Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2].[Cl:40][C:41]1[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43][N:42]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:45]3[CH:44]=[CH:43][N:42]=[C:41]([Cl:40])[CH:46]=3)[CH:23]=2)[C:10]=1[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccnc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccnc(Cl)c3)c2)c1CCC(=O)OCC
Yield: 35.9 %

Procedure:
A similar procedure as described in Example 44, step 3 was used, starting from 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (305 mg, 0.5 mmol), 2-chloro-pyridin-4-ylboronic acid (161 mg, 1.0 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (55 mg, 0.075 mmol), and cesium carbonate (331 mg, 1.0 mmol) to obtain 4-[3-{6-[3-(2-chloro-pyridin-4-yl)-5-ethoxy-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (115 mg, 36%) as a light yellow oil: ES(+)-HRMS m/e calcd for C36H46ClNO7 (M+H)+ 640.3036. found 640.3032.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:9][CH:10]=1)(=O)C.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:13]/[CH:12]=[CH:11]/[C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([O:14][CH3:15])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)O
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Product: COc1cc(/C=C/COC(C)=O)ccc1O

Procedure:
A mixture of eugenol acetate (16 g,0.0777 mol) and mercuric acetate (44.5 g, 1.4 mol) in 160 ml of acetic acid was refluxed for 20 hr. After filtration, the acetic acid solution was poured into water (150 ml) and extracted with ether (200 ml). The etheral solution was washed successively with water, aqueous NaHCO3, saturated NaCl solution and dried (Na2SO4). The solvent was evaporated to give 18 g of coniferyl acetate. Subsequent reduction of the coniferyl acetate with Red-Al gave coniferyl alcohol.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:17][CH:18]([CH2:20][CH2:21][CH2:22][C@H:23]([C@@H:25]1[C@:43]2([CH3:44])[C@H:28]([C@H:29]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:32]([CH2:33][C@H:34]([CH2:36][CH2:37]2)[OH:35])=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH3:19].C(O)(=O)C>O1CCCC1.[Pd]>[NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[CH3:19][CH:18]([CH2:20][CH2:21][CH2:22][C@H:23]([C@@H:25]1[C@:43]2([CH3:44])[C@H:28]([C@H:29]3[C@H:40]([CH2:41][CH2:42]2)[C@:38]2([CH3:39])[C:32]([CH2:33][C@H:34]([CH2:36][CH2:37]2)[OH:35])=[CH:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH3:17]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Agent: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)O

Procedure:
Z-Ala-cholesterol (0.48 mmol) is placed in tetrahydrofuran (20 ml) and glacial acetic acid (3 ml) and hydrogenated in the presence of 5% palladium on charcoal for 2 hours. The reaction mixture is filtered and concentrated in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([N:16]2CN(C)C(=O)N(C)C2)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].[OH-].[Na+]>C(O)(C)(C)C>[NH2:16][C@H:13]1[CH2:14][CH2:15][C@H:10]([O:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:12]1
Reactant: CN1CN([C@H]2CC[C@H](OCC(=O)OC(C)(C)C)CC2)CN(C)C1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)CO[C@H]1CC[C@H](N)CC1

Procedure:
trans-5-[4-[(t-Butoxycabonyl)methyloxy]cyclohexyl]-1,3-dimethylhexahydro-2-oxo-1,3,5-triazine (300mg, 0.879 mmol) was dissolved in t-butanol (5 ml) and a saturated aqueous ammonium chloride solution (5 ml) was added, which was followed by refluxing under heating for 2 hours. The reaction mixture was adjusted to pH 10 with a 1N aqueous sodium hydroxide solution and extracted with benzene. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, low boiling matters were distilled away from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography (methylene chloride/methanol=10/1-5/1) to give 130 mg of t-butyl trans-(4-aminocyclohexyloxy)acetate as a colorless solid (57%).
