Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=O)=[C:10]([OH:19])[C:9]([CH:20]([CH3:22])[CH3:21])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=[N:27]CCC2)CC1.O.CC[O:37][C:38]([CH3:40])=[O:39]>O1CCOCC1>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:27][CH2:40][C:38]([OH:37])=[O:39])=[O:16])=[C:10]([OH:19])[C:9]([CH:20]([CH3:21])[CH3:22])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(C)=O
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)c1c(O)c(C(C)C)nn(C2CCCCC2)c1=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)c1nn(C2CCCCC2)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 130 °C
Yield: 45 %

Procedure:
Ethyl 2-cyclohexyl-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. DBU (0.06 mL, 0.398 mmol) was added to a solution of the compound from example 98b) (92 mg, 0.260 mmol) in 1,4-dioxane (1.5 ml) at room temperature. The reaction was heated in the microwave at 130° C. for 20 minutes. The reaction was cooled and H2O and EtOAc were added. The layers were separated and the aqueous phase backextracted with EtOAc several times. The combined organic layers were washed with Brine, dried (MgSO4), filtered and concentrated. The product was purified by column chromatography (SiO2, 10-20% EtOAc/Hexanes) to give the title compound as a colorless oil (36 mg, 45%). 1H NMR (400 MHz, DMSO-d6) d ppm 12.06 (s, 1H) 4.66 (tt, J=11.37, 4.04 Hz, 1H) 4.26 (q, J=7.07 Hz, 2H) 3.15 (sept, J=6.78 Hz, 1H) 1.51-1.89 (m, 7H) 1.29-1.44 (m, 2H) 1.26 (t, J=7.07 Hz, 3H) 1.16 (d, J=6.82 Hz, 6H) 1.08-1.22 (m, 1H).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1C(C)CCCN1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[NH:15]1
Reactant: Cc1cc(C)nc(N)c1
Agent: CC1CCCNC1=N
Solvent: CC(=O)O
Product: CC1CC(=N)NC(C)C1

Procedure:
The method of preparation of 2-Imino-3-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-4,6-dimethylpyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 163°-166° C. MH+=127; 1H NMR (D2O): δ3.48-3.40 (m, 1H); 2.52-2.40 (m, 1H); 2.07-1.95 (m, 1H); 1.85-1.75 (m, 2H); 1.75 (s, 3H); 1.12 (d, J=6.3 Hz, 3H); 1.02-0.92 (m, 1H); 0.86 (d, J=6.3 Hz, 3H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=2)=O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(OP([CH2:37][C:38]#[N:39])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[C:4]([Si:1]([CH3:2])([CH3:3])[O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=2)=[CH:37][C:38]#[N:39])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])([CH3:6])([CH3:5])[CH3:7]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(OC)cc(C(=O)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1
Yield: 74.1 %

Procedure:
[3-(tert-butyldimethylsilanyloxy)-4-methoxyphenyl]-(3,5-dimethoxyphenyl) methanone (0.74 g, 1.84 mmol), cyanomethylphosphonic acid diethyl ester (0.58 ml, 3.68 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 3.70 ml, 3.68 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)-acrylonitrile. The crude was purified via flash column chromatography (100% hexane gradient to 20% EtOAc in hexane in about 40 min.) to give 3-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-phenyl]-3-(3,5-dimethoxy-phenyl)-acrylonitrile as an clear colorless oil (0.58 g, 74%): 1HNMR (CDCl3) δ 7.09-6.78 (m, 3H, Ar), 6.53-6.51 (m, 2H, Ar), 6.41 (d, J=2 Hz, 1H, Ar), 5.60 (s, 1H, CH), 3.86-3.76 (multiple singlets, 9H), 0.97 (s, 9H, 3OCH3), 0.14 (s, 6H, 2OCH3). The product was carried over to the next step.
Reaction SMILES: C1([C@H]2C[C@H]3N(C)[C@H](CC3)[C@H]2C(OC)=O)C=CC=CC=1.[C:20]1([CH3:39])[CH:25]=[CH:24][C:23]([C@H:26]2[CH2:32][C@H:31]3[N:33]([CH3:34])[C@H:28]([CH2:29][CH2:30]3)[C@H:27]2[C:35](OC)=[O:36])=[CH:22][CH:21]=1>>[CH:35]([C@H:27]1[C@@H:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:39])=[CH:21][CH:22]=2)[CH2:32][C@H:31]2[N:33]([CH3:34])[C@@H:28]1[CH2:29][CH2:30]2)=[O:36]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(C)cc2)C[C@@H]2CC[C@H]1N2C
Agent: COC(=O)[C@H]1[C@@H](c2ccccc2)C[C@@H]2CC[C@H]1N2C
Product: Cc1ccc([C@H]2C[C@@H]3CC[C@H]([C@H]2C=O)N3C)cc1

