Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[O:5][C:6]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[C:14](=[O:27])[C:13]=2[C:12]([O:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:11]2[C:7]=1[N:8]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH:9]=[N:10]2)C.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C1C=CN=CC=1)C.O>[CH:29]([O:28][C:12]1[C:13]2[C:14](=[O:27])[N:15]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[C:16](=[O:18])[C:17]=2[C:6]([OH:5])=[C:7]2[C:11]=1[N:10]=[CH:9][N:8]2[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)Oc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncn(Cc4ccccc4)c13)C(=O)N(Cc1ccc(F)cc1)C2=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1c2c(c(O)c3c(ncn3Cc3ccccc3)c2OC(c2ccccc2)c2ccccc2)C(=O)N1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 94 %

Procedure:
Carbonic acid 8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-yl ester ethyl ester 257 (130 mg, 0.20 mmol) was dissolved in THF (5 mL, 0.1 M) along with DMAP (24 mg, 0.40 mmol, 2 equiv.). A solution of K2CO3 (276 mg, 1.99 mmol, 10 equiv.) was dissolved separately in H2O (6 mL) before transferring to the reaction mixture. The reaction was allowed to stir for 18 hr and quenched with HCl (20 mL, 1 N) and extracted with ethyl acetate (2×30 ml). The organic layer was washed with saturated NH4Cl solution (25 mL), brine solution (25 mL) and dried over Na2SO4 and concentrated in vacuo to yield 4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione 258 (94%, 103 mg, 0.188 mmol) as an off white oil. 1H NMR (300 MHz) CDCl3 δ 8.28 (bs, 1 H), 7.94 (s, 1 H), 7.89 (s, 1 H), 7.64-7.43 (m, 4 H), 7.17-7.43 (m, 12 H), 6.98-7.04 (s, 2 H), 5.57 (s, 2 H), 4.77 (s, 2 H). MS: 584.1 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:20]=[C:12]3[CH2:13][CH:14]([C:17]([O-:19])=[O:18])[CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1.[Na+]>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:20]=[C:12]3[CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C([O-])C1CCn2nc(-c3ccc(F)cc3)nc2C1
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1CCn2nc(-c3ccc(F)cc3)nc2C1
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
Concentrated hydrochloric acid (0.16 ml) was added to an aqueous solution (2 ml) of the sodium 2-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylate (530 mg) obtained in (Example 5.2) <Step 2>, and the obtained mixture was then stirred for 15 minutes. Thereafter, the precipitated solid was collected by filtration, so as to obtain the title compound (196 mg) in the form of a whitish brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:13].C(O)=O.C(N(CC)CC)C.CC1C=CC(S(N[C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1>C(#N)C.C(OC(=O)C)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Br:12])[CH:11]=1)[O:8][CH2:7][CH2:6][C@@H:5]2[OH:13]
Reactant: O=C1CCOc2c(Br)cc(Br)cc21
Agent: Cl[Ru]Cl
Agent: Cc1ccc(S(=O)(=O)N[C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C(C)C)cc1
Product: O[C@H]1CCOc2c(Br)cc(Br)cc21
Reaction time: 24 h

Procedure:
To a mixture containing 6,8-dibromochroman-4-one in acetonitrile (0.3M) and 5/2 formic acid/triethylamine (30% by volume) was added (1S,2S)-(+)-N-p-tosyl-1,2-diphenylethylene diamine (1 mol %) and dichloro(p-cymene)-ruthenium (II) dimer (0.5 mol %). After stirring for 24 h, the reaction was diluted with ethylacetate and washed with brine/sodium bicarbonate (1:1). The organic phase was concentrated under reduced pressure to afford the title compound as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]([NH:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14].P(Cl)(Cl)(Cl)=O>CN(C=O)C>[C:26]1([CH2:25][C@H:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])[C:13]2[O:14][C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:16][N:15]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CNC(=O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)c1ncc(-c2ccccc2)o1
