Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)[CH:10]=2)[NH:5][CH:4]=1)#[N:2].[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:30])[C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)[CH:10]=2)[N:5]([CH3:34])[CH:4]=1)#[N:2]
Reactant: COc1ccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C(=O)NCCc3ccc4c(c3)c(C#N)cn4C)cc2)cn1
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A solution of 0.250 g (0.631 mmol) N-(2-[3-Cyano-indol-5-yl]ethyl)-4-(6-methoxypyrid-3-yl)benzamide (reference example 1p) in 5 mL DMF is added to a cooled (0° C.) solution of 0.0328 g (0.820 mmol) sodium hydride (60% dispersion in mineral oil) in 2 mL DMF. After ten minutes 0.043 mL (0.69 mmol) iodomethane is added, and the cooling bath removed. After 3 hours, the reaction is quenched with water, concentrated, and the resulting residue flash chromatographed (2:2:1 CH2Cl2:EtOAc:hexanes) to provide 0.167 g of the product as a white solid in 65% yield. 1H NMR (CDCl3) δ 3.09 (2H, t, J=7 Hz), 3.80 (2H, m), 3.86 (3H, s), 3.99 (3H, s), 6.17 (1H, m, br), 6.83 (1H, d, J=8 Hz), 7.29 (1H, s), 7.37 (1H, d, J=8 Hz), 7.55-7.58 (3H, m), 7.64 (1H, s), 7.76-7.82 (3 H, m), 8.40 (1H, d, J=2 Hz). MS (ion spray) m/z 411 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([OH:13])(=O)=[O:11])=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([Cl:16])(=[O:13])=[O:11])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)c1sccc1S(=O)(=O)Cl

Procedure:
7.4 G. of crude 3-sulfothiophene-2-carboxylic acid methyl ester are dissolved in 50 ml. of thionyl chloride and boiled to reflux for 16 hours. The mixture is then evaporated to dryness in vacuo and the remaining bright-yellow oil is brought to crystallization with petroleum ether. There is obtained 3-chlorosulfonylthiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]([NH:24][C:25]4[CH:51]=[CH:50][C:28]([C:29]([NH:31][CH:32]([CH:37]5[CH2:42][CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38]5)[C:33]([O:35][CH3:36])=[O:34])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11][C:12]3[N:17]=[C:16]([O:18][CH2:19][C:20]([F:21])([F:22])[F:23])[N:15]=[C:14]([NH:24][C:25]4[CH:51]=[CH:50][C:28]([C:29]([NH:31][CH:32]([CH:37]5[CH2:42][CH2:41][CH2:40][NH:39][CH2:38]5)[C:33]([O:35][CH3:36])=[O:34])=[O:30])=[CH:27][CH:26]=4)[N:13]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1)C1CCCNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 3-(1-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-methoxy-2-oxoethyl)piperidine-1-carboxylate (85 mg) in DCM (5 mL) was added TFA (0.357 mL). The mixture was stirred at room temperature for 4 hours. All the solvents were removed under vacuum to give methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2-(piperidin-3-yl)acetate (70 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.Br[CH2:18][CH:19]([CH3:22])[CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:18][CH:19]([CH3:22])[CH2:20][Cl:21])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: CC(CCl)CBr
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Product: COc1cc2c(cc1OC)CC(=O)N(CC(C)CCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-bromo-2-methyl-3-chloro-propane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:49]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)#[N:50]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:54]3[CH:55]=[CH:56][C:51]([C:49]#[N:50])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(Br)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Product: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(C#N)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