Procedure:
Using a procedure similar to that described in Example 8, sub-part b, except replacing the compound 15 used therein with compound 16, the title compound 19 was prepared as a colorless oil: 1H NMR (CDCl3) δ1.70 (d, 1H. J=8.7 Hz), 1.60-1.78 (m, 1H), 1.89 (dt, 1H, J=3.9 and 12.9), 2.19 (s, 3H), 2.30 (s, 3H), 2.10-2.33 (m, 2H), 2.39-2.53 (m, 2H), 3.14 (dt, 1H, J=5.7 and 12.9 Hz), 3.36-3.45 (m, 1H), 3.46-3.55 (m, 1H), 7.10 (br s, 4H), 9.66 (d, 1H, J=3.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1.Br[CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:25]([CH2:31][CH2:32][CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([S:17]([CH2:20][CH2:21][CH3:22])(=[O:19])=[O:18])[CH:14]=[CH:13][C:12]=2[CH3:23])[CH:3]=1
Reactant: CCCC(Br)C(=O)OCC
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2O)c1
Product: CCCC(Oc1ccc(Cl)cc1C#Cc1cc(S(=O)(=O)CCC)ccc1C)C(=O)OCC

Procedure:
Following the general method as outlined in Intermediate 268, starting from 4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenol (Intermediate 267) and ethyl 2-bromovalerate, the title compound was obtained as a colorless sticky solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:14])[O:8]CC(Cl)(Cl)Cl)[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].C(O)(=O)C.O>C(Cl)Cl.[Zn]>[CH3:1][C:2]1([CH3:33])[C@@H:4]([C:5]#[C:6][C:7](=[O:8])[OH:14])[C@H:3]1[C:15]([O:17][C@H:18]([CH3:32])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:20]=1)=[O:16]
Reactant: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(Cl)(Cl)Cl)C1(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A solution of 4.16 g of the product of Step A in 4 ml of methylene chloride was admixed with 45 ml of acetic acid containing 10% of water and 0.53 g of zinc powder and the mixture was stirred for 30 minutes at room temperature, then another 0.53 g of zinc powder were added 4 times until The reaction was complete and after 3 hours contact, the mixture was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with water, dried and evaporated to dryness by azeotropic distillation with toluene to obtain 3.05 g of (R)α-methyl-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1.[C:21]([N:28]1C=CN=C1)(N1C=CN=C1)=[O:22].[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[NH:34]N>O1CCCC1>[NH:28]([C:21]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18](=[O:20])[CH3:19])[S:15][CH:16]=2)=[CH:6][CH:5]=1)=[O:22])[NH:34][C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]
Reactant: CC(=O)Nc1nc(CCc2ccc(CCO)cc2)cs1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(CCc2ccc(CCOC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a suspension of N-(4-{2-[4-(2-hydroxyethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (552.5 mg, 1.799 mmol) in anhydrous tetrahydrofuran (8 ml) was added 1,1′-carbonyldiimidazole (437.8 mg, 2.700 mmol), and the mixture was stirred at 45° C. for 0.5 hr. tert-Butyl carbazate (356.8 mg, 2.700 mmol) was added. After stirring for 1 hr, tert-butyl carbazate (356.6 mg, 2.698 mmol) was added. After stirring for 3 hr, tert-butyl carbazate (357.0 mg, 2.701 mmol) was further added. After stirring for 24 hr, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. DM1025 60 g, ethyl acetate:hexane=5:5→7:3). The residue was further purified by silica gel column chromatography (Sep pak-5 g, ethyl acetate:hexane=7:3) to give 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethyl tert-butyl hydrazine-1,2-dicarboxylate (755.9 mg, 1.685 mmol, yield 93.6%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[CH3:51][N:52]([CH2:54][CH2:55][CH2:56][NH2:57])[CH3:53]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:57][CH2:56][CH2:55][CH2:54][N:52]([CH3:53])[CH3:51])=[O:28])=[CH:24][CH:23]=3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CN(C)CCCN
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3ccc(C(=O)O)cc3)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CN(C)CCCNC(=O)c1ccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.1 %

