Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][N:8]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:7]=1.C(OC([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=2)[CH2:28][CH2:27]1)=O)(C)(C)C>>[CH:14]1([N:8]2[C:6]3[N:7]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:32]([N:29]5[CH2:28][CH2:27][NH:26][CH2:31][CH2:30]5)=[CH:33][N:34]=4)[N:3]=[CH:4][C:5]=3[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CC(C)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(C)c1cn(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12

Procedure:
(7-Cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine is prepared from 2-Chloro-7-cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidine and 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester using a method similar to that for the preparation of Example 202. [MH+] 406.21
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br)#[N:17]>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:21][C:20]2[CH:19]=[C:18]([CH:25]=[CH:24][CH:23]=2)[C:16]#[N:17])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(COc2ccc(-c3ccccc3)cc2)c1
Temperature: 0 °C
Yield: 103.3 %

Procedure:
To a solution of 4-phenylphenol (10.0 g, 59 mmol) in dry N,N-dimethyl-formamide (45 mL) kept under an atmosphere of nitrogen, sodium hydride (2.82 g, 71 mmol, 60% dispersion in oil) was added in portions and the reaction mixture was stirred until gas evolution ceased. A solution of m-cyanobenzyl bromide (13 g, 65 mmol) in dry N,N-dimethylformamide (45 mL) was added dropwise and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured on to ice water (150 mL). The precipitate was filtered of and washed with 50% ethanol (3×50 mL), ethanol (2×50 mL), diethyl ether (80 mL), and dried in vacuo at 50° C. for 18 hours affording crude 17.39 g of 3-(biphenyl-4-yloxymethyl)benzonitrile as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C@:12]12[CH2:17][C@H:16]1[CH2:15][NH:14][CH2:13]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>O1CCCC1.C(N(CC)CC)C>[Cl:22][CH2:21][CH2:20][CH2:19][N:14]1[CH2:15][C@H:16]2[C@:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])([CH2:17]2)[CH2:13]1
Reactant: Fc1cc(C(F)(F)F)ccc1[C@@]12CNC[C@@H]1C2
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1cc(C(F)(F)F)ccc1[C@]12C[C@H]1CN(CCCCl)C2
Temperature: 25 °C

Procedure:
To a solution of (1S,5R)-1-[2-fluoro-4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (P13, 426 mg) in dry tetrahydrofuran (9 mL), triethylamine (0.79 mL) and 1-bromo-3-chloropropane (0.37 mL) were added and the resulting mixture was refluxed for 16 hours. After cooling at room temperature it was concentrated in vacuo, diluted with ethyl acetate, washed with a saturated solution of NaHCO3 in water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by chromatography (silica gel) eluting with cyclohexane/EtOAc 8:2 to give the title compound as yellow oil (582 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1([O:25][CH3:26])[CH2:8][CH2:7][C:6]([C:23]#[N:24])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-:28].[K+].[K+].OO>CO.O.[Cl-].[Na+].O>[CH3:26][O:25][C:3]1([O:2][CH3:1])[CH2:8][CH2:7][C:6]([C:23]([NH2:24])=[O:28])([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(C2(C#N)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: OO
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C(N)=O)CCC(OC)(OC)CC2)cc1OC1CCCC1
Temperature: 25 °C
Yield: 15.3 %

Procedure:
A solution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one dimethyl ketal (0.34 g, 0.95 mmol) and powdered potassium carbonate (0.7 g, 5.1 mmol) in methanol (20 mL) and water (4 mL) at 0° C. was treated with hydrogen peroxide (30% solution, 2.55 mL). The mixture was allowed to warm to room temperature and, after seven days, brine was added and the mixture was extracted with methylene chloride. The organic extract was washed twice with brine, dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography provided the amide (0.055 g, 15%) along with recovered starting material (0.25 g).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH3:18])[NH:5][C:4]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:2].O.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1COCC1.CC(O)=O>[CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])=[C:6]([CH:18]=[O:27])[NH:5][C:4]=1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C)c1C(=O)OCc1ccccc1
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-benzyl 2-tert-butyl 3-ethyl-5-methyl-1H-pyrrole-2,4-dicarboxylate (2.75 mmol) in THF (32 mL), AcOH (40 mL), and H2O (32 mL) was added CAN in one portion. The reaction was stirred at room temperature for 4 hours, then poured into water (500 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were washed with saturated aqueous sodium bicarbonate (1×200 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography gave a white solid. HRMS (ES) exact mass calcd for C20H23NO5 (M+H+): 358.1649. Found (M+Na+): 380.1478
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH3:11])=[N:6]1.[C:13]1(=O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C>[C:13]1([C:8]2[C:7]([CH3:11])=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:12])[CH3:1])[C:9]=2[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1
Reactant: Cc1cc(N)n(CCN(C)C)n1
Reactant: O=C1CCCCC1
Solvent: CC(=O)O
Product: Cc1nn(CCN(C)C)c(N)c1C1=CCCCC1
Yield: 74.7 %

Procedure:
A solution of 2-(2-dimethylaminoethyl)-5-methyl-2H-pyrazol-3-ylamine (0.998 g, 5.93 mmol) in acetic acid (10 mL) was treated with cyclohexanone (1.23 mL, 11.86 mmol) at ambient temperature for two days. The volatiles were removed and the residue partitioned between dilute sodium hydroxide and ethyl acetate. The organic phase was washed with water, concentrated and the residue purified by flash chromatography on silica gel using 10% methanol in dichloromethane to give a solid (1.10 g, 75%). MS (DCI): m/z 249 (M+H)+.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[N:13][N:14]=2)[CH:5]=1.[C:25]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH3:26].[Li]>>[C:29]([O:28][C:25](=[O:27])[CH2:26][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[S:11][C:12]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[N:13][N:14]=2)[CH:5]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nnc(CCOC3CCCCO3)s2)c1

Procedure:
3-(5-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-benzoic acid methyl ester (1.60 g) was treated with lithium tert.-butyl acetate according to general procedure K (method b) to give 3-oxo-3-(3-{5-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-[1,3,4]thiadiazol-2-yl}-phenyl)-propionic acid tert-butyl ester (2.1 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([O:28]CC)=[O:27])=[CH:9]2.[OH-].[Na+].Cl>O1CCCC1.CO.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=[O:27])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of ethyl 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (5.67 g) in tetrahydrofuran (50 mL) and methanol (25 mL) was added 2M aqueous sodium hydroxide solution, and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and neutralized with 1M hydrochloric acid. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (5.30 g, yield 100%) as a white solid. MS: 406 (MH+).
Reaction SMILES: [OH-].[Na+].C([O:7][C:8]([CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)[C:12]1=[O:33])=[O:9])(C)(C)C>C(O)C>[CH2:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([N:13]2[CH2:14][CH2:15][CH2:16][N:11]([CH2:10][C:8]([OH:9])=[O:7])[C:12]2=[O:33])[CH2:22][CH2:21]1)=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
An aqueous 4N sodium hydroxide solution (10 mL) was added to a solution of benzyl 4-[3-(tert-butoxycarbonylmethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (1.7 g) obtained in Example 35a) in ethanol (20 mL), and the mixture was stirred at room temperature overnight. Ethanol was distilled off under reduced pressure, and 1N hydrochloric acid was added to the residue to adjust pH to 3, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.5 g, quantitative) as a white powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>O1CCOCC1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[C:17]([F:19])[C:15](=[O:16])[N:14]([C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OCc1ccccc1
Reaction time: 2 h
Yield: 78.4 %

Procedure:
To a solution of 0.20 g of 5'-O-acetyl-3'-O-benzyl-2'-deoxy-5-fluorouridine in 10 ml of dioxane were added 0.29 g of benzoyl chloride and 0.73 ml of triethylamine, and the mixture was left to stand at 80° C. for 2 hours. The solvent was distilled off and the residue was dissolved in 50 ml of ethyl acetate. The solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was placed on a silica gel column and eluted with chloroform, giving 0.2 g of the title compound as an oil in a yield of 78%.
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([CH2:7][C@@:8]2([CH3:35])[N:12]3[C:13]([C:16]([NH:18][C:19]4([C:22]([OH:24])=O)[CH2:21][CH2:20]4)=[O:17])=[CH:14][N:15]=[C:11]3[N:10]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=3)[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2].Cl.Cl.[Br:40][C:41]1[CH:42]=[CH:43][C:44]([C@H:47]([NH2:49])[CH3:48])=[N:45][CH:46]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:40][C:41]1[CH:42]=[CH:43][C:44]([C@H:47]([NH:49][C:22]([C:19]2([NH:18][C:16]([C:13]3[N:12]4[C@@:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:37][CH:36]=5)([CH3:35])[C:9](=[O:34])[N:10]([C:25]5[CH:26]=[C:27]([Cl:33])[C:28]([F:32])=[C:29]([Cl:31])[CH:30]=5)[C:11]4=[N:15][CH:14]=3)=[O:17])[CH2:21][CH2:20]2)=[O:24])[CH3:48])=[N:45][CH:46]=1
Reactant: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Reactant: C[C@@H](N)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.8 %

Procedure:
A suspension of 1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarboxylic acid, (500 mg, 0.92 mmol), (R)-1-(5-bromo-pyridin-2-yl)-ethylamine dihydrochloride (303 mg, 1.11 mmol) and diisopropylethylamine (0.640 mL, 3.69 mmol) in 4 mL of DMF was stirred at room temperature for 10 min HATU (386 mg, 1.01 mmol) was added, and the clear yellow reaction mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between 75 mL of ethyl acetate and 25 mL of water. The organic phase was washed with 2×25 mL of 5% aqueous NaCl solution and 25 mL of brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 0-3% MeOH in CH2Cl2, to provide 653 mg (98%) of title compound as a yellow foam, m/z 726.4 [M+1]+.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][C:10]([CH3:12])=O>>[CH3:9][C:10]1([CH3:12])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2]1
Reactant: Oc1ccccc1O
Reactant: CC(C)=O
Product: CC1(C)Oc2ccccc2O1

Procedure:
As depicted in Scheme 3, catechol was cyclized with acetone under catalytic conditions, affording the corresponding 2,2-dimethylbenzo[d]1,3-dioxolane (C1). Intermediate (C1) was then treated with for example lead tetraacetate ubder acidic conditions, yielding the corresponding 2,2-dimethylbenzo[3,4-d]1,3-dioxolan-5-yl acetate (C2). Intermediate (C2) was then deprotected with strong base, providing a phenolic intermediate (C3), which was in turn reacted with intermediate (B5), as taught in scheme 2, affording a compound of formula I. Example 3 set forth below describes in detail the method by which compounds of formula I were prepared as shown in scheme 3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([S:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: Clc1cc(Sc2cccc3ccccc23)ccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1csc(Nc2cc(Sc3cccc4ccccc34)ccn2)n1
Yield: 11.9 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.55 g, 4.82 mmol), 2-chloro-4-(naphthalen-1-ylthio)pyridine (1.44 g, 5.30 mmol), potassium phosphate (1.12 g, 5.30 mmol), Tris(dibenzylideneacetone)dipalladium (0) (0.110 g, 0.120 mmol) and 4,5-bis(diphenyl-phosphino)-9,9-dimethyl-9H-xanthene (0.0767 g, 0.132 mmol) were reacted in toluene (12 mL) and water (4 mL) to afford N-(4-methylthiazol-2-yl)-4-(naphthalen-1-ylthio)pyridin-2-amine (0.2 g, 11% yield) as yellow solid. 1H NMR (CDCl3) δ 8.26 (m, 1H), 8.01 (m, 2H), 7.93 (m, 1H), 7.90 (dd, 1H), 7.54 (m, 3H), 6.49 (dd, 1H), 6.28 (d, 1H), 6.25 (d, 1H), 2.21 (d, 3H); Mass spectrum (esi) m/z 350 (100) (M+H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C:14]1[CH:39]=[CH:38][C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:34]=[CH:33][C:26]3[CH2:27][CH2:28][CH:29]([CH2:31][OH:32])[O:30][C:25]=3[C:24]=2[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:40][CH2:41][CH3:42])[C:15]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.O>[C:11]([C:14]1[CH:39]=[CH:38][C:17]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:34]=[CH:33][C:26]3[CH2:27][CH2:28][CH:29]([CH:31]=[O:32])[O:30][C:25]=3[C:24]=2[CH2:35][CH2:36][CH3:37])=[C:16]([CH2:40][CH2:41][CH3:42])[C:15]=1[O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=[O:13])[CH3:12]
Reactant: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCc3ccccc3)c2CCC)ccc2c1OC(CO)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCc3ccccc3)c2CCC)ccc2c1OC(C=O)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.7 %

Procedure:
A solution of 1.2 ml (13.3 mmole) of oxalyl chloride in 30 ml methylene chloride was cooled to -70°, and a solution of 1.9 ml (26.6 mmole) of dimethylsulfoxide in 9 ml of methylene chloride was added. The mixture was stirred for 5 minutes and a solution of 6.6 g (12.1 mmole) of the title compound of Example 39 in 20 ml of methylene chloride was added. After stirring an additional 15 minutes, 8.5 ml (60.5 mmole) of triethylamine was added, and the mixture was stirred at -70° for 5 minutes and allowed to warm to room temperature. Water was added and the layers were separated. The organic layer was washed successively with dilute hydrochloric acid, 5% sodium bicarbonate solution, water and brine, dried over MgSO4, and filtered. Removal of the solvent gave 6.44 g of the title compound as a yellow oil. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=O)[CH3:2].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH:14]=[C:21]1[S:17][C:18](=[O:23])[NH:19][C:20]1=[O:22])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Br)cc1C=O
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1ccc(Br)cc1C=C1SC(=O)NC1=O
Temperature: 120 °C
Yield: 70.8 %