Aryl halide 9 was coupled to 4-cyanophenylboronic acid to give 33 on a 0.1 mmol scale via General Procedure H (73 mg, 71%): δH (400 MHz, CDCl3) 2.39 (s, 3H, CH3), 2.82 (s, 3H, CH3), 3.68 (s, 2H, CH2), 4.85 (s, 2H, CH2), 5.05 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.67 (s, 1H, CH), 6.69 (d, J=1.2 Hz, 1H, CH), 7.22-7.34 (m, 13H, CH), 7.38-7.40 (m, 2H, CH), 7.61 (d, J=8.0 Hz, 2H, CH), 7.64 (d, J=8.4 Hz, 2H, CH), 7.70-7.72 (m, 3H, CH), 7.84 (d, J=8.4 Hz, 1H, CH); δC (100 MHz, CDCl3) 21.4, 36.0, 51.4, 52.7, 67.0, 70.7, 111.0, 114.0, 118.7, 119.9, 120.8, 126.9, 127.3, 127.4, 127.5, 128.0, 128.2, 128.2, 128.5, 128.5, 128.7, 129.5, 130.8, 132.4, 132.5, 133.1, 135.6, 135.7, 137.1, 138.4, 143.3, 144.8, 158.8, 165.2, 167.1, 167.6; LRMS (ES+) calcd for [C45H39N3O6S+H] 750.26 found 750.26.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2].[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CS(C)=O>[N+:1]([C:4]1[CH:17]=[CH:16][C:15]([N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-:3])=[O:2]
Reactant: O=C(c1cc(Cl)ccc1[N+](=O)[O-])N1CCOCC1
Reactant: OCCNCCO
Solvent: CS(C)=O
Product: O=C(c1cc(N(CCO)CCO)ccc1[N+](=O)[O-])N1CCOCC1
Temperature: 140 °C
Yield: 53.3 %

Procedure:
Dissolved in 4 ml of DMSO were 1.0 g (3.69 mmol) of N-(2-nitro-5-chlorobenzoyl)morpholine and 1.16 g (11 mmol) of diethanolamine. The resulting mixture was stirred under heat at 140° C. for 3 hours. After the reaction, the reaction mixture was concentrated and the resulting yellow syrup was purified by chromatography on a silica gel column (chloroform/methanol=10/1), whereby 667 mg of the title compound were obtained as yellow powder (yield: 53.5%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1.[Br:12][CH2:13][CH2:14]Br>O.CCOC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:6]1[CH:5]=[C:4]([Cl:3])[CH:9]=[C:8]([Cl:10])[CH:7]=1
Reactant: BrCCBr
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cc(Cl)cc(OCCBr)c1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
To a solution of NaOH (2.45 g, 61.3 mmol) in water (20 mL) was added 3,5-dichlorophenol (5 g, 30.7 mmol). The solution was heated at reflux for 1 h and was cooled to room temperature. 1,2-Dibromoethane (11.52 g, 61.3 mmol) was added and the reaction was heated at reflux for 24 h. The cooled solution was diluted with EtOAc and the organic solution was washed sequentially with HCl (1N, 1×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered, and concentrated. Purification by flash chromatography (hexanes to 5% EtOAc in hexanes ) provided the title compound (3.79 g). 1H NMR (400 MHz, CDCl3) δ 6.98 (m, 1H), 6.82 (m, 2H), 4.25 (t, 2H), 3.61 (t, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C(O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Nc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1nc(Cl)cc(Nc2ccccc2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To 4,6-dichloro-2-pyrimidinamine (0.50 g, 3.05 mmol) in ethanol (EtOH) (10 mL) was added aniline (0.3 mL, 3.3 mmol) and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto ethyl acetate (EtOAc) and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was further extracted with more EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to provide the crude title compound (620 mg) as a yellow solid. Product contains ˜25% of bis-addition product. LC-MS (ES) m/z=221 [M+H]+.
