickel (1.1 g, previously washed with water (2×50 mL) and ethanol (2×50 mL), Ra--Ni). Charge the atmosphere with hydrogen at 50 psi (344.74 kPa) and shake the mixture. After 20 minutes, filter the solution and treat the filtrate with triethylamine (1.0 mL, 7.2 mmol). After one hour concentrate the solution under vacuum and distill the residue by Kugelrohr distillation (60°-80° C., 1 mm Hg), to provide the title compound (9.74 g, 87%) as a colorless oil.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[CH:8]=1.C([Li])CCC.[F:21][C:22]([F:27])([F:26])[C:23]([CH3:25])=[O:24]>O.CCCCCC>[F:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]([F:15])[C:8]=1[C:23]([OH:24])([CH3:25])[C:22]([F:27])([F:26])[F:21]
Reactant: CC(=O)C(F)(F)F
Reactant: COc1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)(O)C(F)(F)F)c(F)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
To a tetrahydrofuran (100 ml) solution of 1,3-difluoro-5-methoxybenzene (7 g, 48.6 mmol) was added 1.6 M hexane solution of n-butyllithium (30 ml, 48.6 mmol) dropwise at −78° C. over 30 minutes and the mixture was stirred for 2 hours at −78° C. 1,1,1-Trifluoroacetone (6.5 g, 58.3 mmol) was added at −78° C. and the mixture was stirred for 2 hours at −78° C. followed by additional stirring for 1 hour at room temperature. Then, the reaction was diluted with water and the product was extracted with ethyl acetate. Then, the organic layer was filtrated, evaporated and concentrated. The residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate (10:1), to furnish 9.7 g (78% yield) of the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10].[F:13][C:14]([F:21])(I)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CS(C)=O.[Cu]>[F:13][C:14]([F:21])([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([F:12])([F:11])[F:10])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C(F)(F)I
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [Cu]
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 10 h
Yield: 49.1 %

Procedure:
To a mixture of 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.5 g, 2.092 mmol) in DMSO (10 mL) was added ethyl 2,2-difluoro-2-iodoacetate (0.410 mL, 2.000 mmol) and copper (0.439 g, 6.90 mmol) at rt. The mixture was stirred at 20° C. for 10 h. The mixture was extracted with EA, washed with brine, and the organic layer was concentrated to give ethyl 2,2-difluoro-3-(2-(trifluoromethyl)phenyl)propanoate (320 mg, 0.981 mmol, 46.9% yield): 1H NMR (400 MHz, CD3OD-d4) δ 7.72 (d, J=7.8 Hz, 1H), 7.60-7.45 (m, 3H), 4.26 (d, J=7.1 Hz, 2H), 3.63 (t, J=16.9 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:13]([C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)c1cc(F)ccc1S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C(=O)C(C)(C)C)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5.20 g 1-(5-fluoro-2-mercaptophenyl)ethanone in 100 mL anhydrous DMF was added 5.47 g 1-bromopinacolone and 10.95 g cesium carbonate. The resulting mixture was stirred at room temperature overnight and then heated at 70° C. for 3 days. After diluting the reaction mixture with ice and water, it was extracted with ether several times. The combined ether extract was washed with 0.05 N NaOH (2×), water (3×), and saturated brine, dried over anhydrous Na2SO4, and evaporated to give the crude product. The latter was purified by SGC using 10˜15% EtOAc in hexanes to give the title compound as an oil. 1H NMR (CDCl3, 500 MHz) 7.77 (dd, JH-H=8.7 Hz, JH-F=4.8 Hz, 1H), 7.49 (dd, JH-H=2.5 Hz, JH-F=9.6 Hz, 1H), 7.24 (ddd, JH-H=2.5 & 8.7 Hz, JH-F=8.7 Hz, 1H), 2.53 (s, 3H), 1.40 (s, 9H). LC-MS: 4.11 min. (m/Z=209.1, 251.1).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][CH:12]=1.C1C(=O)N([Cl:25])C(=O)C1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH2:16][CH3:17])[N:14]=[CH:13][C:12]=1[Cl:25]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCn1nccc1-c1cc(C(=O)OC)sc1Cl
Solvent: C1CCOC1
Product: CCn1ncc(Cl)c1-c1cc(C(=O)OC)sc1Cl
Yield: 73.9 %

