Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=3)[CH:29]=1)=[CH:17]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.3 %

Procedure:
4-Hydroxy-3-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.47 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution stirred at room temperature for 7 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture stirred for 2 hours. The mixture was shaken, the organic layer separated and dried over Na2SO4. The solvent was evaporated to give an orange solid. Recrystallization from methanol gave the product (300 mg), mp 195-196° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:26]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(-c3ccccc3)cc2)cc1N
Yield: 118.7 %

Procedure:
Prepared from (3″-nitro-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acid tert.-butyl ester (Example C12) (160 mg, 0.409 mmol) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a beige solid (175 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[N:23]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=[CH:25][C:17]=23)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][NH2:37].CC(O)=O>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[N:36][NH2:37])[C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]3[NH:23][CH:24]=[CH:25][C:17]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCN(Cc4ccccc4)CC3)c(Cl)cnc21
Solvent: CC(=O)O
Product: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCN(Cc2ccccc2)CC1
Yield: 63.7 %

Procedure:
The mixture of (1-benzylpiperidin-4-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.85 g, 3.63 mmol), anhydrous hydrazine (0.341 mL, 10.9 mmol) and AcOH (0.21 mL, 3.63 mmol) was heated at reflux over 3 Å molecular sieves in a Dean-Stark trap for about 48 h. The reaction mixture was cooled to ambient temperatures, the solvent was removed under reduced pressure and the residue partitioned between saturated NaHCO3 (100 mL) and EtOAc (100 mL). The organic layer was separated, washed with brine (100 mL), dried in vacuo over anhydrous MgSO4 and concentrated. The residue was suspended in Et2O (15 mL) and the resulting precipitate was collected by filtration and dried in vacuo to yield 4-((1-benzylpiperidin-4-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (0.85 g, 64%) as an off-white solid: LC/MS (Table 2, Method n) Rt=1.48 min; MS m/z: 368 and 370 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].O[CH2:6][NH:7][C:8](=[O:23])[CH2:9][CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+](C1C=CC=CC=1)([O-])=O.Cl>O>[C:11]1([CH:10]2[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:6][NH:7][C:8](=[O:23])[CH2:9]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CC(c1ccccc1)c1ccccc1)NCO
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: O=C1CC(c2ccccc2)c2ccccc2CN1
Temperature: 100 °C
Reaction time: 6 h
Yield: 34 %

Procedure:
8.7 g. (0.065 moles) of aluminium chloride are added to a solution of 7.7 g. (0.030 moles) of N-hydroxymethyl-3,3-diphenyl-propionamide in 300 ml. of nitrobenzene. The reaction mixture is heated, with stirring, at 100° C. for 6 hours and then cooled and poured into 1 liter water containing 5 ml. of concentrated hydrochloric acid. The nitrobenzene is removed by steam distillation and the residue is extracted with chloroform. The organic phase is dried over anhydrous sodium sulfate and then evaporated to dryness. The residual solid is purified by chromatography on a silica column, using a mixture of benzene and ethanol (85:15 v/v) as eluent, and then recrystallized from 2-propanol. 2.4 g. (34% of theory) of 5-phenyl-1,2,4,5-tetrahydro-3H-2-benzazepin-3-one are obtained. M.P. 182°-183° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:32][CH2:31]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[Cl:37][C:38]1[CH:39]=[N+:40]([O-:63])[CH:41]=[C:42]([Cl:62])[C:43]=1[CH2:44][C@@H:45]([C:47]1[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:56])[F:55])=[C:49]([O:57][CH2:58][CH:59]2[CH2:61][CH2:60]2)[CH:48]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][C@H:45]([C:47]2[CH:52]=[CH:51][C:50]([O:53][CH:54]([F:55])[F:56])=[C:49]([O:57][CH2:58][CH:59]3[CH2:60][CH2:61]3)[CH:48]=2)[CH2:44][C:43]2[C:42]([Cl:62])=[CH:41][N+:40]([O-:63])=[CH:39][C:38]=2[Cl:37])=[O:22])=[O:18])=[CH:15][C:14]=1[O:28][CH2:29][CH:30]1[CH2:31][CH2:32]1)[S:9]([CH3:12])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OC(C)(C)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.2 %