Yield: 41 %

Procedure:
The product from Example 48 Part A (412 mg, 1 mmol) was dissolved in DMF and treated with phosphorous oxychloride (460 mg, 3 mmol) at 90° C. according to the procedure described by Robert Dow et al. (J. Org. Chem., 1990, 55, 386) to yield 160 mg (41% yield) of the product. MS 395.2 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][OH:17]>C(Cl)Cl.O=[Mn]=O>[CH3:1][Si:2]([CH3:19])([CH3:18])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH:16]=[O:17]
Reactant: C[Si](C)(C)CCOCn1c(CO)nc2ccccc21
Agent: O=[Mn]=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a stirred solution of the alcohol from above (26.58 g, 0.096 mol) in dry CH2Cl2 (450 mL) was added activated MnO2 (<5 micron, ˜85%, 93 g, 0.91 mol) and the suspension stirred at room temperature overnight. The mixture was filtered through celite© (175 g) and the cake was washed with CH2Cl2. The solvent was removed from the eluent under reduced pressure and the resultant residue purified by column chromatography on silica gel (3% MeOH/CH2Cl2) to provide the title aldehyde (14.41 g, 55%) as a pale yellow oil. 1H NMR (CDCl3) δ −0.07 (s, 9H), 0.90 (t, 2H, J=9 Hz), 3.56 (t, 2H, J=9 Hz), 6.04 (s, 2H), 7.43-7.51 (m, 2H), 7.66 (d, 1H, J=9 Hz), 7.95 (d, 1H, J=9 Hz), 10.13 (s, 1H); 13C NMR (CD3OD) δ −1.19, 17.94, 66.62, 73.30, 112.22, 122.51, 124.64, 127.43, 136.62, 143.11, 146.39, 185.10; ES-MS m/z (M+H);
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH2:22])[CH:16]=1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:22][C:17]2[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[N:18]=2)[CH:7]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C)n1
Temperature: 140 °C
Yield: 15.1 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (790 mg, 3.57 mmol) in acetonitrile (11.9 mL) was added 4,6-dimethylpyridin-2-amine (873 mg, 7.15 mmol) and heated at 140° C. in a sealed vial for 20 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 0-8% acetone in dichloromethane) to give ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (165 mg, 538 μmol, 15%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.60 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 1.52 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 306.1 [M+H].
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](OC)=[O:11].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[CH2:10][OH:11]
Reactant: COC(=O)c1cc2ncccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc2ncccc2s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl thieno[3,2-b]pyridine-2-carboxylate (C-3) (600 mg, 3.1 mmol) in 30 mL of anhydrous THF at 0° C. was added LiAlH4 (472 mg, 12.4 mmol) in anhydrous THF (25 mL) dropwise over 20 mins. The reaction mixture was stirred at 0° C. for 30 mins. MeOH was added and the resulting mixture was purified by chromatography to afford the title compound. MS (m/z): 166 (M+1)+.
Reaction SMILES: [F-].[Cs+].[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:8][C:7]([OH:17])=[C:6](I)[CH:5]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>C(#N)C.C(OCC)(=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:3][C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:8][C:7]([OH:17])=[C:6]([C:24]2[CH:29]=[CH:28][N:27]=[N:26][CH:25]=2)[CH:5]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Reactant: Oc1cc(-c2cccc(F)c2)c(Cl)cc1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Oc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ccnnc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