Procedure:
4-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-benzoic acid (prepared in example 45, 40 mg, 0.08 mmol) was suspended in methylene chloride (1 mL) and a 2.0 M solution of oxalyl chloride in methylene chloride (38 μL, 0.08 mmol) was added and the reaction stirred at 25° C. for 20 min. The solution was chilled to 0° C. and 2,6-lutidine (18 μL, 0.15 mmol) was added. The reaction continued to stir at 0° C. for 20 min. N,N-Di-methyl-3-amino-propyl-amine (12 μL, 0.09 mmol) was added, the ice bath was removed and the reaction continued to stir at 25° C. for 16 h. The reaction was diluted with methylene chloride (10 mL), washed with water (2×4 mL), saturated aqueous brine solution (1×4 mL), dried over magnesium sulfate and concentrated in vacuo to a beige foam. Purification by reverse phase preparative HPLC (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) followed by flash column chromatography (Merck silica gel 60, 40-63 μm; 0.5% ammonium hydroxide/methanol) afforded 4-{3-[2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-N-(3-dimethylamino-propyl)-benzamide (3 mg, 6.5%) as a clear oil: ESI-LRMS m/e calcd for C31H40ClN5O4S [M+] 613.25, found 614.21 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.08-1.24 (m, 2H, CH2), 1.44-1.94 (m, 8H, 4×CH2), 2.10-2.32 (m, 3H, CH), 2.78 (s, 6H, 2×NCH3), 3.06 (t, J=6.4 Hz, 2H, NCH2), 3.25 (s, 3H, SO2CH3), 3.56-3.66 (m, 2H, CH2), 3.69 (t, J=7.6 Hz, 1H, CH), 5.15 (s, 2H, NCH2), 6.72 (d, J=2.3 Hz, 1H, Ar), 7.13 (d, Jo=8.1 Hz, 2H, Ar), 7.33 (d, J=2.3 Hz, 1H, Ar), 7.49 (dd, Jo=8.1, Jm=1.6 Hz. 1H, Ar), 7.65 (d, Jm=1.6 Hz, 1H, Ar), 7.91 (d, Jo=8.1 Hz, 2H, Ar), 8.05 (d, Jo=8.1 Hz, 1H, Ar), 8.37 (brm, 1H, NH), 8.59 (s, 1H, NH).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C.CCOC(C)=O>[N:22]([CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([C:14]2[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([NH2:21])[N:15]=2)[CH2:8]1)=[N+:23]=[N-:24]
Reactant: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1c1cc(Cl)nc(N)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1CO[C@H](CN=[N+]=[N-])CN1c1cc(Cl)nc(N)n1
Temperature: 80 °C
Reaction time: 20.5 h
Yield: 80.8 %

Procedure:
A mixture of crude [(2S,5R)-4-(2-amino-6-chloro-4-pyrimidinyl)-5-methyl-2-morpholinyl]methyl methanesulfonate (1.53 g, about 85% pure, 3.88 mmol) and sodium azide (0.382 g, 5.88 mmol) in DMF (75 mL) was stirred at 80° C. under nitrogen for 20.5 hours. Another portion of sodium azide (0.094 g, 1.45 mmol) was then added and stirring continued at 80° C. for an additional 6.5 hours. The mixture was then cooled, diluted with EtOAc (200 mL), washed with water (2×150 mL) and brine (1×150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (60 g SiO2, 1:1 hexanes/CH2Cl2 to 45:45:10 hexanes/CH2Cl2/CH3CN gradient) to give the title compound (890 mg) as a thick colorless oil. LC-MS (ES) m/z=284, 286 [M+H]+.
Reaction SMILES: [CH2:1]=CCCCCCC.[CH3:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH2:11]>>[CH3:16][CH2:17][C:12]([CH3:1])([CH3:13])[CH3:10].[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:9]
Reactant: C=CCCCCCC
Reactant: C=C(C)c1ccccc1
Product: CC(C)c1ccccc1
Product: CCC(C)(C)C
Yield: 97 %
Yield: 48 %

