Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>C(#N)C.Cl>[C:12]([O:16][C:17](=[O:24])[NH:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](=[O:9])(=[O:10])[NH2:11])=[CH:4][CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
To a solution of 4-hydroxybenzenesulfonamide (1.211 g, 7.0 mmol) and tert-butyl(4-bromobutyl)carbamate (1.26 g, 5.0 mmol) in acetonitrile (50 mL) was added anhydrous K2CO3 (1.38 g, 10 mmol). The reaction mixtures were stirred at 75° C. for overnight. Solvent was evaporated under reduced pressure to give a residue. The residue was diluted with 1 N HCl (20 mL), extracted with DCM, and dried over Na2SO4. Solvent was evaporated under reduce pressure to afford a residue, which was purified by biotage eluting with DCM to 10% MeOH in DCM to afford tert-butyl(4-(4-sulfamoylphenoxy)butyl)carbamate as a white solid (0.720 g, 42%). 1H NMR (400 MHz, DMSO) 7.70 (d, J=8.8 Hz, 2H), 7.16 (s, 2H), 7.04 (d, J=8.8 Hz, 2H), 6.82 (brs, 1H), 4.01 (t, J=6.6 Hz, 2H), 2.94 (q, J=6.4 Hz, 2 II), 1.69-1.64 (m, 2H), 1.52-1.46 (m, 2H), 1.35 (s, 9H); MS (ESI), 367.1 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1C(O)=O.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[Cl:1]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(Br)c1Cl
Temperature: 90 °C
Yield: 99.9 %

Procedure:
To an oven dried round-bottom flask fitted with stir bar and an oven dried condenser under N2 at room temperature was added 2-chloro-3-nitrobenzoic acid (6.0 g, 29.8 mmol), mercuric oxide, red (9.67 g, 44.7 mmol) and carbon tetrachloride (200 mL). The reaction mixture heated to 90° C. for 30 minutes with irradiation from a 150 W TYPE A utility light bulb. The reaction mixture was then cooled to approximately 60° C. and bromine (2.30 mL, 44.7 mmol) added dropwise via syringe and the nitrogen inlet was replaced with an Ar balloon. The reaction mixture was heated again to 90° C. for 4 hours under constant irradiation from the light bulb. The reaction was allowed to cool to room temperature, quenched with saturated aqueous NaHCO3 solution and DCM and stirred for 30 minutes. The phases partitioned upon standing and then were separated. The aqueous portion was extracted with DCM. The combined organic phases were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 7.04 g of 1-bromo-2-chloro-3-nitrobenzene: 1H NMR (400 MHz, CDCl3) δ 7.31 (t, J=8.0 Hz, 1H) 7.74 (dd, J=8.2, 1.2 Hz, 1H) 7.87 (dd, J=8.0, 1.4 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[C:6]([CH:11]1[S:16][CH2:15][CH2:14][CH2:13][S:12]1)([O:8][CH2:9][CH3:10])=[O:7].[H-].[Na+]>CN(C)C=O>[CH:5]1([CH2:4][C:11]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:12][CH2:13][CH2:14][CH2:15][S:16]2)[CH2:3][CH2:2]1
Reactant: BrCC1CC1
Reactant: CCOC(=O)C1SCCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A solution of bromomethylcyclopropane (19.5 g, 0.144 mol) and 2-carboethoxy 1,3-dithiane (25.0 g, 0.130 mol) in dry N,N-dimethylformamide (55 mL) was added drop wise over 20 minutes to an ice cooled suspension of sodium hydride (60% oil dispersion, 6.24 g, 0.156 mol, 1.2 eq; pre-washed twice with n-pentane) in benzene (165 mL). The suspension was stirred at room temperature for 18 hours and then poured into 15% aqueous ammonium chloride. The mixture was extracted with methyl tert-butyl ether and the organic phase was separated, washed with water and then brine, dried over magnesium sulfate and filtered. The solvent was evaporated from the filtrate to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate (31.2 g, 97.4%) as a light brown oil. 1H-NMR (400 MHz, CDCl3): δ=0.07-0.15 (m, 2H), 0.37-0.47 (m, 2H), 0.76-0.89 (s, 1H), 1.25 (t, J=8 Hz, 3H), 1.70-1.85 (m, 1H), 1.88 (d, J=8 Hz, 2H), 2.01-2.13 (m, 1H), 2.54-2.65 (m, 2H), 3.13-3.26 (m, 2H), 4.19 (q, J=8 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31].C(=O)(O)[O-].[Na+]>CN(C=O)C.O.C1COCC1>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)=[CH:3][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:11][CH:10]=2)#[N:13]
Reactant: C=CC(=O)Cl
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(I)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1ccc2ncc(C#N)c(Nc3cccc(I)c3)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.8 %