Procedure:
To a mixture of 2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoyloxy)-2-methylpropanoic acid (300 mg, 0.636 mmol) and EDC (366 mg, 1.909 mmol) in dry DCM (10 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (267 mg, 0.636 mmol) and DMAP (78 mg, 0.636 mmol) were added, and the resulting solution was stirred at RT for 2 days. The solvent was evaporated and the residue was portioned between ethyl acetate and water; the organic phase was washed with 0.5N HCl, aqueous sat. NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/32% NH4OH=95/5/0.5) to give (S)-4-(2-(2-(4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoyloxy)-2-methylpropanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide as a white powder (168 mg, 0.192 mmol, 30.2% yield, MS/ESI+873.4 [MH]+).
Reaction SMILES: [CH3:1][NH2:2].[ClH:3].[CH2:4]([O:6][C:7]([CH2:9][C:10](=[NH:14])OCC)=[O:8])[CH3:5]>C(O)C>[ClH:3].[CH3:1][NH:2][C:10](=[NH:14])[CH2:9][C:7]([O:6][CH2:4][CH3:5])=[O:8]
Reactant: CN
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)NC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 7.0 gm. (0.22 mole) of methylamine dissolved in 50 ml. of absolute ethanol at ice-bath temperature is added 41.4 gm. (0.207 mole) of ethyl ethoxycarbonylacetimidate hydrochloride. The reaction mixture is allowed to warm to room temperature and stirred for 5 hours. The solvent is removed and a mixture of acetone-ether is added to induce crystallization. 36.8 Gm. of crystalline product is collected as the hydrochloride salt.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:7]([F:13])=[C:8]([F:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.[O:19]1[C:23]2([CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[O:22][CH2:21][CH2:20]1.Cl>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:26]2([OH:29])[CH2:27][CH2:28][C:23]3([O:22][CH2:21][CH2:20][O:19]3)[CH2:24][CH2:25]2)=[C:8]([F:12])[C:7]=1[F:13])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(F)c1F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(C2(O)CCC3(CC2)OCCO3)c(F)c1F
Reaction time: 2 h
Yield: 99.7 %