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH:37]([CH:40]1[CH2:51][CH:50]=[CH:49][CH2:48][CH2:47][CH:46]=[CH:45][CH2:44][CH:43]([CH:52]([CH3:54])[CH3:53])[N:42]=[N:41]1)([CH3:39])[CH3:38]>>[NH2:41][CH:40]([CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH:43]([NH2:42])[CH:52]([CH3:54])[CH3:53])[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C1CC=CCCC=CCC(C(C)C)N=N1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CC(C)C(N)CCCCCCCCC(N)C(C)C
Yield: 92.8 %

Procedure:
If there are used in the manner described under (a), intead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 250 g (1 mol) of 3,12-diisopropyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with the procedure otherwise being the same, there is obtained, as the main fraction, 238 g (92% of theory) of 3,12-diamino-2,13-dimethyltetradecane as colourless oil [b.p. 106°-109° C./0.01 Torr; nD20 =1.4600; IR (liquid) inter alia bands at 3355, 3278 and 1613 cm-1 ].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 1-bromo-4-methoxybenzene (5 g, 27 mmol) in THF (100 mL) at −78° C. was added a solution of 1.6 M N-butyl lithium/hexanes (18.4 mL, 29.4 mmol), and the reaction mixture was stirred for 1 hr. Then a solution of 1-benzylpiperidin-4-one (4.81 g, 25.4 mmol) in 50 mL of THF was added. After the addition, the mixture was allowed to warm up to rt and was stirred for 1 h. The reaction was then quenched by the addition of 100 mL of 1.5 M aqueous HCl and the mixture was extracted with 200 mL of ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to yield 7.1 g (72% yield) of 1-benzyl-4-(4-methoxyphenyl)piperidin-4-ol. LCMS (method F) RT 2.19 min, 81% AP, m/z298.4 (M+H+), 1H NMR (300 MHz, DMSO-d6) δ 7.23-7.39 (m 8.5H), 6.94 (m, 0.5H), 6.84-6.94 (m, 2H), 4.66 (s, 1H), 3.74 (s, 0.8H), 3.72 (s, 3H), 3.32 (s, 2H), 2.50-2.67 (m, 2H), 2.34-2.45 (m, 3H), 1.83-1.90 (m, 2H), 1.55 (d, J=11, 2H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH:14]1[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:15]1>N1C=CC=CC=1>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCC1CCc2ccccc2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
38.16 g (0.2 mol) of p-toluenesulphonyl chloride are added at room temperature while stirring to a solution of 31 g (0.189 mol) of 2-hydroxymethylchroman in 110 ml of absolute pyridine, the slightly exothermic reaction being maintained at room temperature by means of an ice bath. The reaction mixture is stirred for a further 3 hours at room temperature and then poured onto ice-water. The oil which separates out is removed by decanting the aqueous phase, dissolved in diethyl ether and washed with ice-cold 2N hydrochloric acid and ice-water. The ethereal phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 58.15 g (96.6%) of 2-(p-toluenesulphonyloxymethyl)chroman are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6]1)[CH2:33][CH3:34]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCC[C@H]1CC[C@H](CCC)N1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCC[C@H]1CC[C@H](CCC)N1C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 23.3 mg trans-2,5-dipropylpyrrolidine from the Step D above, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 70-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.48 min. (m/Z=428.4, 450.3).