Procedure:
4-Bromo-2-formylphenoxyacetic acid ethyl ester (2.47 g, 8.7 mmol), 2,4-thiazolidinedione (1.13 g (90%), 8.7 mmol), and ammonium acetate (671 mg, 8.7 mmol) was mixed with toluene (9 mL) in a sealed vial and heated by microwaves to 120° C. for 600 s. After cooling to room temperature and scratching the inside of the glass, the product precipitated out. The precipitate was filtered and washed with toluene to give the title compound as a yellow solid (2.38 g, 71%).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)#[N:4].[CH3:13][O:14][C:15]([CH2:17]P(OC)(OC)=O)=[O:16]>O1CCCC1>[C:3]([C:5]1[CH:12]=[CH:11][C:8](/[CH:9]=[CH:17]/[C:15]([O:14][CH3:13])=[O:16])=[CH:7][CH:6]=1)#[N:4]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: N#Cc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(C#N)cc1
Reaction time: 48 h
Yield: 97.8 %

Procedure:
To a stirring suspension of NaH (6.1 g of 60% oil suspension, 153 mmol) and p-cyanobenzaldehyde (20 g, 153 mmol) in tetrahydrofuran (250 mL) at 0° C. was added via addition funnel a solution of trimethyl phosphonoacetate (28 g, 153 mmol) in tetrahydrofuran (50 mL). After stirring for 48 hours, the solvent was removed in vacuo and the crude residue was dissolved in ethyl acetate (500 mL). The ethyl acetate solution was washed once with water, three times with saturated aqueous NaHSO3 and once with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo to give 28 g (98%) of a white solid.
Reaction SMILES: C1COCC1.[CH3:6][C:7]1([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][CH:8]1[C:10]([O:12]CC)=[O:11].[OH-].[Na+]>CO>[CH3:6][C:7]1([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH2:9][CH:8]1[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(c2ccc(C(F)(F)F)cc2)CC1C(=O)O
Yield: 94.4 %

Procedure:
The procedure described in Example 2I was followed using a THF (30 ml) solution of 14A (5.92 g, 21.7 mmol), 2M sodium hydroxide aqueous solution (22 ml) and MeOH (30 ml) to give 5.0 g (94% yield) of the title compound as white solids.
Reaction SMILES: Br[C:2]1[C:3]([Cl:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][N:14]=[C:7]1[CH2:6][CH2:5]2.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O>[Cl:16][C:3]1[C:2]([C:20]2[CH:21]=[N:22][CH:23]=[C:18]([F:17])[CH:19]=2)=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]1[N:8]2[C:12]([CH3:15])=[N:13][N:14]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: Cc1nnc2n1-c1ccc(Br)c(Cl)c1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nnc2n1-c1ccc(-c3cncc(F)c3)c(Cl)c1CC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 7-bromo-6-chloro-1-methyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (143-7; 0.20 g, 0.0006 mol) and (5-fluoropyridin-3-yl)boronic acid (0.93 g, 0.0006 mol) in the mixture of 1,4-dioxan (10 mL) and water (10 mL) was added sodium carbonate (0.127 g, 0.0012 mol). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.048 g, 0.00006 mol) was added and allowed to stir at 80° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic part was concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.659-8.652 (d, J=2.8 Hz, 1H), 8.514 (s, 1H), 7.908-7.884 (d, J=9.6 Hz, 1H), 7.789-7.768 (d, J=8.4 Hz, 1H), 7.566-7.504 (d, J 8.4 Hz, 1H), 3.186-3.152 (m, 2H), 3.084-3.035 (m, 2H), 2.695 (s, 3H). MS (M+1): 315.1.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22](C)(C)[O:23][SiH2]C(C)(C)C)[CH:16]=1)[CH:10]1[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([O:7][C:8](=[O:31])[N:9]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][OH:23])[CH:16]=1)[CH:10]1[CH2:11][CH2:12]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C(C)(C)O[SiH2]C(C)(C)C)c1)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CO)c1)C1CC1
Temperature: 25 °C
Yield: 86.2 %

Procedure:
Aq. 1M NaOH (48 mL) was added to a suspension of {2-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-phenyl]-ethyl}-cyclopropyl-carbamic acid tert-butyl ester (2.10 g, 4.77 mmol) in MeOH (96 mL). The mixture was heated to reflux for 90 min. The mixture was allowed to cool to rt, and the solvents were partially removed under reduced pressure. The resulting aq. mixture was diluted with water (100 mL), and was extracted with Et2O (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 40:60) yielded the title compound (1.34 g, 86%). LC-MS: tR=0.98 min; ES+: 326.30.