Procedure:
3-Butoxy-1,2-difluorobenzene (7) (30.0 g) and THF (500 ml) were added to a reaction vessel under an atmosphere of nitrogen, and cooled to −74° C. n-Butyllithium (1.66 M in n-hexane solution; 120 ml) was added dropwise in the temperature range of −74° C. to −70° C. and the stirring was continued for another 2 hours. Successively, 1,4-dioxaspiro[4.5]decan-8-one (8) (30.2 g) in THF (200 ml) solution was added dropwise in the temperature range of −75° C. to −70° C., and the stirring was continued for another 8 hours while the mixture was allowed to come to 25° C. The resulting reaction mixture was poured into a 1N—HCl aqueous solution (500 ml) and ethyl acetate (500 ml) in a vessel and mixed with them. The mixture was then allowed to stand until it had separated into organic and aqueous phases, and the extraction into an organic phase was carried out. The resulting organic phase was separated, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to leave 8-(4-butoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (9) (55.0 g). The resulting compound (9) was a pale yellow oil.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:11]=[CH:10][S:9][C:8]=1[C:12]([O:14][CH3:15])=[O:13]>C(Cl)(Cl)Cl>[Cl:4][C:8]1([C:12]([O:14][CH3:15])=[O:13])[C:7](=[O:6])[CH:11]=[CH:10][S:9]1
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)c1sccc1O
Solvent: ClC(Cl)Cl
Product: COC(=O)C1(Cl)SC=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sulphuryl chloride (0.11 mol) was added to a stirred solution of methyl 3-hydroxythiophene-2-carboxylate (0.1 mol) (C. Corral, J. Lissavetzty; Syntheses (1984), 847) in anhydrous chloroform (50 ml). After stirring at room temperature for 4 hours the solvent was removed under reduced pressure and the residue used crude in the following preparations (m.p. 70°-71° C., hexane).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16](O)=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9][CH3:10].C[N:23](C)C=O>ClCCl>[CH2:7]([C:11]1[NH:15][N:14]=[C:13]([C:16]([NH2:23])=[O:17])[C:12]=1[N+:19]([O-:21])=[O:20])[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1[nH]nc(C(=O)O)c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (12.3 ml, 141 mmol) was added dropwise to a suspension of 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid (10 g, 46.9 mmol) in dichloromethane (100 ml) containing dimethylformamide (0.5 ml) under nitrogen at 0° C. The reaction was stirred at 0° C. for 1 hours, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in toluene (100 ml) and ammonia gas was bubbled into the solution for 2 hours. The reaction was stirred under nitrogen at room temperature for 18 hours, concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (9:1, by volume) to give 5-butyl-4-nitro-1H-pyrazol-3-carboxylic acid amide (3.1 g) as an orange solid. 1H NMR (400 MHz, DMSO-D6): δ=7.87-7.96 (1H, brs), 7.57-7.66 (1H, brs), 2.83-2.90 (2H, t), 1.56-163 (2H, quin), 1.24-1.36 (2H, sext), 0.84-0.92 (3H, t) ppm. LRMS (electrospray): m/z [M−H]+ 211. Anal. Found C, 44.66; H, 5.56; N, 25.50. C8H12N4O3.0.23 mol H2O requires C, 44.41; H, 580; N, 25.90%.
Reaction SMILES: [NH:1]([C:59]([CH3:61])=[O:60])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([C:50]([O:52]C1C=CC=CC=1)=[O:51])[CH2:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6].OO.[OH-].[Na+].OS(O)(=O)=O>O>[NH:1]([C:59]([CH3:61])=[O:60])[C@H:2]([C:9]([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:38]([NH:40][C@H:41]([C:50]([OH:52])=[O:51])[CH2:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:39])[CH:35]([CH3:37])[CH3:36])=[O:32])[CH3:30])=[O:27])[CH3:25])=[O:22])[CH2:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)C(C)C
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(=O)N[C@@H](COC(C)(C)C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ac-Ser(tBu)-Asp(OtBu)-Ala-Ala-Val-Asp(OtBu)-OPh (30.2 g, 35 mmol) was dissolved in 180 ml TFE and 20 ml water and 30% H2O2 (3.9 ml, 38 mmol) was added. The reaction mixture was adjusted to pH 10.5 with 4N NaOH and stirred for 2 h at 25° C. The resulting dark brown solution was poured into 2.1 l 0.05N H2SO4 and the resulting precipitate was filtered off, washed with water and crystallized from ethanol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].[NH2:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@:12]12[S:28][CH3:29].C([O-])(O)=O.[Na+]>O.CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:10][CH:11]1[C:26](=[O:27])[N:13]2[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:16][S:17][C@:12]12[S:28][CH3:29])=[O:8]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CS[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CS[C@]12SCC(COC(C)=O)=C(C(=O)O)N1C(=O)C2NC(=O)Cc1cccs1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
2-Thienylacetyl chloride (28 μl, 0.209 mMol) is added to an ice-cold, stirring mixture of 7-amino-6-methylthio-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (66.4 mg., 0.209 mMol) and NaHCO3 (35 mg., 0.418 mMol) in H2O (1.5 ml.) and acetone (3.0 ml.). After stirring for 30 mins. in the cold, the mixture is evaporated under reduced pressure to remove acetone. The aqueous residue is diluted with more H2O (4.5 ml). and extracted with three portions of Et2O. The aqueous phase is acidified to pH 2.5 with 10% HCl and extracted with three portions of EtOAc. The EtOAc solution is dried over MgSO4, filtered, and evaporated in vacuo to a solid (72 mg.). This material is extracted with φH to remove 2-thienylacetic acid and the residue recrystallized from CH3CN-Et2O to provide 7-(2-thienylacetamido)-6-methylthio-3-acetoxymethyl-ceph-3-em-4-carboxylic acid (31 mg.) as an off-white solid.
Reaction SMILES: [N:1]([C:4]1[C:19]([O:20]CC2C=CC=CC=2)=[CH:18][C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36])=[N+]=[N-]>[Pd].[Ni]>[NH2:1][C:4]1[C:19]([OH:20])=[CH:18][C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[C:5]=1[F:36]
Reactant: [N-]=[N+]=Nc1c(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c(Nc2ccccc2F)c1F
Agent: [Ni]
Agent: [Pd]
Product: Nc1c(O)cc(C(=O)O)c(Nc2ccccc2F)c1F

Procedure:
Benzyl 4-azido-5-(benzyloxy)-3-fluoro-2-((2-fluorophenyl)amino)benzoate can be hydrogenated in the presence of appropriate catalyst (such as Pd/C, Pt, Ni). The reaction normally completes within several hours (1-12 h, prefer 3-10 h). 4-Amino-3-fluoro-2-((2-fluorophenyl)amino)-5-hydroxybenzoic acid is obtained after conventional workup.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([NH:17][CH3:18])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34]([OH:36])=O)[CH:31]([CH3:33])[CH3:32])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.F[B-](F)(F)F.BrC1C=CC=C[N+]=1CC.C(N(CC)C(C)C)(C)C.[Cl-].[Na+]>ClCCl>[CH2:19]([O:26][C:27]([NH:29][C@H:30]([C:34]([N:17]([CH3:18])[C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:36])[CH:31]([CH3:32])[CH3:33])=[O:28])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC[C@H](C)[C@H](NC)[C@@H](CC(=O)OC(C)(C)C)OC
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC[n+]1ccccc1Br
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: -10 °C