Reaction SMILES: O[CH:2]([CH2:10][CH2:11][CH2:12][CH2:13]C)[CH2:3][CH2:4][CH2:5][C:6](=[O:9])C=C.CC1C(=[O:21])CCC1=O.C1(C)C(C)=CC=CC=1>C(O)(=O)C>[O:9]1[C:13]2[CH2:12][C:11](=[O:21])[CH:10]=[CH:2][C:3]=2[CH:4]=[CH:5][CH2:6]1
Reactant: CC1C(=O)CCC1=O
Reactant: C=CC(=O)CCCC(O)CCCCC
Solvent: Cc1ccccc1C
Solvent: CC(=O)O
Product: O=C1C=CC2=C(C1)OCC=C2

Procedure:
A mixture of the optically active 7-hydroxy-1-dodecen-3-one, obtained as described in Example 4, 2.25 grams of 2-methylcyclopentane-1,3-dione, 50 milliliters of xylene, and 25 milliliters of acetic acid was refluxed for 11/2 hours under a nitrogen atmosphere. After evaporation under vacuum, the residue was extracted with cold benzene leaving 400 milliliters of unreacted methylcyclopentanedione as an insoluble residue. The benzene solution was then evaporated to yield 5.56 grams of optically active 3-pentyl-6aβ-methyl-1,2,3,5,6,6a-hexahydrocyclopenta]f][1]benzopyran-7(8H)-one. After chromatographing the crude product on alumina, followed by crystallization from methanol-water, the product melted at 60°-61°C., [α]D25 -166°.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH2:21][C:22]([O:24]C)=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C.C1COCC1>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:8][CH2:9][CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH2:21][C:22]([OH:24])=[O:23])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)COc1cccc2c1ccn2CCNC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COc1cccc2c1ccn2CCNC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
Methyl (1-(2-(N-(diphenylmethyl)amino)ethyl)indole-4-yloxy)acetate (99 mg) was dissolved in a mixed solvent of ethanol (5 ml) and THF (2 ml), and the obtained solution was stirred at room temperature. To this solution, 1N aqueous sodium hydroxide solution was added and the resulting solution was stirred at room temperature. After confirming vanishment of the materials, the solvent was removed under reduced pressure. Water (5 ml) was added to the obtained residue and 1N hydrochloric acid was added to the mixture to neutralize the same. The precipitated solids were collected by centrifugation and washed twice with water and twice with methanol. The solids were dried under reduced pressure to obtain the desired compound (58 mg, yield: 61%)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[F:34]C(F)(F)S([O-])(=O)=O.ClC1C=CC=C(Cl)[N+]=1F>ClCCl.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[C:23]([F:34])[CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(O)c1cnc(-c2[nH]c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)cc2F)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (420 mg) in dichloromethane (5 mL) was added 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate (410 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (35.0 mg). The mixture of the obtained positional isomers was dissolved in hexane-ethanol (850:150, volume ratio, 114 mL), and the solution was subjected to HPLC using TSK GEL SHILICA-60 (20 mm ID×250 mL, manufactured by Tosoh Corporation silica). Using hexane-ethanol (850:150, volume ratio) as a mobile phase, the solution was eluted at flow rate 20 mL/min and at room temperature, and the fraction was separated at retention time 39.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (26.8 mg, yield 4%) as a colorless amorphous solid. MS: 505 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([NH:7][CH:8]=[C:9]2[C:14](=[O:15])OC(C)(C)OC2=O)=[CH:5][C:4]=1[C:21]([O:23][CH3:24])=[O:22].C1(C2C=CC=CC=2)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH3:1][O:2][C:3]1[CH:20]=[C:19]2[C:6](=[CH:5][C:4]=1[C:21]([O:23][CH3:24])=[O:22])[NH:7][CH:8]=[CH:9][C:14]2=[O:15]
Reactant: COC(=O)c1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1OC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COC(=O)c1cc2[nH]ccc(=O)c2cc1OC
Temperature: 260 °C
Reaction time: 0.08 h
Yield: 58.2 %

Procedure:
5-(4-Methoxy-3-methoxycarbonylanilinomethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (28.9 g) was added portionwise to a mixture (200 ml) of biphenyl and diphenyl ether (‘Dowtherm A’) that had been warmed to 260° C. The solution was stirred at that temperature for 5 minutes. The resultant mixture was cooled to ambient temperature and added to a mixture of petroleum ether (250 ml) and diethyl ether (250 ml). The precipitate was collected by filtration and washed with petroleum ether. The material so obtained was purified by column chromatography on silica using increasingly polar solvent mixtures of methylene chloride and methanol (from 10:0 to 17:3) as eluent. There was thus obtained a 7:3 mixture (11.7 g) of 6-methoxy-7-methoxycarbonyl-1,4-dihydroquinolin-4-one and 6-methoxy-5-methoxycarbonyl-1,4-dihydroquinolin-4-one; 1H NMR: (DMSOd6) 3.85 (s, 3H), 3.88 (s, 3H), 6.05 (d, 1H), 7.61 (s, 1H), 7.87 (s, 1H), 7.94 (d, 1H) and 3.75 (s, 3H), 3.82 (s, 3H), 5.92 (d, 1H), 7.55 (d, 1H), 7.63 (d, 1H), 7.88 (m, 1H); Mass Spectrum: M+H+ 234.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH:28]3[CH2:29][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31]3)=[CH:26][CH:27]=2)[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(N)cc2)C1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (0.150 g, 0.518 mmol), tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (A77) (0.141 g, 0.569 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), Cs2CO3 (0.506 g, 1.55 mmol) and Xantphos (11.9 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwave irradiation at 100° C. for 1.5 hours. The resulting mixture was dry loaded onto silica gel and purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 Cartridge, 0-5% MeOH in DCM) to give the title compound A123 as a light orange foam (0.087 g, 33%); 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.53 (s, 1H), 7.26-7.28 (m, 6H), 5.59 (brs, 2H), 4.32 (t, J=8.7 Hz, 2H), 3.97 (dd, J=6.0, 8.4 Hz, 2H), 3.70-3.76 (m, 3H), 3.08-3.13 (m, 2H), 2.90-2.98 (m, 2H), 2.13 (s, 3H), 1.48 (s, 9H). LCMS-B: rt 7.208 min; m/z 502 [M+H]+.