Procedure:
Dissolved 500 mg (1.29 mmol) 6-amino-4-[(3-iodophenyl)amino]-3-quinolinecarbonitrile in 1.0 ml of DMF and added 6 ml THF. Chilled to 0° C. under N2 and added 200 μl (1.43 mmol) triethyl amine and 120 μl (1.44 mmol) acryloyl chloride. Removed ice bath at 15 minutes. At 1.5 hours stripped solvent. Slurried residue with water and dilute sodium bicarbonate. Collected, washed with water, air dried. Boiled solids in ethyl acetate. Filtered off solids, removed solvent of the filtrate, and dried in vacuo, giving 391 mg of orange-brown solid: mass spectrum (electrospray m/e): M+H=441.1.
Reaction SMILES: [C:1]([C:3]1[CH:42]=[CH:41][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10](O)[C:11]3[C:19]([O:20][CH:21]([F:23])[F:22])=[CH:18][C:17]([CH3:24])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].[C:43](C1C=CC2N=C(C(O)C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#[N:44].CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:23][CH:21]([F:22])[O:20][C:19]1[C:11]([CH:10]([NH:44][CH3:43])[C:8]2[NH:7][C:6]3[CH:41]=[CH:42][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)=[C:12]2[C:16](=[C:17]([CH3:24])[CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: Cc1cc(OC(F)F)c(C(O)c2nc3cc(C#N)ccc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Reactant: Cc1cc(OC(F)F)c(C(O)c2nc3ccc(C#N)cc3n2COCC[Si](C)(C)C)c2ccn(C(=O)OC(C)(C)C)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(c1nc2cc(C#N)ccc2[nH]1)c1c(OC(F)F)cc(C)c2[nH]ccc12
Temperature: 55 °C

Procedure:
To a solution of a mixture of tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(hydroxy)methyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (20 mg, 0.033 mmol) and methylamine (2.0M in THF, 0.17 mL, 0.33 mmol) in THF (0.33 mL) at room temperature, TBAF (1M in THF, 0.33 mL, 0.33 mmol) was added and the mixture was stirred at 55° C. After stirring overnight the reaction was cooled to room temperature, quenched with sat. aq. NH4Cl, extracted with EtOAc, and the organic extract was dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (br. s., 1H) 7.94 (br. s., 1H) 7.60 (d, J=8.34 Hz, 1H) 7.49 (dd, J=8.34, 1.52 Hz, 1H) 7.29 (t, J=2.78 Hz, 1H) 7.06 (t, J=75.5 Hz, 1H) 6.81 (s, 1H) 6.49 (dd, J=3.03, 2.02 Hz, 1H) 5.55 (s, 1H) 2.46 (d, J=0.76 Hz, 3H) 2.36 (s, 3H). HRMS calcd. for C20H17F2N5O (M+H)+ 382.1474. found 382.1489.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][Si:24]([CH3:46])([CH3:45])[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)[C:29]([C:42](O)=[O:43])=[CH:28]2.[NH2:47][C:48]1[CH:49]=[N:50][C:51]([N:54]2[CH2:57][CH2:56][CH2:55]2)=[CH:52][CH:53]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[N:54]1([C:51]2[N:50]=[CH:49][C:48]([NH:47][C:42]([C:29]3[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=4)[C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([Si:24]([CH3:46])([CH3:23])[CH3:45])=[CH:33][CH:32]=4)=[O:43])=[CH:53][CH:52]=2)[CH2:57][CH2:56][CH2:55]1
Reactant: C[Si](C)(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)c1ccc2c(c1)cc(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
98 mg (0.51 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and 69 mg (0.51 mmol) of 1-hydroxybenzotriazole (HOBt) are added to a solution, stirred at 20° C. under an inert atmosphere, of 0.16 g (0.47 mmol) of 5-trimethylsilyl-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 3.6, in 10 ml of DMF. The reaction mixture is stirred at ambient temperature for 15 minutes. 84 mg (0.56 mmol) of 3-amino-6-(azetidin-1-yl)pyridine, prepared according to the protocol described in stage 1.6, are subsequently added to the reaction mixture. After stirring at 20° C. for 16 h, the reaction mixture is poured into a mixture of 30 ml of a saturated aqueous solution of NaHCO3 and 30 ml of EtOAc. The aqueous phase is extracted with 20 ml of EtOAc. The combined organic phases are washed with 3×30 ml of water, dried over Na2SO4, and then concentrated under reduced pressure. The solid obtained after evaporation of the solvent under reduced pressure is washed with isopropyl ether at reflux, filtered under hot conditions and then dried under reduced pressure. 75 mg of the expected product are thus isolated.
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].CC([O-])(C)C.[K+].[NH2:21][CH:22]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24][CH:23]1[OH:31]>C(O)(C)C>[OH:31][CH:23]1[CH:22]([NH:21][C:8]([C:7]2[C:6]([CH3:11])([CH3:12])[NH:5][C:4]([CH3:3])([CH3:13])[CH:14]=2)=[O:9])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]1
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Reactant: CC1(C)OCC(N)C(O)CO1
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1(C)C=C(C(=O)NC2COC(C)(C)OCC2O)C(C)(C)N1

