Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=O)[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:19][C:20]1[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([C:16]([NH:19][C:20]3[O:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][N:24]=3)=[O:18])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1cnc(N)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(NC(=O)c2nnn(Cc3ccc(Cl)c(Cl)c3)c2C)o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Intermediate 4) (1 g, 3.4 mmol), ethyl 2-amino-1,3-oxazole-5-carboxylate (0.82 g, 5.2 mmol), HOBt (0.708 g, 5.2 mmol), EDCI (1.005 g, 5.2 mmol) and NEt3 (730 μL, 5.2 mmol) in DMF (50 mL) was stirred at room temperature for 2 days. The reaction was not completed and 2.5 eq of EDCI and HOBt were added and the reaction was heated at 40° C. and stirred for a further 14 days. Again no completed reaction was obtained. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM/MeOH (90/10) to give after crystallisation from diisopropyl ether, the title compound as a yellow solid (98 mg, 6%). LC/MS: m/z 424 (M+H)+. Rt: 3.17 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:28]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (259.2 mg) described in Example 465 and methyl iodide (65 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (187 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:14][O:15][CH:16]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydro-4H-pyran-4-one (5.00 g, 50 mmol) was dissolved in tetrahydrofuran (250 ml) and cooled in an ice-water bath. To this solution was added n-butyl lithium (24 ml of a 2.5M solution in hexane, 60 mmol) and the reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. This was then cooled to 0° C. and a solution of (methoxymethyl)triphenyl phosphonium chloride (25.6 g, 75 mmol) in tetrahydrofuran (10 ml) was added and the reaction stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the residue triturated with diethyl ether (10×), decanting the supernatant each time. The combined supernatants were then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (95:5 to 90:10) to provide the title compound, 1.80 g.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH3:16][NH:17][CH3:18].CO>>[CH3:16][N:17]([CH3:18])[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: Cc1cc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: CO
Product: Cc1cc(N(C)C)nc2ccc([N+](=O)[O-])cc12

Procedure:
The product was obtained from the product of Step A and a solution of 2N dimethylamine in methanol (5 mL, 25 mmol) according to the procedure of Example 1, Step C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1cccc(I)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(I)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
3-Iodophenol (1.00 g, 4.55 mmol) and 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.37 g, 6.82 mmol) were dissolved in toluene (30 mL), and the mixture was stirred at room temperature for 1 hour after adding triphenylphosphine (1.79 g, 6.82 mmol) and a 40% toluene solution of diethyl azodicarboxylate (3.09 mL, 6.82 mmol). The mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give 1-tert-butoxycarbonyl-4-(3-iodophenoxy)piperidine (1.81 g, 98%).
Reaction SMILES: [CH:1]1([C:4]([CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[C:10](=[O:24])[CH:9]([NH:25]C(OC(C)(C)C)=O)[C:8]2=[O:33])=[O:5])[CH2:3][CH2:2]1.Cl>C(OCC)(=O)C>[CH:21]1([C:19]([CH2:18][N:11]2[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]([CH2:6][C:4]([CH:1]3[CH2:2][CH2:3]3)=[O:5])[C:8](=[O:33])[CH:9]([NH2:25])[C:10]2=[O:24])=[O:20])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N(CC(=O)C2CC2)c2ccccc2N(CC(=O)C2CC2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC1C(=O)N(CC(=O)C2CC2)c2ccccc2N(CC(=O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of previously prepared 1,5-bis-(cyclopropylcarbonylmethyl)-3-(t-butoxycarbonylamino)-1H-1,5-benzodiazepine-2,4(3H,5H)-dione 14 h (3.188 g) in ethyl acetate (16 ml) is added a solution of 4N HCl in ethyl acetate (14 ml) under ice-cooling. After stirring the reaction mixture for 15 hr at room temperature, crystalline preparations are filtered off. The resultant crystals are dissolved into methylene chloride/methanol (5:1) and washed with saturated aqueous sodium hydrogencarbonate solution. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Crystallization from a mixture of methylene chloride, methanol and diisopropyl ether yields the titled Compound 16 h (2.092 g; yield, 84%).
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].I[CH2:29][CH:30]([CH3:32])[CH3:31]>C1COCC1.CCCCCC>[CH2:26]([O:25][C:23]([C:20]1([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:21][CH2:22][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18][CH2:19]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)CI
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: CCOC(=O)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
4.7 g (47 mmol) DIPEA in THF at −5° C. was treated slowly with 29.1 mL (47 mmol) n-Buli (1.6N in hexane) and stirred for 30 min at −5° C. and subsequently cooled to −75° C. and stirred for 2 h. A solution of 10 g (39 mmol) ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate (commercially available) in THF was added and the mixture was stirred for 2 h at −75° C. 8.51 g (47 mmol) 1-iodo-2-methylpropane was added and the mixture was allowed to stir to room temperature over night. The mixture was quenched at 0° C. with citric acid 10% aq. and extracted with ethyl acetate. The combined organic layers were washed with NaCl aq. sat., dried with Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with a gradient formed heptane and t-butyl-methylether. The combined product fractions were evaporated to yield 10.2 g (84%) of the title compound as light yellow oil. MS (m/e): 331.2 (M+NH4+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]1([CH3:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=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>[C:32]1([C:38]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:25]=[CH:24][C:23]4[C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]5[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=5)[C:10]=4[CH:9]=3)=[CH:4][CH:3]=2)=[C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1ccccc1
Reactant: Brc1ccc(-c2ccc3c4ccccc4c4ccccc4c3c2)cc1
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: [K+]
Product: c1ccc(C(=C(c2ccccc2)c2ccc(-c3ccc4c5ccccc5c5ccccc5c4c3)cc2)c2ccccc2)cc1
Temperature: 60 °C
Yield: 82 %