Reaction SMILES: CO[C:3](=[O:33])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:21]=1[F:30])=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.Cl.[NH:35]([C:37]1[N:38]=[N:39][CH:40]=[CH:41][CH:42]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[F:30][C:21]1[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[CH:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1)[C:5]1[NH:4][C:3](=[O:33])[N:35]([C:37]2[N:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[N:36]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Reactant: NNc1cccnn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3cccnn3)c(=O)[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
To a solution of 98 mg of [2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (1d)) in 3 ml of DMF there were added 30.5 mg of 3-hydrazinopyridazine hydrochloride [CAS No. 117043-87-5] and 29 μl of triethylamine, and the mixture was stirred at 85° C. for 18 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of a methanol:THF=1:1 mixed solvent. After adding 44 μl of acetic acid and 65 mg of sodium cyanotrihydroborate to the reaction mixture, it was stirred at room temperature for 6 hours. After filtering the reaction mixture, it was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% trifluoroacetic acid) to give 5-{(2-fluoro-4,5-dimethoxyphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyridazin-3-yl-2,4-dihydro-[1,2,4]triazol-3-one (60 mg).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.O1CCOCC1.[H][H]>[Ni].O>[F:1][CH:2]([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH2:11])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(OC(F)F)ccc1O
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(OC(F)F)ccc1O
Yield: 57.9 %

Procedure:
A mixture of 4-(difluoromethoxy)-2-nitrophenol (D94, 450 mg, 1.974 mmol), Raney-nickel (est. 200 mg), 1,4-dioxane (10 mL) and water (5 mL) was stirred at room temperature in a hydrogen atmosphere for 20 h. The reaction mixture was filtered through kieselguhr under an argon atmosphere and evaporated to dryness. The unreacted starting material was sufficiently volatile that most of it was removed by using a rotary evaporator. The residue was purified by flash column chromatography on a pre-packed silica cartridge (column size 50 g), eluting with 0-30% ethyl acetate in hexane, followed by 10-50% 2 M ammonia in methanol in DCM. The residue was further purified on an IST SCX-2 cartridge 20 g, washing with methanol (125 mL) and eluting with 2 M ammonia in methanol (125 mL). The basic eluent was evaporated to dryness to afford the desired product (D95) as a brown solid (200 mg). (M+H)+=176.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CCCCCC.O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:15][C:14]([CH3:16])([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:13]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCBr
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(C)(C)CCCCBr
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (1.6M, 63 ml, 0.10 mol) in hexane was added dropwise to a solution of diisopropylamine (10.1 g, 0.10 mol) in anhydrous tetrahydrofuran (100 ml) at -50° C. The mixture was stirred for 0.5 hours. The mixture was cooled to -70° C. and a solution of ethyl isobutyrate (12.2 g, 0.105 mol) in tetrahydrofuran (20 ml) was added. The resulting mixture was stirred at -70° C. for 1 hour. 1,4-Dibromobutane (30.4 g, 0.14 mol) was added to the mixture followed by hexamethylphosphoramide (30 g). The resulting mixture was maintained at -70° C. for 0.5 hours and then warmed to room temperature over 1 hour. The solvent was evaporated off under reduced pressure and the residue was treated with saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (2×150 ml). The combined extracts were washed with water (100 ml), hydrochloric acid (1N, 2×100 ml) was saturated aqueous sodium hydrogen carbonate (100 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated off under reduced pressure and the residue was distilled to yield ethyl 2,2-dimethyl-6-bromohexanoate as a pale yellow oil, having a boiling point of 73° C., 0.06 mm.Hg and the following physical characteristics: