Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16][C:17](OCC)=[O:18])[CH2:14][O:13][C@@H:12]([CH3:22])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[O:1]([CH2:9][C@H:10]1[C@@H:15]([CH2:16][CH:17]=[O:18])[CH2:14][O:13][C@@H:12]([CH3:22])[O:11]1)[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C[C@H]1CO[C@@H](C)O[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: C[C@@H]1OC[C@H](CC=O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A solution of (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-ethoxycarbonylmethyl-2-methyl-1,3-dioxane (9.30 g) in toluene (93 ml) was cooled in a dry ice acetone bath and to the solution was added dropwise diisobutyl aluminum hydride (1.5 M solution in toluene, 26.4 ml). The mixture was stirred at the same temperature for 1 hour. After quenching the mixture with saturated aqueous ammonium chloride, to the solution was added a mixture of ethyl acetate (300 ml) and water (300 ml). Insoluble materials were filtered off. The filtrate was extracted with ethyl acetate and organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel column (250 g) with a mixture of n-hexane and ethyl acetate (10:1) as an eluent to give (2R,4R,5S)-4-t-butyldimethylsiloxymethyl-5-formylmethyl -2-methyl-1,3-dioxane (6.61 g) as a colorless oil.
Reaction SMILES: C([CH2:8][NH:9][CH:10]([C:12]([CH3:26])([OH:25])[CH2:13][CH2:14][CH2:15][C:16]([CH3:24])([OH:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH3:11])C1C=CC=CC=1>[Pd].C(O)C>[CH3:8][NH:9][CH:10]([C:12]([CH3:26])([OH:25])[CH2:13][CH2:14][CH2:15][C:16]([CH3:24])([OH:23])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:21])[CH3:22])[CH3:11]
Reactant: CC(C)CCCC(C)(O)CCCC(C)(O)C(C)NCCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNC(C)C(C)(O)CCCC(C)(O)CCCC(C)C
Yield: 63.8 %

Procedure:
An autoclave was charged with 7.5 g of 2-(benzylmethylamino)-3,7,11-trimethyl-3,7-dodecanediol, 0.75 g of palladium-on-carbon and 30 ml of ethanol, and the reaction was conducted at 40° C. under hydrogen pressure (10 atm). After completion of the reaction, the ethanol was distilled off and the residue was subjected to silica gel column chromatography (elution with 95% ethanol-5% triethylamine) to give 3.6 g of 2-(methylamino)-3,7,11-trimethyl-3,7-dodecanediol [Compound (70)]. Yield 65%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:7]=1[C:13]([F:16])([F:15])[F:14])[CH3:2].[Br:18][C:19]1[CH:20]=[CH:21][C:22](F)=[C:23]([CH:26]=1)[CH:24]=[O:25]>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:22]2[CH:21]=[CH:20][C:19]([Br:18])=[CH:26][C:23]=2[CH:24]=[O:25])[CH:9]=[CH:8][C:7]=1[C:13]([F:15])([F:16])[F:14])[CH3:2]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: CCOC(=O)Cc1cc(O)ccc1C(F)(F)F
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2C=O)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 4, using the following starting materials: (5-hydroxy-2-trifluoromethyl-phenyl)-acetic acid ethyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C([Sn](CCCC)(CCCC)[C:44]1[C:49]([O:50][C@H:51]([CH2:53][CH:54]=[CH2:55])[CH3:52])=[CH:48][C:47]([F:56])=[CH:46][C:45]=1[F:57])CCC.[F-].[Cs+].[SnH4]>CN(C=O)C.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.[Cu]I>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:48]5[C:49]([O:50][C@H:51]([CH2:53][CH:54]=[CH2:55])[CH3:52])=[CH:44][C:45]([F:57])=[CH:46][C:47]=5[F:56])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(F)cc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.25 g, 0.428 mmol, 1 equiv) and (S)-tributyl(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)stannane (0.25 g, 0.513 mmol, 1.2 equiv) in DMF (2 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (49 mg, 0.043 mmol, 0.1 equiv), CsF (195 mg, 1.28 mmol, 3 equiv), and CuI (20 mg, 0.107 mmol, 0.25 equiv). The reaction was heated at 80° C. for 2 h. After 2 h, more stannane (300 mg) was added. Stir for 2 h and remove from heat. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (160 mg, 53%) as a film. LCMS (ESI, M+1): 702.25.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[OH-].[Na+].[CH2:23]([S:25][C:26]#[N:27])[CH3:24]>>[CH2:1]([NH:8][C:26](=[NH:27])[S:25][CH2:23][CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCSC#N
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Product: CCSC(=N)NCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
Benzylamine (13.8 mg) was dissolved in ethyl thiocyanate (50 μl). To this solution, trimethylsilyl trifluoromethanesulfonate (25.7 μl) was added dropwise at room temperature. After continued stirring for 1 day at room temperature, 2N aqueous sodium hydroxide was added to the solution, which was then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (25.4 mg, yield 100%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][N:3]=1.[CH3:20][N:21](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:14]1([CH2:13][O:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([C:20]#[N:21])=[N:3][CH:4]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Clc1ncc(OCc2ccccc2)c2ccccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ncc(OCc2ccccc2)c2ccccc12
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-chloro-4-(phenylmethoxy)isoquinoline (2.26 g, 8.4 mmol), Zn(CN)2 (590 mg), tris(dibenzylideneacetone)dipalladium (219 mg), 1,1′-bis(diphenylphosphino)ferrocene (270 mg) in 100 ml of DMF is heated at 150° C. for 24 h under nitrogen. TLC and LC-MS analysis indicates complete consumption of starting material after 24 h. The mixture is then cooled to 80° C. and gradually diluted with 4:1:4 saturated aq. NH4Cl: concentrated NH4OH:water (200 mL) over 0.5 hours. The slurry is cooled to 0° C. and filtered through celite. The tan solid is collected by filtration, washed and dried to give the titled compound as a tan solid (1.5 g), m.p. 124-125° C.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[F:9][C:10]([F:40])([F:39])[C:11]1[CH:12]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=C)[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=[O:5])[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:12]=[C:11]([C:10]([F:39])([F:40])[F:9])[CH:16]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
N-Methylmorpholine N-oxide (1 g, 8.6 mmol) and osmium tetroxide (2 ml, 2.5% solution in tert-butanol) were added to a solution of (2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727; 2 g, 4.3 mmol) in tetrahydrofuran (25 ml) and water (10 ml). The mixture was stirred at room temperature for one hour before sodium periodate (9 g, 43 mmol) was added. This mixture was stirred for 45 minutes and then filtered through Celite™. The filtrate was diluted with ethyl acetate (50 ml) and washed with brine. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/iso-hexanes to give the title compound (1.6 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=1.[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([O:18][CH2:17][CH:16]([OH:19])[CH2:15][N:14]1[C:13]2[C:20]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])=[CH:21][CH:22]=[CH:23][C:12]=2[N:11]=[C:10]1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)CO)c12
Solvent: c1ccncc1
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CC(O)COC(C)=O)c12
Reaction time: 5 h
Yield: 64 %

Procedure:
To a solution of 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propane-1,2-diol (Reference Example 88; 46.2 mg, 0.109 mmol) in pyridine (0.5 mL) was added acetyl chloride (0.0155 mL, 0.218 mmol) at 0° C. After 5 hr, the mixture was quenched with aqueous sodium hydrogen carbonate, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by NH flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (32.5 mg, 0.0698 mmol, 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(NC(=O)c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-aminophenyl)phthalimide (332 mg) in tetrahydrofuran (4 mL) is added lithium borohydride (1.0 g) and the mixture is stirred for 1 hour at 25° C. The mixture is poured into water and extracted into ethyl acetate. The ethyl acetate solution is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white foam, which when triturated with diethyl ether provides the desired product as a white powder.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:14]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([O:16][CH2:15][CH:14]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:8]1[C:6]([OH:7])=[O:5])(=[O:19])[CH3:18]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)O)cc1
Temperature: 25 °C

Procedure:
To a solution of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (266 mg, 0.6 mmoL) in 1.5 mL dichloromethane at 0° C. was added 1.5 mL of trifluoroacetic acid. The reaction was gradually allowed to warm to ambient temperature, and the solvent was removed under reduced pressure after 1.4 hours. The residue was azeotroped twice with toluene and purified by column chromatography (silica: 30% ethyl acetate in hexanes with 1% acetic acid to 4% methanol in dichloromethane with 1% acetic acid) to yield 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid quantitatively; MS: (M+H)+ =386, (M+NH4)+ =403.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:10]([OH:22])[CH2:11][CH2:12][NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+].[N-]=[N+]=[N-].[Na+].C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CN(C=O)C>[CH2:27]([NH:34][C:19](=[O:21])[C@H:14]([CH2:15][CH:16]([CH3:17])[CH3:18])[NH:13][CH2:12][CH2:11][C@H:10]([OH:22])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:23][CH:24]([CH3:26])[CH3:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)C[C@H](NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCc1ccccc1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NCC[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: -30 °C
Reaction time: 72 h

Procedure:
3 (540 mg) was suspended in DMF (23 ml) and treated with benzylamine (0.374 ml), TEA (0.401 ml), NaHCO3 (solid) (924 mg) and sodium azide (117 mg). The suspension was cooled to -30° C., treated with DPPA (0.934 ml), and stirred at 0° C. for 72 hours. After removal of the DMF in vacuo, the residue was treated with 10% citric acid and extracted with EtOAc (3x). The combined extracts were washed with 10% citric acid (1x), H2O (1x), 10% NaHCO3 (aqueous) (1x), and brine (1x), dried over MgSO4, filtered and evaporated to dryness in vacuo to give a crude colorless oil (1.5 g). Flash chromatography on silica gel (90/10/1/1 of CH2Cl2 /MeOH/H2O/HOAc) gave 7 as a sticky foam (440 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](Cl)=[O:12])=[O:5])[CH3:2].[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]2[CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:26]=[C:18]2[CH:17]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:14])[C:10]=1[C:11](=[O:12])[NH:15][C:16]1[C:21]([C:22]#[N:23])=[CH:20][N:19]2[CH:24]=[C:25]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:26]=[C:18]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Cl
Reactant: N#Cc1cn2cc(-c3ccccc3)nc2cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
5-Chlorocarbonyl-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (940 mg, 4.33 mmol) was added slowly to a solution of 7-amino-2-phenyl-imidazo[1,2-a]pyridine-6-carbonitrile (410 mg, 1.8 mmol) and triethylamine (363 mg) in dichloromethane (8 ml), and the mixture was stirred at r.t. overnight. The mixture was extracted with dichloromethane, the combined organic layers were dried (Na2SO4), and evaporated. The title compound (310 mg, 42%) was obtained by column chromatography (silica gel, heptane:ethyl acetate=80:20-60:40). MS (m/e)=413.3 [M−H+].
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccnc2ccccc12
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Product: O=C(Nc1ccnc2ccccc12)c1cc(N(CC2CC2)C2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidine-4-carboxylic acid (Intermediate 13) and 4-aminoquinoline (Tyger), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]12[C:15]([Cl:17])([Cl:16])[C:5]([Cl:18])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[C:8]([CH3:13])[C:7]3=[O:14])[C:4]([Cl:19])=[C:3]2[Cl:20].CO>N1C=CC=CC=1>[Cl:1][C:2]12[C:15]([Cl:16])([Cl:17])[C:5]([Cl:18])([C:6]3[C:7]([OH:14])=[C:8]([CH3:13])[CH:9]=[C:10]([OH:12])[C:11]=31)[C:4]([Cl:19])=[C:3]2[Cl:20]
Reactant: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Solvent: c1ccncc1
Solvent: CO
Product: Cc1cc(O)c2c(c1O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
30 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-6-methyl-1,4-methanonaphthalene-5,8-dione, prepared according to Example 45, were suspended in 150 ml. of methanol. 2 ml. of pyridine were added and the mixture was refluxed for 4 hours. Upon cooling in an ice-water bath, a crude white solid formed. This solid was recrystallized from methanol and white crystals were obtained, m.p. 159°-161° C.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1(C)CCC2C(=CC=CC=2)C1=O>>[CH2:14]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1)[CH3:15]
Reactant: CC1(C)Cc2ccc(F)cc2C1=O
Reactant: CC1(C)CCc2ccccc2C1=O
Product: CCc1ccc2c(c1)C(=O)C(C)(C)C2

Procedure:
6-Fluoro-2,2-dimethyl-1-indanone, a white crystalline solid melting at 64.5°-66.5° C. and 2,2-dimethyl-1-tetralone, a colorless liquid boiling at 88°-89° C. under 0.75 mm Hg (100 Pascals) pressure were prepared similarly.
Reaction SMILES: C(O)(=O)C.[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13])(=[O:8])=[O:7].Cl[C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[N:19]=1.CCN(CC)CC>O1CCOCC1>[CH3:5][S:6]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:13][C:22]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:18][N:19]=[C:20]([NH:28][C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH2:31][C:32](=[O:38])[NH:33]3)[N:21]=1)(=[O:7])=[O:8]
Reactant: CS(=O)(=O)c1cccc(CN)c1
Reactant: O=C1Cc2c(cccc2Nc2ncc(C(F)(F)F)c(Cl)n2)N1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(CNc2nc(Nc3cccc4c3CC(=O)N4)ncc2C(F)(F)F)c1
Temperature: 25 °C

Procedure:
3-methanesulfonyl-benzylamine mono-acetate (150 mg, 0.61 mmol) and 4-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one (200 mg, 1 eq) were combined with Et3N (136 mg, 2.2 eq) in dioxane (3 mL) at 100° C. for 3 hours. The reaction was cooled to RT and product crystallized by the addition of water to the crude reaction. The product was filtered of as a tan solid, 139 mg (48%). 1H NMR (DMSO-d6, 400 MHz) δ 3.11 (s, 3H), 3.39 (s, 2H), 4.62 (d, J=5.8 Hz, 2H), 6.48 (d, J=7.5 Hz, 1H), 6.96 (m, 1H), 7.07 (d, J=8.3 Hz, 1H), 7.53 (m, 2H), 7.75 (d, J=7.5 Hz, 1H), 7.83 (m, 2H), 8.19 (s, 1H), 9.08 (s, 1H), 10.31 (s, 1H); HPLC ret. time: 5.314 min. LRMS (M+) 478.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:14][C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[C:21]=1[CH2:22][CH2:23][C:24]([NH:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)=[O:25]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1CCCC2)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
3-[2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (11 g) was dissolved in 150 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. 4-(2-Aminoethyl)morpholine (7.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 11.5 g (80%) of 3-[2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-N-(2-morpholin-4-ylethyl)-propionamide.
Reaction SMILES: [I:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10]C)[N:5]=[CH:4][CH:3]=1.I[Si](C)(C)C>>[OH:10][C:6]1[N:5]=[CH:4][CH:3]=[C:2]([I:1])[C:7]=1[CH:8]=[O:9]
Reactant: COc1nccc(I)c1C=O
Agent: C[Si](C)(C)I
Product: O=Cc1c(I)ccnc1O

Procedure:
In another embodiment, general acid 2 can be prepared from an acid of formula 40 as illustrated in Scheme 7. Thus, 4-iodo-2-methoxynicotinaldehyde (37; See: WO95/29917) is de-methylated, for example by treatment with iodotrimethylsilane, to provide 2-hydroxy-4-iodonicotinaldehyde (38). Reacton of 38 with arylboronic acid 34 in the presence of copper(II) acetate and pyridine affords N-aryl pyridone aldehyde 39. Oxidation of 39 using sodium chlorite provides acid 40. Alternately, treatment of methyl 2-hydroxy-4-iodonicotinate (41) with arylboronic acid 34 in the presence of copper(II) acetate and pyridine affords N-aryl pyridone ester 42. Saponification of 42 under standard conditions, for example sodium hydroxide, affords acid 40. Treatment of iodo acid 40 with a compound of formula 20, optionally in the presence of a base, for example potassium carbonate, and/or optionally with heating, provides acid 2. Additionally, acid 40 can be used as a general example of acid 17 (W is Iodo, Scheme 3).