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[C:4]([CH3:7])=[CH:5][CH:6]=1>[Ni].CO>[CH3:1][C:2]1[N:3]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C)n1S(=O)(=O)c1ccc(N)cc1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
A mixture of 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]nitrobenzene (Step 1) (7.3 g, 26 mmol) and Raney Nickel (0.7 g) in 70 mL of methanol was hydrogenated in a Parr apparatus at a pressure of 50 psi. After 3 hours, the catalyst was filtered and the filtrate was concentrated to give 4-[(2,5-dimethyl-1H-pyrrol-1-yl)sulfonyl]benzenamine (6.4 g) as a pale yellow solid: mp (DSC): 110-111° C. Anal. Calc'd. for C12H14N2O2S: C, 57.58; H, 5.64; N, 11.16; S, 12.81. Found: C, 57.44; H, 5.78; N, 11.11; S, 12.30.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[CH:12]=[N+:13]([O-:27])[CH:14]=[C:15]([F:18])[C:16]=2[N:17]=1
Reactant: Fc1cccc(Cl)c1-c1nc2c(F)cncc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(F)cccc3Cl)sc2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To an ice-cooled solution of 2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridine (4.0 g, 14.16 mmol) in DCM (50 mL) was added m-CPBA (4.82 g, 0.028 mol) and the mixture was stirred at 5° C. for 1 hour. Additional m-CPBA (4.82 g, 28.0 mmol) was added and stirring at room temperature was continued for 18 hours. The suspension was diluted with DCM (50 mL) and washed with a potassium carbonate solution (100 mL). The aqueous phase was extracted with DCM (2×50 mL) and the combined organic layers were washed with water (100 mL), then dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was triturated with diethyl ether (25 mL) to afford the title compound as a white solid (3.1 g, 73%). LCMS (Method E): RT=2.70 min, m/z: 299 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[C:5](=[O:14])[N:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[C:17]([N+:26]([O-])=O)[CH:16]=2)[C:3]1=[O:29].Cl>O.[Zn]>[NH2:26][C:17]1[CH:16]=[C:15]([N:4]2[C:3](=[O:29])[C:2]([CH3:30])([CH3:1])[N:6]([CH2:7][C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[C:5]2=[O:14])[CH:20]=[CH:19][C:18]=1[O:21][C:22]([F:23])([F:24])[F:25]
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c([N+](=O)[O-])c2)C(=O)N1Cc1ccncc1
Agent: Cl
Agent: [Zn]
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Temperature: 25 °C
Yield: 57.6 %

Procedure:
8.8 g (20.7 mmol ) 5,5-dimethyl-3-(3-nitro-4-trifluormethoxy-phenyl)-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 200 ml semi-conc. hydrochloric acid. 30 g zinc dust were added in portions and the resulting mixture was refluxed for 1 h, cooled to RT, diluted with 100 ml water and extracted with ethyl acetate. The aqueous phase was made alkaline with saturated sodium hydroxide solution and extracted with methylene chloride. Separating zinc salts were removed by filtration over cellite. Evaporation of the combined organic phases and flash chromoatography of the residue (Silica gel, methylene chloride:methanol=95:5) gave 4.7 g of the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=O.C(OCC)C.[NH3:30]>CO>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]([O:10][C:9]1[CH:8]=[C:7]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[S:6][C:5]=1[C:3]([NH2:30])=[O:2])[CH3:12]
Reactant: N
Reactant: COC(=O)c1sc(-n2ccnc2)cc1OC(C)c1ccccc1Cl
Solvent: CO
Solvent: CCOCC
Product: CC(Oc1cc(-n2ccnc2)sc1C(N)=O)c1ccccc1Cl
Temperature: 80 °C
Yield: 64 %

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-imidazol-1-yl-thiophene-2-carboxylic acid methyl ester (265 mg, 0.73 mmol, 1.0 Eq.) was suspended in 7M NH3 in MeOH (10 mL) and heated to 80° C. in a pressure tube for 3 days. The solvent was removed in vacuo and the product isolated by column chromatography (2% to 5% MeOH/EtOAc) followed by tritruation from diethyl ether to give the title compound as cream powder (163 mg, 0.47 mmol, 64%); 1H NMR (400 MHz, d-6 DMSO) δ 1.71 (3H, d), 5.89 (1H, q), 7.03 (1H, br s), 7.11 (1H, s), 7.23 (1H, s), 7.36-7.42 (2H, m), 7.49 (1H, dd), 7.63 (1H d), 7.66 (1H, dd), 7.78 (1H, br s), 8.17 (1H, s)