Caesium fluoride (219 mg, 1.44 mmol) was added to a solution of 6-chloro-3′-fluoro-4-iodobiphenyl-3-ol (Preparation 99, 251 mg, 0.72 mmol) and 4-(tributylstannyl)pyridazine (345 mg, 0.93 mmol) in acetonitrile (5 mL). The reaction mixture was degassed and copper iodide (28 mg, 0.15 mmol) and tetrakistriphenylphosphinepalladium (0) (83 mg, 0.07 mmol) were added. The reaction mixture was stirred at 80° C. for 3 hours. The cooled reaction mixture was diluted with ethyl acetate (20 mL) and quenched with a solution of ammonia (10%, 10 mL) and stirred for a further 10 minutes. The organic layer was separated and washed with brine (1×10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified using silica gel chromatography (Biotage) eluting with heptane:ethyl acetate (93:7 to 0:100) to give the title compound (185 mg, 62%) as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24](COCC[Si](C)(C)C)[CH:25]=[C:26]([C:28]#[N:29])[N:27]=3)=[O:22])=[C:16]([C:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>C(Cl)Cl.CCO>[F:47][C:46]([F:49])([F:48])[C:44]([OH:50])=[O:45].[C:38]1([C:16]2[CH:15]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=[CH:18][C:17]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[N:27]=2)=[O:22])[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of 4-(4-{[4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonyl]-amino}-3-cyclohex-1-enyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 2.5 mmol) (as prepared in the previous step) in 10 mL of DCM and 0.3 mL EtOH was added 3 mL of TFA and the solution stirred for 3 h at 25° C. The reaction was diluted with 5 mL of EtOH and then concentrated. The residue was crystallized from methanol and ethyl ether to give 0.85 g (70%) of the title compound as a white solid. 1H-NMR (400 MHz, CD3OD) δ 8.18 (d, 1H), 8.04 (s, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 5.76 (m, 1H), 3.54. (m, 2H), 3.16 (m, 2H), 2.92 (m, 1H), 2.30 (m, 4H), 2.10 (m, 2H), 1.75 (m, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H25N5O, 376.2 (M+H). found 376.2.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]#[N:17])=[N:14][CH:15]=1)([OH:9])=[O:8].Cl>CN(C)C=O.O>[C:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[NH:17][N:3]=[N:2][N:1]=2)=[N:14][CH:15]=1)([OH:9])=[O:8]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2nnn[nH]2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium azide (12.0 g, 0.18 mol) and anhydrous ammonium chloride (1.5 g) are added to a stirred solution of 5-carboxy-2-cyanopyridine (22.0 g, 0.15 mol) in dry dimethylformamide (375 ml). The reaction mixture is heated to 80° and held at this temperature for 24 h. After this time, a further portion of sodium azide 6.0 g, 0.09 mol) is added and heating continued for a further 24 h. The reaction mixture is then allowed to cool to ambient temperature and diluted with water (560 ml). This solution is acidified to pH 3 with 5N hydrochloric acid and, while a solid precipitates, stirred at this pH for 30 min. The product is filtered off and stirred in refluxing water (60 ml) for 15 min. It is then refiltered, washed with dichloromethane (5×20 ml) and dried in vacuo at 60° to yield the title compound as a light solid; m.p. 257°-259°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[CH:6]([O:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[CH3:7].C(O)C>C(Cl)(Cl)Cl.O1CCCC1.CN(C)C1C=CN=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[O:8][CH:6]([C:5]1[NH:4][CH2:3][CH2:2][N:1]=1)[CH3:7]
Reactant: CC(Oc1c(Cl)cccc1Cl)C(=O)NCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
58.6 (0.3089 mols) of titanium tetrachloride are dissolved in a mixture of 700 ml of absolute chloroform and 25 ml of tetrahydrofuran at 0° C. and are mixed with 35.0 g (0.1263 mols) of (-)-2-(2,6-dichlorophenoxy)-propionic acid-N-(2-aminoethyl)-amide. A solution of 74.0 g (0.6056 mols) of 4-dimethylaminopyridine is then added dropwise very slowly at 0° C. with stirring and the mixture is further stirred for 36 hours at room temperature after the solution has been added. After working up and after purification by column chromatography (silica gel-dry column, eluant: chloroform/tetrahydrofuran 3:1), 21.0 g of (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene C11H12Cl2N2O [259.1], are obtained, Mp.: 126°-127° C.: [α]D20 =-80.2° (c=1/ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH:22](=O)[CH:23]([CH3:25])[CH3:24].[BH3-]C#N.[Na+].NC1C=CC=CC=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2].[BH3-]C#N.[Na+].[Cl-].[Cl-].[Zn+2].CO.C1COCC1>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:2]([NH:1][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:7]=1)[CH3:10]
Reactant: CCOc1ccc(NC(=O)CCc2ccccc2)c(N)c1
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOc1ccc(NC(=O)CCc2ccccc2)c(NCC(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
A 250 mL 3-neck flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with aniline 76 (3.30 g, 11.6 mmol), THF (35 mL), and MeOH (10 mL). To the resultant solution was added isobutyraldehyde (1.17 g, 1.48 mL, 16.2 mmol), and the mixture stirred 15 min at rt. Meanwhile, in a 100 mL flask fitted with a stir-bar and septum with an Ar inlet, NaCNBH3 (1M in THF, 16.2 mL, 16.2 mmol) was added to MeOH (10 mL). ZnCl2 (1M in Et2O, 8.1 mL, 8.1 mmol) was added next forming a cloudy mixture. After 15 min, this mixture was added to the above aniline solution. After stirring at rt 2.3 hr, another 0.3 mL isobutyraldehyde was added, followed by a second portion of 20% of the original amount of the NaCNBH3/ZnCl2 mixture as made previously. The mixture stirred overnight at rt. The cloudy solution was diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3 (2×125 mL) and brine (100 mL). The solution was filtered through phase separation paper and concentrated in vacuo to a yellow solid. The solid was triturated with hexanes:EtOAc 20:1 (20 mL), filtered, pressed with a rubber dam, and rinsed with hexanes (2×10 mL) to give 3.5 g of 77 as a yellow solid (89%). 1H NMR (Two isomers evident ˜3:2) (300 MHz, CDCl3): δ 7.38-7.18 (m, 5H), [6.87 (d, 0.6H), 6.78 (d, 0.4H)], [6.62 (s, 0.6H), 6.48 (s, 0.4H)], 6.24-6.12 (m, 2H), [4.02 (qt, 1.2H), 4.00 (qt, 0.8H)], [3.07 (t, 1.2H), 2.92 (t, 0.8H)], [2.86 (d, 1.2H), 2.84 (d, 0.8H)], [2.71 (t, 1.2H), 2.40 (t, 0.8H)], [1.85 (nonet, 0.4H), 1.84 (nonet, 0.6H)], [1.41 (t, 1.2H), 1.38 (t, 1.8H)], 0.94 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 98% with a retention time of 4.5 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([F:24])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19](I)=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4].[CH:25]([Sn](CCCC)(CCCC)CCCC)=[CH2:26]>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1([F:24])[C:14]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:25]=[CH2:26])=[CH:18][C:17]=2[F:23])=[CH:13][C:8]2=[N:9][CH2:10][N:11]([CH3:12])[C:7]2=[CH:6]1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)C1(F)C=C2C(=NCN2C)C=C1Nc1ccc(I)cc1F
Solvent: C1COCCO1
Product: C=Cc1ccc(NC2=CC3=NCN(C)C3=CC2(F)C(=O)OC)c(F)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
A solution of 5-Fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (6.36 g, 14.4 mmol) and vinyl tributylstannane (5.0 g, 15.8 mmol) in dioxane (100 mL) was de-gassed by freeze-pump-thaw cycle (twice). Tetrakis(triphenylphoshine)palladium was added and the reaction mixture was refluxed under an atmosphere of nitrogen until mass spectrometry indicated complete consumption of the aryl iodide. The reaction mixture was allowed to cool to ambient temperature and was filtered through a pad of Celite and washed with ethyl acetate (255 mL). Aqueous potassium fluoride (1M, 50 mL) was added to the filtrate and the biphasic mixture was shaken. The resultant precipitate was removed by filtration and the organics were further washed with aqueous potassium fluoride (1M, 50 mL), water (2×100 mL), and saturated brine (100 mL). The solution was dried over anhydrous sodium sulfate, concentrated in vacuo and chromatographed on silica gel. Elution with ethyl acetate afforded 5-Fluoro-6-(2-fluoro-4-vinyl-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid methyl ester (2.13 g, 44% yield): 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1 H), 8.09 (br s, 1 H), 8.06 (s, 1 H), 5.36 (dd, J=13.2, 1.5 Hz, 1 H), 5.05 (dd, J=8.3, 1.5 Hz, 1 H), 6.60 (dd, J=15.5, 10.9 Hz, 1 H), 6.50 (td, J=8.8, 4.6 Hz, 1 H), 5.65 (d, J=15.4 Hz, 1 H), 5.11 (d, J=11.2 Hz, 1 H), 3.92 (s, 3 H), 3.82 (s, 3 H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][OH:29]>CN(C)C=O>[OH:29][CH2:28][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(OCCO)cc2)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-methoxybenzyl 4-hydroxybenzoate (7.0 g, 27 mmole) in dry N,N-dimethylformamide (50 ml) was added potassium carbonate (4.15 g, 30 mmole) and 2-bromoethanol. The mixture was stirred 48 hours at 80° C., evaporated under reduced pressure and ethyl acetate and water were added. The organic phase was washed five times with water and dried with sodium sulfate. The solution was evaporated under reduced pressure and the product was isolated by silica gel column chromatography with hexane/ethyl acetate.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[CH3:6][C:7]1[CH:8]=[C:9](C2SCCS2)[CH:10]=[CH:11][CH:12]=1.[C:18]([Cl:22])(Cl)([Cl:20])[Cl:19]>>[CH3:6][C:7]1[CH:12]=[C:11]([C:18]([Cl:22])([Cl:20])[Cl:19])[CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1cccc(C2SCCS2)c1
Solvent: O=S(=O)(Cl)Cl
Product: Cc1cccc(C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
0.38 moles of sulfuryl chloride in an equal volume of carbon tetrachloride was added dropwise to 21.6 gm (0.11 moles) of 2-(3-methylphenyl)-1,3-dithiolane dissolved in 22 mls of carbon tetrachloride while refluxing and stirring. After the addition, the reaction mixture was stirred for 1 hour at reflux and allowed to cool to room temperature. The solvent was evacuated and the residue Kugelrohr distilled at 65°-70° C. (0.43 mm/Hg) to give 18.32 gm (89.9% yield) of product. NMR and Gas Chromatograph/Mass Spectrometry (GC/MS) Analysis: 1H--NMR (CCl4) δ2.27 (S, CH3), 6.9 to 7.2 and 7.5 to 7.65 (m+ 4H, aryl protons); GCMS (70 ev), M/e (% rel. int.) 212 (M +4, 4), 210 (M+ +2, 12), 208 (M+, 13), 177 (13), 175 (79), 173 (100), 138 (15), 103 (26), 102 (25), 101 (19), 87 (20), 86 (16), 77 (23), 75 (19), 69 (22), 68 (24), 51 (64).
Reaction SMILES: Br[C:2]1([CH:9]=[CH:8][CH:7]=[CH:6][CH2:5]1)[CH:3]=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:24]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[CH:3]=[O:4])[C:25]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=CC1(Br)C=CC=CC1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.1 %

Procedure:
To a suspension of 1-bromobenzaldehyde (200 μL, 1.71 mmol), sodium carbonate (218 mg, 2.06 mmol), and 1-naphthaleneboronic acid (353 mg, 2.05 mmol) in 3.4 mL of N,N-dimethylformamide/water (2:1) was added palladium acetate (20 mg, 89 μmol) under nitrogen. After being stirred at room temperature overnight, the reaction mixture was filtered. The filtrate was diluted with diethyl ether, and the solution was washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (346 mg, 87%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]3[CH:18]=[CH:19][C:20]4[N:21]([CH:23]=[C:24]([NH:26]C(=O)C(F)(F)F)[N:25]=4)[CH:22]=3)[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:33])=[N:3]1.[OH-].[Na+].C(O)C>O>[NH2:26][C:24]1[N:25]=[C:20]2[CH:19]=[CH:18][C:17]([O:16][C:12]3[CH:11]=[C:10]([NH:9][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[C:4]([CH3:33])[CH:5]=4)=[O:8])[CH:15]=[CH:14][CH:13]=3)=[CH:22][N:21]2[CH:23]=1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C(F)(F)F)cn4c3)c2)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A mixture of 1,3-dimethyl-N-[3-({2-[(trifluoroacetyl)amino]imidazo[1,2-a]pyridin-6-yl}oxy)phenyl]-1H-pyrazole-5-carboxamide (328 mg, 0.715 mmol), 1N aqueous sodium hydroxide solution (3 mL) and ethanol (3 mL) was stirred at 40° C. for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, methanol/ethyl acetate=0/100→20/80) to give the title compound (205 mg, 79%) as a white solid.