Procedure:
The product B (1.25 g, 3.26 mmol), D (1.37 g, 3.58 mmol), potassium carbonate solution (K2CO3(aq), 2.0 M, 8.0 mL), and dried toluene (24 mL) were charged in a two-necked bottle. The bottle was deoxygenated and purged with nitrogen, and the mixture in the bottle was stirred at 60° C. until it was totally dissolved. The nitrogen pressure of the bottle was increased, and Pd(PPh3)4 (381 mg, 0.33 mmol) was rapidly added into the bottle. The reaction was heated to 110° C., and stirred for 48 hours. The resulting was filtered to remove metal. The filtrate was condensed to remove the solvent. The solid was washed by water and methanol, and then sublimated at a temperature of 260° C. to obtain TSTP (1.50 g, yield=82%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])=[CH:24][C:20]=1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(Cl)Cl.CCO>C1COCC1>[F:17][CH:15]([F:16])[CH2:14][O:13][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[C:25]([CH2:28][NH:29][C:30]([C:32]([CH3:33])([CH3:35])[CH3:34])=[O:31])[CH:26]=[CH:27][C:19]=2[Cl:18])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(N)ccc1OCC(F)F
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(NC(=O)c2cc(CNC(=O)C(C)(C)C)ccc2Cl)ccc1OCC(F)F