Procedure:
Complex 6 was also tested for the hydrogenation of several other substrates. Heating 1-octene with complex 6 (10 mol %) under 4 atm H2 (THF-d8 solvent, 80° C., 24 hours) produced n-octane (70%) and internal octene isomers (30%, arising from isomerization of the 1-octene) (Table 6, entry 2). Prolonging the reaction time to 48 hours resulted in a higher yield (76%) of n-octane. Internal octene isomers (24%) remained at the end of the reaction, indicating that the terminal 1-octene is hydrogenated more rapidly than its internal isomers. The more sterically hindered olefins 3,3-dimethyl-1-butene and α-methylstyrene were also hydrogenated under the same reaction conditions (4 atm H2, 80° C.), albeit somewhat more slowly, affording neohexane (97%) and isopropylbenzene (48%) after 48 hours (Table 6, entries 3 and 4).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1.[Cl:18][C:19]1[N:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)(=O)C>[Cl:18][C:19]1[C:20]([C:21]([C:16]2[NH:15][CH:14]=[C:13]([C:7]3[C:6]([Cl:5])=[CH:11][CH:10]=[CH:9][C:8]=3[Cl:12])[CH:17]=2)=[O:22])=[CH:24][CH:25]=[CH:26][N:27]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Clc1cccc(Cl)c1-c1cc[nH]c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1cc(-c2c(Cl)cccc2Cl)c[nH]1)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (1.4 g, 10.5 mmol) was added to a mixture of 3-(2,6-dichloro-phenyl)-1H-pyrrole (2 g, prepared as described in Journal of Organic Chemistry, 62: 2650 (1997) (incorporated herein by reference) and 2-chloronicotinoyl chloride (1.8 g, 10.5 mmol) in DCM (55 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 168 mg of (2-chloro-pyridin-3-yl)-[4-(2,6-dichloro-phenyl)-1H-pyrrol-2-yl]-methanone.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[C:6]2[CH:28]=[C:29]([C:32]3[N:36]([CH3:37])[C:35]4[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=4[N:33]=3)[CH:30]=[CH:31][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1nc2ccc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-ethyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([CH:13]3[CH2:15][CH2:14]3)[CH3:12])=[C:8]([C:16]([NH2:18])=[O:17])[CH:7]=[N:6][N:5]2[CH:19]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C:21]1=[O:25]>>[CH:13]1([C@H:11]([NH:10][C:9]2[C:4]3[N:5]([CH:19]=[C:2]([N:20]4[CH2:24][CH2:23][CH2:22][C:21]4=[O:25])[CH:3]=3)[N:6]=[CH:7][C:8]=2[C:16]([NH2:18])=[O:17])[CH3:12])[CH2:15][CH2:14]1
Reactant: O=C1CCCN1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1CC1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(N3CCCC3=O)cc12)C1CC1

Procedure:
Example 185 was prepared from 6-bromo-4-(((1R)-1-cyclopropylethyl)amino)-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 4) and 2-pyrrolidinone according to the procedure described for Example 37. HPLC (condition G): retention time=7.10 min. LCMS (ES+) m/z: 328.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]2[CH2:18][CH2:17][O:16][C:15]2=[O:19])[N:7]=1.[CH3:29][NH:30][CH3:31]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:28])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[Br:27])[NH:10]/[C:11]/2=[N:12]\[O:13][CH:14]([CH2:18][CH2:17][OH:16])[C:15]([N:30]([CH3:31])[CH3:29])=[O:19])[N:7]=1
Reactant: Cc1nc(N)nc2c1/C(=N/OC1CCOC1=O)N[C@@H](c1ccc(F)cc1Br)C2
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1nc(N)nc2c1/C(=N/OC(CCO)C(=O)N(C)C)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of 3-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)dihydrofuran-2(3H)-one (310 mg, 0.668 mg) in THF (2 mL) was added N,N-dimethylamine (2.0M solution in MeOH, 0.86 mL, 1.72 mmol) and the reaction mixture was stirred overnight at r.t. The solvent was removed and purified by LCMS to afford the title compound 2-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-4-hydroxy-N,N-dimethylbutanamide (89, 80 mg, 24%) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 2.63 (d, J=2.78 Hz, 3H) 2.84-2.99 (m, 1H) 3.01 (d, J=3.28 Hz, 3H) 3.08-3.25 (m, 4H) 3.61-3.93 (m, 2H) 4.99 (dddd, J=15.03, 4.86, 2.59, 2.27 Hz, 1H) 5.09-5.23 (m, 3H) 5.91 (d, J=9.09 Hz, 1H) 6.98-7.14 (m, 1H) 7.33 (ddd, J=7.89, 4.99, 2.53 Hz, 1H) 7.38-7.48 (m, 1H). MS (ES) [M+H] calculated for C20H25BrFN6O3, 495.34. found 495.30.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3].[H-].[Na+].[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:15]=1[C:16](Cl)=[O:17]>CN(C=O)C.O>[N:1]([C:4]1[CH:9]=[C:8]([NH:10][C:16](=[O:17])[C:15]2[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: [N-]=[N+]=Nc1cc(N)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.2 %