Procedure:
Analogously to Example 7, 78.79 g (200 mmol) of 3,5-dibromo-2,2,6,6-tetramethylpiperidin-4-one hydrobromide, 69.34 g of potassium tert-butylate, and 35.47 g (220 mmol) of 6-amino-2,2-dimethyl-1,3-dioxepan-5-ol are reacted in 800 ml of isopropanol and then extracted with dichloromethane. Yield: 37.66 g (60.3% of theory) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)amide which, crystallized from diethyl ether/hexane, shows a melting point of 125°-127° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]([CH:14]3[CH2:16][CH2:15]3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:25][CH2:24]1>O1CCOCC1.O.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>[CH:14]1([C:11]2[O:10][C:9]([C:4]3[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][N:26]5[CH2:27][CH2:28][O:23][CH2:24][CH2:25]5)[CH:31]=4)[CH:3]=3)=[N:13][N:12]=2)[CH2:16][CH2:15]1
Reactant: Nc1ncc(Br)cc1-c1nnc(C2CC2)o1
Reactant: OB(O)c1cccc(CN2CCOCC2)c1
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+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccc(CN3CCOCC3)c2)cc1-c1nnc(C2CC2)o1
Temperature: 100 °C
Reaction time: 18 h
Yield: 16.8 %

Procedure:
To a solution of 5-bromo-3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-ylamine (400 mg; 1.42 mmol) in dioxane (10 mL) and water (6 mL) were added K2CO3 (587 mg; 4.26 mmol), (3-(morpholinomethyl)phenyl)boronic acid (348 mg; 1.56 mmol) in a sealed tube. The reaction mixture was degassed with argon for 30 min, then added Pd(PPh3)4 (82.0 mg; 0.07 mmol) to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (50 mL) extracted with ethyl acetate (2×50 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel and eluted with 100% ethyl acetate, which is further purified by washing with 30% chloroform in hexane to afford 90 mg (Yield: 16.7%) of the title compound, as a yellow colour solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.O([C:17]([NH:19][C:20]1[CH:25]=[C:24]([O:26][C:27]2[C:32]([F:33])=[CH:31][C:30]([NH:34][C:35]([C:37]3([C:40]([O:42][CH2:43][C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)=[O:41])[CH2:39][CH2:38]3)=[O:36])=[C:29]([F:50])[CH:28]=2)[CH:23]=[CH:22][N:21]=1)=[O:18])C1C=CC=CC=1.Cl.[OH:52][C@@H:53]1[CH2:57][CH2:56][NH:55][CH2:54]1.C(=O)([O-])O.[Na+]>CN1CCCC1=O>[F:50][C:29]1[CH:28]=[C:27]([O:26][C:24]2[CH:23]=[CH:22][N:21]=[C:20]([NH:19][C:17]([N:55]3[CH2:56][CH2:57][C@@H:53]([OH:52])[CH2:54]3)=[O:18])[CH:25]=2)[C:32]([F:33])=[CH:31][C:30]=1[NH:34][C:35]([C:37]1([C:40]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:41])[CH2:38][CH2:39]1)=[O:36]
Reactant: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)Oc1ccccc1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)OCc4ccccc4)CC3)cc2F)ccn1)N1CC[C@@H](O)C1
Reaction time: 5 h
Yield: 90.2 %