Procedure:
Methyl 5-chloro-4-(1-ethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (1.8 g, 6.65 mmol) and NCS (1.3 g, 9.74 mmol) in THF (10 mL) were heated to 70° C. under N2 for 2 h. The reaction solution was concentrated and purified on silica (EtOAc/Hex, 10-30%) to afford the title compound (1.5 g, 74%) as a syrup: LC-MS (ES) m/z 305 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6](=O)[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1.C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:30][OH:31]>O.CC(C)=O>[CH3:1][C:2]1([CH3:19])[C:6](=[N:30][OH:31])[CH2:5][C:4]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:8][CH3:9])[O:3]1
Reactant: CCC1(COCc2ccccc2)CC(=O)C(C)(C)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: CCC1(COCc2ccccc2)CC(=NO)C(C)(C)O1
Yield: 94.6 %

Procedure:
The ketone of Example 6 (1 g), ethanol (20 ml) hydroxylamine hydrochloride (280 mg) and potassium carbonate (330 mg) were refluxed together for 2 hours. Thin layer chromatography, using 15% acetone in petrol as eluant, showed partial conversion. Additional quantities of hydroxylamine hydrochloride (280 mg) and potassium carbonate (330 mg) were added three times, with refluxing for 2 hours after each addition. Water was then added, and the mixture was extracted with diethyl ether. The ether extract was dried over magnesium sulphate and evaporated and the residue was purified on a silica gel column using 5% acetone in petrol as eluant to give 1 g (94%) of the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][N:34]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 84.1 %

Procedure:
tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (110 mg, 0.289 mmol) and 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (75 mg, 0.318 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (130 mg, 84%) as a colorless oil: ESI MS m/z 535 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:24]([O-])=O)=[C:13]([CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:14]=2)[CH:5]=[N:6][CH:7]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:24][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[CH:14][C:13]=1[CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1cc(Oc2cncc(Br)c2)ccc1N
Yield: 93.2 %

Procedure:
The reaction and post-treatment were carried out according to Example (1b) using tert-butyl {5-[(5-bromopyridin-3-yl)oxy]-2-nitrophenyl}methylcarbamate produced in Example (19a) (11.1 g, 26.2 mmol), iron powder (4.38 g, 78.5 mol), ammonium chloride (0.70 g, 13.1 mmol), ethanol (87 mL) and water (40 mL) to obtain the title compound (9.63 g, 94%) as a brown solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:24])[N:13]([C:15]4[CH:23]=[CH:22][C:18]([C:19]([Cl:27])=[O:20])=[CH:17][CH:16]=4)[NH:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Product: O=C(Cl)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Temperature: 70 °C

Procedure:
Crude 4-(6-fluoro-3-oxo-1,3-dihydro-2H-pyrazolo[4,3-c]cinnolin-2-yl)-benzoic acid (1.45 g) from the previous stage was dissolved in thionyl chloride (50 ml). The mixture was heated to 70° C. for 2-3 h until no further gas evolution was observed. The mixture was cooled to room temperature and excess thionyl chloride was removed under vacuum. The residues were azeotroped with toluene (2×20 ml) to give a solid. The solid was collected by filtration, washed with toluene and dried under vacuum. The product was isolated as a yellow powder (670 mg, 1.95 mmol). LCMS: m/z [M+H]+ 339 (methyl ester resulting from sample make-up in methanol).
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][SH:22])=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][S:22][C:2]1[C:6]2[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Fc1ccc2onc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSc1noc2ccc(F)cc12
Temperature: 0 °C
Yield: 80.1 %

Procedure:
To a solution of 3-chloro-5-fluoro-1,2-benzisoxazole (0.83 g) in dimethylformamide (8 ml) was added 2-t-butoxycarbonylaminoethanethiol (0.86 g) and potassium carbonate (0.67 g) with stirring under nitrogen atmosphere, and the mixture was then stirred at 80° C. for 3 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate and the combined extracts were washed with brine and dried over anhydrous magnesium sulphate. After filtration, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography, to give the title compound (1.21 g, 80%) as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.CCOC(C)=O>[N:15]([CH2:2][CH2:3][C@@:4]([CH3:14])([S:10]([CH3:13])(=[O:12])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@@](C)(CCBr)S(C)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@](C)(CCN=[N+]=[N-])S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a solution of ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (4.5 g, 15.7 mmol, 1 eq) in DMSO (5 mL) was added sodium azide (1.02 g, 15.7 mmol, 1 eq). The mixture was heated at 80° C. for 3 h. The mixture was then diluted with EtOAc and washed with water. The organic layer was dried (MgSO4), filtered and concentrated to give ethyl (2R)-4-azido-2-methyl-2-(methylsulfonyl)butanoate which was used without further purification.