Procedure:
To a cooled (0° C.) solution of 2-azidopyridin-4-amine (500 mg, 3.7 mmol) in dry DMF (10 ml) was added NaH (178 mg, 7.4 mmol). After stirring for 10 min, a solution 2,4,6-trichlorobenzoyl chloride (1.8 g, 7.4 mmol) in DMF (5 mL) was added dropwise. The reaction was warmed to 25° C. and stirring was continued for 30 min. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (petroleum ether/ethyl acetate=1:1) to afford N-(2-azidopyridin-4-yl)-2,4,6-trichlorobenzamide (180 mg, yield: 14%). LCMS (ESI) m/z: 342.0 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17]Cl)[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2].[CH3:38][NH:39][CH3:40]>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:39]([CH3:40])[CH3:38])[N:9]=[CH:8][CH:7]=[C:6]2[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:28])=[CH:22][CH:21]=1)#[N:2]
Reactant: CNC
Reactant: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCCl)c(C#N)cc34)cc2)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OCCCCN(C)C)c(C#N)cc34)cc2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
N-(4-(6-Cyano-7-(4-chlorobutoxy)-4-quinolyl)oxyphenyl)-N′-(4-methoxyphenyl)urea (120 mg) was dissolved in dimethylformamide (3 ml), and then a 50% dimethylamine solution (93 μl) was added and the mixture was heated and stirred at 70° C. for 5 hours. The reaction solution was poured into saturated saline and extracted with ethyl acetate, and the organic layer was dried over magnesium sulfate and concentrated. The residue was passed through NH silica gel (Fuji Silicia Chemical) and eluted with a solvent (ethyl acetate), and then further eluted with another solvent (ethyl acetate:methanol=10:1) and concentrated. The obtained solid was passed through Merck Silica Gel using tetrahydrofuran, and after eluting the insoluble portion with tetrahydrofuran and ethyl acetate, it was further eluted with solvents (tetrahydrofuran:methanol:triethylamine=10:1:1, ethyl acetate:methanol:triethylamine=10:1:1) and concentrated to obtain 10 mg of the title compound as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][NH:3]1.[I:12]N1C(=O)CCC1=O>C(Cl)Cl>[I:12][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc[nH]c1=O
Solvent: ClCCl
Product: COC(=O)c1cc(I)c[nH]c1=O
Yield: 46.7 %

Procedure:
A solution containing 19.48 g of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate and 36.15 g of N-iodosuccinimide in 500 ml of anhydrous methylene chloride is heated at reflux under a nitrogen atomosphere in the dark for 48 hours. The reaction mixture is concentrated to 150 ml under reduced pressure and the solid which forms is collected by filtration and washed with small portions of cold methylene chloride and benzene to give 16.59 g (47%) of methyl 5-iodo-2-oxo-1,2-dihydro-3-pyridinecarboxylate as a pale yellowish solid. This material is sufficiently pure for the next reaction; its properties upon recrystallization from methyl acetate are as follows: m.p. 190°-192° C.; NMR (DMSO-d6, 300 MHz) delta 3.71 (s, 3H), 7.93 (d, 1H, J=2.26 Hz), 8.10 (d, 1H, J=2.26 Hz), IR (KBr) 2500-3050 (broad), 1725, 1630, 1585, 1475, 1425, 1320, 1260, 1235, 1180, 1150, 1105, 1065, 965, 875 and 800 cm-1 ; M/S (279, M+), 247, 127 and 93.