Procedure:
N,N-Diisopropylethylamine (0.249 ml) was added to a mixture of benzyl 1-({[4-({2-[(phenoxycarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]amino}carbonyl)cyclopropanecarboxylate (200 mg), (R)-3-hydroxypyrrolidine hydrochloride (88.2 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 hours. (R)-3-Hydroxypyrrolidine hydrochloride (44.1 mg) and N,N-diisopropylethylamine (0.125 ml) were added at room temperature, and the mixture was stirred for 15 hours and 40 minutes. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added to the mixture to quench the reaction, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (50 ml) and (30 ml). The organic layer was washed with brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (178.2 mg, 90%) as a white solid.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].Cl[CH2:7][C:8]([N:10]([CH3:12])[CH3:11])=[O:9]>C1(C)C=CC=CC=1>[C:1]([O:4][CH2:7][C:8]([N:10]([CH3:12])[CH3:11])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CN(C)C(=O)CCl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(=O)OCC(=O)N(C)C
Temperature: 25 °C

Procedure:
A suspension of anhydrous sodium acetate (16.4 g, 0.2 mole) and 2-chloro-N,N-dimethylacetamide (24.3 g, 0.2 mole) in toluene (70 ml) was refluxed for 4 h. After cooling to room temperature the mixture was filtered and the filtrate washed with water (2×10 ml), dried and evaporated in vacuo. The solid residue obtained was recrystallized from ether yielding 22.0 g (76%). Mp 52°-53° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C@@H:5]([C:6]2[N:10]=[CH:9][N:8](C3CCCCO3)[N:7]=2)[CH2:4][C@H:3]1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20](S(C)(=O)=O)[N:19]=1.Cl.[NH2:32][CH2:33][CH2:34][CH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][C:36]1=[O:44].CCN(C(C)C)C(C)C.N>CN1C(=O)CCC1.O.Cl.CO>[CH3:30][C:2]1([CH3:1])[C@@H:5]([C:6]2[N:10]=[CH:9][NH:8][N:7]=2)[CH2:4][C@H:3]1[NH:17][C:18]1[C:23]([C:24]#[N:25])=[CH:22][N:21]=[C:20]([NH:32][CH2:33][CH2:34][CH:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][C:36]2=[O:44])[N:19]=1
Reactant: CC1(C)[C@@H](c2ncn(C3CCCCO3)n2)C[C@H]1Nc1nc(S(C)(=O)=O)ncc1C#N
Reactant: NCCC1C(=O)Nc2ccccc21
Agent: Cl
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CO
Product: CC1(C)[C@@H](c2nc[nH]n2)C[C@H]1Nc1nc(NCCC2C(=O)Nc3ccccc32)ncc1C#N
Temperature: 100 °C
Reaction time: 1 h
Yield: 23.1 %

Procedure:
A mixture of 4-(((1R,3S)-2,2-dimethyl-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)cyclobutyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (140 mg, crude), 3-(2-aminoethyl)indolin-2-one hydrochloride (80 mg, 0.376 mmol) and DIEA (194 mg, 1.50 mmol) in NMP (2.0 mL) was stirred at 100° C. for 1 h. Th reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a crude product, which was dissolved in a solution of hydrochloride in MeOH (2N, 5 mL) and stirred at room temperature for 5 h. The reaction was neutralized with ammonia and concentrated. The residue was purified by standard methods to afford the title compound (33.4 mg, 0.075 mmol, 20% yield for two steps). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 13.49 (brs, 1H), 10.24 (s, 1H), 8.52-7.41 (m, 3H), 7.29 (t, J=7.6 Hz, 1H), 7.25-7.07 (m, 2H), 7.01-6.93 (m, 1H), 6.87-6.82 (m, 1H), 4.41-4.29 (m, 1H), 3.59-3.43 (m, 2H), 3.42-3.25 (m, 1H), 3.10-2.96 (m, 1H), 2.81-2.66 (m, 1H), 2.49-2.34 (m, 1H), 2.16-1.94 (m, 2H), 1.49-1.00 (m, 3H), 0.63-0.62 (m, 3H). MS (ESI) m/z 444.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])O1>C([P+]([Pd](Cl)(Cl)[P+](C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.O>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[CH2:45])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)c1ccccc1
Reactant: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: CN(C)c1ccc([P+](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[P+](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Temperature: 80 °C
Yield: 91 %