Reaction SMILES: I[C:2]1[NH:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([O-])([O-])=O.[K+].[K+].CO.CO[CH2:22][CH2:23]OC>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>[CH3:7][C:5]1[NH:6][C:2]([CH:22]=[CH2:23])=[C:3]([C:8]([F:11])([F:10])[F:9])[N:4]=1
Reactant: Cc1nc(C(F)(F)F)c(I)[nH]1
Reactant: COCCOC
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: CO
Product: C=Cc1[nH]c(C)nc1C(F)(F)F
Temperature: 80 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
To a solution of 5-iodo-2-methyl-4-(trifluoromethyl)-1H-imidazole (1.98 g, 7.2 mmol) in DME (20 mL) and H2O (4 mL) was added K2CO3 (10 g, 71.9 mmol), trivinylboronic anhydride pyridine complex (1.73 g, 7.19 mmol) and Pd(PPh3)4 (830 mg, 0.719 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. MeOH (100 mL) was then added to the reaction mixture and the mixture was filtered, concentrated in vacuo, and purified by flash chromatography (SiO2, 10% MeOH/CH2Cl2) to obtain 2-methyl-4-(trifluoromethyl)-5-vinyl-1H-imidazole (911 mg, 5.17 mmol, 72% yield) as a brown syrup.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[C:28](O)[CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[N:23][N:24]=2)[CH:21]=1>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[C:28]([O:1][CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH:29]=[CH:30][CH:31]=4)[N:26]=3)=[N:23][N:24]=2)[CH:21]=1
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: Oc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12
Product: CC(C)(CNC(=O)OC(C)(C)C)COc1cccc2ccc(-c3nnc4ccc(Br)cn34)nc12

Procedure:
Prepared as described in Example 9, Step A, using tert-butyl 3-hydroxy-2,2-dimethylpropylcarbamate in place of tert-butyl-4-hydroxypiperidine-1-carboxylate and 2-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol in place of 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Product: COc1ccc(C(F)(F)F)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-methoxy-5-(trifluoromethyl)benzoic acid (0.68 g, 3.1 mmol) in thionyl chloride (10 mL) was warmed to reflux and was allowed to stir for 2 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure and diluted with 10 mL of toluene. This material was again concentrated under reduced pressure and was again diluted with 10 mL of toluene. This concentration and dilution was repeated for an additional time and the crude acid chloride was carried on to the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[N:17]=[C:16](C(OC)(OC)OC)[N:15]([CH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])OC(C)(C)C)[C:14]=3[CH:36]=2)=[O:9])[CH:2]=1.Cl.C(N(CC)CC)C>CO.C(Cl)Cl>[O:35]=[C:29]1[C:16]2=[N:17][C:13]3[CH:12]=[CH:11][C:10]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:9])=[CH:36][C:14]=3[N:15]2[CH2:25][CH2:26][CH2:27][NH:28]1
Reactant: COC(OC)(OC)c1nc2ccc(C(=O)Nc3cccnc3)cc2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1ccc2nc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
To a solution of tert-butyl {3-[6-(pyridin-3-ylcarbamoyl)-2-(trimethoxymethyl)-1H-benzimidazol-1-yl]propyl}carbamate (85 mg, 0.17 mmol) in methanol (2 mL) was added concentrated HCl (1 mL). The solution is stirred at room temperature for 2 h and is evaporated to dryness. The residue is dissolved in methanol (5 mL), triethylamine (0.14 mL, 1.0 mmol) added, and the solution heated at reflux for 2 h. The cooled solution was diluted with CH2Cl2, and washed with Na2CO3. The organic layer was dried (MgSO4) and evaporated. The crude product was purified via preparative HPLC. The major peak was collected by passing the HPLC fractions, without concentrating, directly through an SCX cartridge (Silicycle tosic acid, 1 g). The cartridge was washed with methanol, then CH2Cl2/methanol (50:50). Finally, the product was eluted with CH2Cl2/methanol containing 1% NH4OH. The solution containing product was evaporated to afford the title compound (13 mg, 22%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C@H:12]([C:14]2[N:15]=[C:16]([CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][C:18]=3Cl)[CH3:13])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C(N(CC)CC)C>[Pd].CO>[O:30]1[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:23]=[C:14]([C@@H:12]([NH:11][C:4]3[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=[CH:2][CH:3]=3)[CH3:13])[N:15]=2)[CH2:32][CH2:31]1