Procedure:
10.65 g (41.058 mmol) of tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate (starting compound 2b) were taken up in 250 ml of dichloromethane and the solution was cooled to −10° C. Then, while stirring, 10.317 g (41.058 mmol) of N-[(benzyloxy)carbonyl]-L-valine, 16.866 g (61.586 mmol) of 2-bromo-1-ethylpyridinium tetrafluoroborate (BEP) and 28.6 ml of N,N-diisopropylethylamine were added, and the mixture was subsequently stirred at RT for 20 h. The reaction mixture was then diluted with dichloromethane and shaken twice with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography on silica gel with 4:1 petroleum ether/ethyl acetate as the eluent. The corresponding fractions were concentrated and the residue was dried under high vacuum overnight. 10.22 g (51% of theory) of the title compound were obtained as a yellowish oil.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C(O)=O>>[NH:8]1[CH2:9][CH:10]([CH2:12][N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(CN2CCCCC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CCN(CC2CNC2)CC1
Yield: 100 %

Procedure:
3-Piperidin-1-ylmethylazetidine-1-carboxylic acid tert-butyl ester (180 mg, 0.70 mmol) was treated with a solution of TFA:DCM (1:1 v/v, 5 mL) and the resultant solution stirred at room temperature for 1 h. The solution was concentrated in vacuo afford 1-azetidin-3-ylmethylpiperidine (INTERMEDIATE III.1) (190 mg, 0.70 mmol, 100%) as the trifluoroacetic acid salt which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([NH2:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][C:11]=1[CH3:20].O>O1CCCC1>[CH3:20][C:11]1[CH:12]=[C:13]([N+:17]([O-:19])=[O:18])[C:14]([NH2:16])=[N:15][C:10]=1[O:4][CH2:3][C:2]([F:6])([F:5])[F:1]
Reactant: OCC(F)(F)F
Reactant: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(N)nc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,2,2-Trifluoroethanol (340 mg, 3.4 mmol) was dissolved in the tetrahydrofuran (10 ml), sodium hydride (60%) (120 mg, 3.0 mmol) was added thereto, and the reaction mixture was stirred for 30 minutes at room temperature under nitrogen atmosphere. A solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine crude product (400 mg) in tetrahydrofuran (10 ml) was dropped, and the reaction mixture was stirred at room temperature for 2.5 days. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with a sodium bicarbonate solution, dried over magnesium sulfate. The residue obtained by evaporating the solvent was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=15/85) to yield the title compound (225 mg, 0.90 mmol) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Br[C:25]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=1[CH:27]=[O:28]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:25]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:26]=2[CH:27]=[O:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: Cc1ccc(C=O)c(Br)c1
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc(C)ccc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester and 2-bromo-4-methylbenzaldehyde.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([O:22]CC)=[O:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:1]1([N:7]2[C:11]3[C:12]4[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=4[S:14][CH2:15][C:10]=3[C:9]([C:20]([OH:22])=[O:21])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1nn(-c2ccccc2)c2c1CSc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.9 %

Procedure:
1,4-Dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid, ethyl ester (3.36 g) suspended in dioxane (60 ml) is treated with N/1 NaOH (30 ml) under stirring at room temperature for 5 hours. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HCl. The precipitate is filtered, washed with water and dried in vacuo at 50° C. to give 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carboxylic acid (2.8 g) which is reacted with oxalyl chloride (17 g) under stirring, at room temperature for 8 hours. The reaction mixture is evaporated to dryness in vacuo and the residue, 1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazole-3-carbonyl chloride (2.9 g), is dissolved in dimethylformamide (10 ml) and added under stirring to a suspension obtained by treatment of 2-cyano-acetylamino-pyridine (1.62 ) with 50% sodium hydride (0.5 g) in dimethylformamide (5 ml). The reaction mixture is kept at room temperature for 20 hours. The basic aqueous solution is washed with ethyl ether and then is acidified to pH 5 with 37% HCl. The precipitate is filtered, washed with water and then crystallized from ethanol to give 2.7 g of 2-cyano-3-(1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-(2-pyridyl)-propanamide, m.p. 258°-260° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][O:7][C:8]([C:10]1C(C2C=CC=C([N+]([O-])=O)C=2)C(C(OC)=O)=C(C)[NH:14][C:15]=1[CH3:16])=[O:9]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][O:7][C:8](=[O:9])/[CH:10]=[C:15](\[NH2:14])/[CH3:16]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(OC)c(OC)c2)C1c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: COc1ccc(COC(=O)/C=C(/C)N)cc1OC
Yield: 75 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-n1trobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3,4-dimethoxybenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dimethoxybenzyl ester of melting point 129° C (from ethanol).