Procedure:
Prepared analogously to Example 4c from 2 ethyl 5-amino-2-(2,2-difluoroethyl)oxy-benzoate and 2-chloro-5-(tert-butylcarbonylamino)methyl-benzoic acid with TBTU and TEA in THF. Yield: (quantitative). MS [M+H]+=497 (Cl isotope pattern); TLC: Rf=0.35 (silica gel, DCM:EtOH 19:1).
Reaction SMILES: [C:1]1([C@@H:7]2[C@H:12]3[C@H:10]([CH2:11]3)[C@H:9]([NH2:13])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=C1CCC(=O)N1[O:30][C:31]([NH:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:35]=1[CH:36]=[N:37][N:38]2C(OC)=O)=O.[OH-].[Na+]>CCOC(C)=O.CO.CN(C=O)C>[NH:38]1[C:39]2[C:35](=[C:34]([NH:33][C:31]([NH:13][C@@H:9]3[CH2:8][C@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C@H:12]4[C@@H:10]3[CH2:11]4)=[O:30])[CH:42]=[CH:41][CH:40]=2)[CH:36]=[N:37]1
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Reactant: N[C@@H]1C[C@H](c2ccccc2)[C@@H]2C[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2[nH]ncc12)N[C@@H]1C[C@H](c2ccccc2)[C@@H]2C[C@@H]21
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
An orange solution of Example 55C (20 mg, 0.115 mmol), DMF (1 mL), DIPEA (0.042 mL, 0.242 mmol), and methyl 4-((2,5-dioxopyrrolidin-1-yloxy)carbonylamino)-1H-indazole-1-carboxylate (40.3 mg, 0.121 mmol) was stirred at ambient temperature. After 15 minutes, MeOH (2.00 mL) and sodium hydroxide (50 wt % in water, 0.018 mL, 0.346 mmol) were added. After 20 minutes of stirring, the mixture was diluted with EtOAc (30 mL) and washed with water (10 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (75-100% EtOAc/hexanes, gradient elution) to provide the title compound (27.5 mg, 0.083 mmol, 71.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 13.0 (brs, 1H), 8.63 (s, 1H), 8.09 (d, J=1.0 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.39-7.33 (m, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.24-7.16 (m, 2H), 7.05 (d, J=8.2 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 4.49-4.38 (m, 1H), 3.50-3.41 (m, 1H), 2.24 (dt, J=12.7, 7.6 Hz, 1H), 1.66-1.58 (m, 2H), 1.29-0.90 (m, 1H), 0.69 (q, J=4.2 Hz, 1H), 0.48 (td, J=7.7, 5.2 Hz, 1H). MS (DCI) M/Z 350 [M+NH4]+.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH3:12])[CH3:6]>O>[CH2:5]([N:7]1[CH2:8][CH2:9][N:10]([CH2:11][CH3:12])[CH2:3][C:1]1=[O:2])[CH3:6]
Reactant: CCNCCNCC
Reactant: O=CC=O
Solvent: O
Product: CCN1CCN(CC)C(=O)C1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
To 10.0 g (69.0 mmoles) of 40 percent glyoxal and 200 ml of distilled water is rapidly added 8.0 g (69.0 mmoles) of N,N'-diethylethylenediamine. The solution is heated rapidly to reflux and heating maintained for 5 minutes. The dark brown solution is allowed to cool to room temperature and is then evaporated at 60° C. under water pump vacuum to a viscous brown oil. The oil is distilled in a short path distillation apparatus to yield 10 g (93 percent yield) of 1,4-diethylpiperazin-2-one in the form of a yellow oil. Purity is greater than 99 percent by capillary gas chromatograph.
Reaction SMILES: C(N1C2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC=CC=4)=S)=CC=3F)C=2C=C1)C1C=CC=CC=1.[F:38][C:39]1[CH:40]=[C:41]([NH:55]C(NC(=O)CC2C=CC=CC=2)=S)[CH:42]=[CH:43][C:44]=1[O:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[CH:52]=[CH:53][S:54][C:47]=12.[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=1[CH2:76][C:77]([N:79]=[C:80]=[S:81])=[O:78]>>[F:68][C:69]1[CH:74]=[CH:73][CH:72]=[C:71]([F:75])[C:70]=1[CH2:76][C:77]([NH:79][C:80](=[S:81])[NH:55][C:41]1[CH:42]=[CH:43][C:44]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[C:48]3[CH:52]=[CH:53][S:54][C:47]=23)=[C:39]([F:38])[CH:40]=1)=[O:78]
Reactant: O=C(Cc1c(F)cccc1F)N=C=S
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3c2ccn3Cc2ccccc2)c(F)c1
Product: O=C(Cc1c(F)cccc1F)NC(=S)Nc1ccc(Oc2ccnc3ccsc23)c(F)c1
Yield: 23 %

Procedure:
Starting from the amine 169 (scheme 33), following the procedures described above for the synthesis of compound 170a (example 133) but replacing 2-phenylacetyl isothiocyanate with 2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c was obtained in 23% yield. Characterization of 192c is provided in table 18.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[NH:4][N:3]=1.[F:12][C:13]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][F:29])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:30])[C:14]=1[C:15](O)=[O:16].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:12][C:13]1[C:21]([NH:22][S:23]([CH2:26][CH2:27][CH2:28][F:29])(=[O:25])=[O:24])=[CH:20][CH:19]=[C:18]([F:30])[C:14]=1[C:15]([NH:11][C:8]1[CH:9]=[C:10]2[C:2]([CH3:1])=[N:3][NH:4][C:5]2=[N:6][CH:7]=1)=[O:16]
Reactant: Cc1n[nH]c2ncc(N)cc12
Reactant: O=C(O)c1c(F)ccc(NS(=O)(=O)CCCF)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)CCCF)c3F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.5 %

Procedure:
3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-amine (0.100 g, 0.675 mmol, Example 4, Step B), 2,6-difluoro-3-(3-fluoropropylsulfonamido)benzoic acid (0.211 g, 0.709 mmol), EDCI (0.136 g, 0.709 mmol) and HOBt (0.091 g, 0.675 mmol) were dissolved in DMF (1.9 mL) and stirred at room temperature for 16 hours. The reaction mixture was purified by reverse phase HPLC to give 2,6-difluoro-3-(3-fluoropropylsulfonamido)-N-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.085 g, 29%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.22 (s, 1H), 11.05 (s, 1H), 9.93 (br s, 1H), 8.60-8.59 (m, 1H), 8.55-8.54 (m, 1H), 7.59-7.53 (m, 1H), 7.30-7.25 (m, 1H), 4.62 (t, 1H), 4.50 (t, 1H), 3.26-3.23 (m, 2H), 2.20-2.07 (m, 2H); m/z (ES-MS) 428.1 (100.0%) [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[Sn](Cl)Cl>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:11]2[C:12]([C:17]#[N:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:4]=1
Reactant: N#Cc1ncccc1-c1cc([N+](=O)[O-])ccc1F
Agent: Cl[Sn]Cl
Product: N#Cc1ncccc1-c1cc(N)ccc1F

Procedure:
By the method of Example 1, 3-(2-fluoro-5-nitrophenyl)pyridine-2-carbonitrile was reduced with tin(II) chloride to afford 3-(5-amino-2-fluorophenyl)pyridine-2-carbonitrile, which in turn was converted to 3-(5-bromo-2-fluorophenyl)pyridine-2-carbonitrile. Crystallisation from toluene/isohexane furnished off-white needles: δH (400 MHz, CDCl3) 8.77 (1H, dd, J 5 and 2 ), 7.83 (1H, t, J 1.5), 7.59 (3H, m), 7.16 (1H, t, J 9); m/z (ES+) 277, 279.
Reaction SMILES: [CH2:1]([CH:10]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[CH:13]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:12]1=[O:48])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(C1C=CC(S([N:70]=[N+:71]=[N-])(=O)=O)=CC=1)(O)=O.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:49]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:31])[C:17]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])=[N+:70]=[N-:71])[CH:13]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:36])[CH3:33])[C:12]1=[O:48])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(=[N+]=[N-])C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.25 h

Procedure:
1.9 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone and 660 mg of p-carboxybenzenesulfonyl azide were dissolved in 50 ml of dried acetonitrile, and 1.4 ml of triethylamine was added thereto dropwise in a nitrogen stream under ice-cooling. After stirring at that temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, and the thus formed precipitate was filtered. The filtrate was concentrated under reduced pressure, and the resulting oily residue was subjected to silica gel chromatography to obtain 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([O:18]C(C)(C)C)=[N:9][C:10]([O:13]C(C)(C)C)=[N:11][CH:12]=1.[CH3:23][C:24]1[CH:40]=[CH:39][C:27]2[C:28](=O)[C:29]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:30]=3[CH2:31][CH2:32][C:26]=2[CH:25]=1>O1CCCC1>[CH3:37][C:34]1[CH:35]=[CH:36][C:29]2[CH:28]([C:7]3[C:8](=[O:18])[NH:9][C:10](=[O:13])[NH:11][CH:12]=3)[C:27]3[CH:39]=[CH:40][C:24]([CH3:23])=[CH:25][C:26]=3[CH:32]=[CH:31][C:30]=2[CH:33]=1
Reactant: Cc1ccc2c(c1)CCc1cc(C)ccc1C2=O
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (5.6 ml of a 2.5M solution in hexanes) was added dropwise to a solution of the product of example 1 step (iii) (3.85 g) in tetrahydrofuran (30 ml) at -78° C. The solution was stirred for 30 minutes and a solution of 10,11-dihydro-2,8-dimethyl-5H-dibenzo[a,d]cyclohepten-5-one (European Patent, 1993, 0 589 322 A1) (3.0 g) in tetrahydrofuran (20 ml) was added. The mixture was stirred at -78° C. for 45 minutes and room temperature for 15 minutes and then partitioned between brine and ethyl acetate. The organic phase was dried (MgSO4) and evaporated. The residue was dissolved in glacial acetic acid (100 ml) and heated at 120° C. for 30 minutes. The solvent was evaporated and the residue azeotroped with toluene and triturated with diethyl ether to give a solid. Yield 4.03 g.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)OC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To a solution of 4-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)piperidine (3.31 g, 9.24 mmol) (obtained as described in Reference Example 51(2)) in dimethylformamide (100 ml) was added sodium azide (660 mg, 10.2 mmol), and the mixture was stirred in an oil bath (100° C.) for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 4-azido-1-(p-nitrobenzyloxycarbonyl)piperidine (2.81 g, yield 100%) as pale yellow crystals.