Reactant: C[C@H](Nc1cc(Cl)nn2ccnc12)c1cc2cccc(Cl)c2c(CCN2CCOCC2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H](Nc1ccnn2ccnc12)c1cc2ccccc2c(CCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Palladium on carbon (10%, 10 mg) was added to a mixture of (S)-6-chloro-N-(1-(8-chloro-1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)imidazo[1,2-b]pyridazin-8-amine 76 (40 mg, 0.085 mmol, 1.0 eq) and triethylamine (0.2 mL, 1.5 mmol, 17.6 eq) in MeOH (10 mL). The resulting mixture was degassed and back-filled with hydrogen three times and then stirred at RT under hydrogen for 5 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1-4% MeOH-DCM) to afford the product (S)—N-(1-(1-(2-morpholinoethyl)isoquinolin-3-yl)ethyl)imidazo[1,2-b]pyridazin-8-amine 77. ESI-MS m/z: 403.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:39])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:14][CH:13]=2)([C:8]([F:11])([F:10])[F:9])[NH:6][C:5](=[O:26])[C:4]([C:27]([O:29]CC)=[O:28])=[C:3]1[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1.[Li+].[OH-]>CO>[F:39][C:2]1([F:1])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[CH:14][CH:13]=2)([C:8]([F:9])([F:10])[F:11])[NH:6][C:5](=[O:26])[C:4]([C:27]([OH:29])=[O:28])=[C:3]1[C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C1=C(c2ccc(C)cc2)C(F)(F)C(c2ccc(OCCCC(F)(F)F)cc2)(C(F)(F)F)NC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C2=C(C(=O)O)C(=O)NC(c3ccc(OCCCC(F)(F)F)cc3)(C(F)(F)F)C2(F)F)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a solution of Intermediate 103H (100 mg, 0.177 mmol) in MeOH (2 mL) was added 2 M LiOH (0.4 mL, 0.800 mmol). The resulting mixture was stirred at 100° C. for 15 min. LC-MS indicated the product to be the major component along with a trace amount of SM and 14% of the corresponding methyl ester. 2 M LiOH (100 uL) was then added and the reaction was stirred at 100° C. for an additional 15 min. The reaction was concentrated, acidified with 1 N HCl, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated to yield the desired product (75 mg, 78%) as a solid. LCMS Anal. Calc'd for C24H19F8NO4 537.12, found [M+H] 537.9.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1([F:17])[O:16][C:7]2=[CH:8][C:9]3[NH:13][C:12](=[S:14])[NH:11][C:10]=3[CH:15]=[C:6]2[O:5]1.[N+]([C:21]1[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1)([O-])=O>O1CCCC1>[F:17][C:4]1([F:3])[O:5][C:6]2=[CH:15][C:10]3[NH:11][C:12]([S:14][C:21]4[O:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=4)=[N:13][C:9]=3[CH:8]=[C:7]2[O:16]1
Reactant: FC1(F)Oc2cc3[nH]c(=S)[nH]c3cc2O1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
Aldehyde intermediate preparation: Sodium hydride (60% dispersion in mineral oil, 0.212 g, 5.3 mmol) in tetrahydrofuran (3 ml) is added dropwise over a 15 minute period to a solution of 2,2-difluoro-5,7-dihydro-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazole-6-thione (0.763 g, 3.31 mmol) in tetrahydrofuran (5 ml). The mixture is stirred at room temperature for 2 hours. 5-nitro-2-furaldehyde (0.468 g, 3.31 mmol) in 7 ml of tetrahydrofuran is then added dropwise over a 15 minute period and the mixture is stirred for 2 hours at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in 100 ml of ethyl acetate and washed with water (2×30 ml). The organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue is purified on a silica gel column (120 g) eluted with a mixture of dichloromethane and methanol (92/5, v/v). The fractions containing the expected product are concentrated under reduced pressure and the residue is triturated in diisopropylether and pentane and dried under vacuum to yield 5-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-ylsulfanyl)-furan-2-carbaldehyde as a brown powder. Yield=56%. Analytical LC/MS (method B): retention time=3.66 min., m/z=324.97 (positive ion mode).