Procedure:
A mixture of 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1: 3 g, 9.18 mmol), dioxane (32.1 ml) and water (9.64 ml) was degassed and to this was added mono(bis(di-tert-butyl(4-(dimethylamino)phenyl)phosphonio)palladium(IV)) dichloride (0.195 g, 0.275 mmol), cesium carbonate (10.14 g, 31.1 mmol) and 4,4,5,5-tetramethyl-2-(1-phenylethenyl)-1,3,2-dioxaborolane (3 g, 13.04 mmol). The mixture was heated to 80° C. for 6 hours and upon cooling was partitioned between dichloromethane and water. The organic portion was dried (MgSO4), filtered and concentrated to give an orange oil. The crude oil was purified by silica chromatography eluting with 0-60% ethyl acetate in petrol to afford 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine as a brown oil (yield=91%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.OS(O)(=O)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:32][C:22]1[CH:27]=[CH:26][C:25]([S:28]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
201 g tert-Butyl 4-hydroxypiperidine-1-carboxylate, 160 ml triethylamine and 6.0 g 4-dimethylaminopyridine are dissolved in 750 ml DCM. 191 g 4-toluenesulfonylchloride is added and the mixture is refluxed for 7 h. The mixture is cooled in ice and acidified with 100 ml of 1M H2SO4; the organic layer is washed with 300 ml of water (twice), 250 ml of 1 M Na2CO3 solution (twice), dried over MgSO4, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]1[S:8][C:9]([S:12][CH3:13])=[N:10][N:11]=1)=[O:5])[NH2:3].[CH2:14]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:4](=[O:5])[N:6]([C:7]2[S:8][C:9]([S:12][CH3:13])=[N:10][N:11]=2)[CH2:14][NH:3]1
Reactant: C=O
Reactant: CSc1nnc(NC(=O)N(C)N)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1nnc(N2CNN(C)C2=O)s1
Reaction time: 0.33 h

Procedure:
2-Methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl)-semicarbazide (0.1 mole) dissolved in methanol (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. Aqueous formaldehyde (0.2 mole; 37% concentration) is then added to the reaction vessel with stirring. Dilute aqueous potassium hydroxide is added to the reaction mixture to adjust the pH to between 7 and 8 and stirring is continued for a period of about 20 minutes resulting in the formation of a solid precipitate. The precipitate is recovered by filtration, is recrystallized and is dried under vacuum to yield the desired product 2-methyl-4-(5-methylthio-1,3,4-thiadiazol-2-yl)-1,2,4-triazolidin-3 -one.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH2:42])(=[O:41])=[O:40].Cl.CN(C)CCCN=C=NCC.O1CCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([CH2:6][C:7]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[C:17]3[CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH:42][S:39]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[CH3:32])(=[O:40])=[O:41])=[O:26])=[CH:23][C:22]=3[O:30][CH3:31])=[CH:12][CH:11]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cccc2ccc(NC(=O)CC3CCCC3)cc12
Reaction time: 24 h
Yield: 51.3 %

Procedure:
To a mixture of 4-[7-(cyclopentylacetamido)naphth-1-ylmethyl]-3-methoxybenzoic acid (375 mg), 2-methylbenzenesulfonamide (231 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (259 mg) in methylene chloride (9 ml) was added 4-dimethylamino pyridine (165 mg); and the mixture was stirred for 24 h. The mixture was added to 60 ml of 1:9 tetrahydrofuran:ethyl acetate: and the organic solution was washed (1N HCl, water, brine), dried (MgSO4), and evaporated. The residue was purified by flash chromatorgraphy, eluting methylene chloride:acetone:methanol (90:8:0, 90:8:1, 90:8:2 successively). The crude product was recrystallized from 2:8 methanol:methylene chloride and petroleum ether to give the title compound as a colorless solid (263 mg, 51%); mp 248.0°-249.0° C.