Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:36]([NH2:38])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:27]=1)=[O:22])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:36]([NH2:38])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:35])([CH3:33])[CH3:34])[CH:27]=1)=[O:22])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@H](CC2CCCCC2)NC(=O)[C@@H](N)Cc2ccccc2)C(N)=O)c1

Procedure:
To a solution of 188 mg (0.287 mmol) of Z-Phe-Cha-Phe(3-tBu)-NH2 in 3 ml of methanol, 100 mg of 10% palladium carbon was added and the mixture was stirred overnight in a hydrogen atmosphere at room temperature. After filtering, the filtrate was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent, chloroform:methanol=10:1) to yield Phe-Cha-Phe(3-tBu)-NH2 in the amount of 69.0 mg (46%).
Reaction SMILES: [OH:1][CH2:2][C:3]1(S)[N:7]=[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]2=[N:4]1.[CH2:13](Cl)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].C([O-])(O)=O.[Na+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[CH2:2][OH:1]
Reactant: CC(C)=CCC/C(C)=C/CCl
Reactant: OCC1(S)N=c2ccccc2=N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [I-]
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/Cn1c(CO)nc2ccccc21

Procedure:
A solution of 2-hydroxymethyl-2-mercaptobenzimidazole (2.68 g, 20 mmol), geranyl chloride (3.44 g, 20 mmol), tetrabutylammonium iodide (0.740 g, 2 mmol), saturated NaHCO3 (50 mL) and CH2Cl2 (40 mL) was stirred at ambient temperature for 72 hours. The methylene chloride layer was separated, washed with water and dried over Na2SO4. Evaporation and flash chromatography (Merck Kieselgel, 5% MeOH/CH2Cl2) gave 1-[3,7-dimethyl-2,6(E)-octadienyl]-2-hydroxymethyl-1H-1,3-benzimidazole free base) (1.45 g) which was converted to its hydrochloride salt, a gray solid. m.p. 120°-123° C. NMR (DMSO-d6)δ7.80(m,4H), 5.20(m,6H), 2.90(s,3H), 2.10(m,4H), 1.64(s,3H), 1.62(s,3H).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[O:32][C:31]([Si](C(C)C)(C(C)C)C(C)C)=[N:30][CH:29]=2)O1.C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[O:32]1[C:28]([C:2]2[C:3]3[N:4]([C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=2)=[CH:29][N:30]=[CH:31]1
Reactant: CC(C)[Si](c1ncc(B2OC(C)(C)C(C)(C)O2)o1)(C(C)C)C(C)C
Reactant: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
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: COCCOC
Solvent: O
Product: CCOC(=O)c1cnc2c(-c3cnco3)cc(C(F)(F)F)cn12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
A mixture of ethyl 8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate (500 mg), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(triisopropylsilyl)oxazole (573 mg), tetrakis(triphenylphosphine)palladium(0) (171 mg), potassium carbonate (410 mg), DME (12 mL) and water (3 mL) was stirred with microwave irradiation at 120° C. for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in THF (6 mL), and 1N hydrochloric acid (2 mL) was added thereto. The mixture was stirred at room temperature for 2 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (0.13 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[OH:27].[Cl-].[NH4+]>CN(C)C=O>[CH2:9]([O:8][C:6]1[CH:7]=[C:2]([O:27][C:21]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=2[F:19])[N:3]=[CH:4][N:5]=1)[C:10]#[C:11][CH3:12]
Reactant: Oc1cc(F)ccc1F
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2cc(F)ccc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 85.9 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.17 g of 2,5-difluorophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.26 g of 4-(2-butynyloxy)-6-(2,5-difluorophenoxy)pyrimidine (the present compound (43)).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[C:10](=[NH:21])([O-:20])[C:11]1[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:13](=N)[O-:14].[K+].[K+].O.C(Cl)Cl>CN(C=O)C>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:21]1[C:10](=[O:20])[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13]1=[O:14]
Reactant: OCCCCCCCBr
Reactant: N=C([O-])c1ccccc1C(=N)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCCCCO
Reaction time: 4 h

Procedure:
585 mg of 7-bromoheptanol was dissolved in 5 mL of DMF. 833 mg of potassium phthalimidate was added, and the mixture was stirred for 4 h. 50 mL of water and 50 mL of DCM were added to the reaction system, which was violently vibrated and then isolated. The water layer was once again extracted with 50 mL of DCM. The two organic layers were combined, successively washed with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of anh. MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain a pale yellow transparent oily liquid.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(O[CH:8]=[C:9]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1[F:22])[C:10]#[N:11])C>C(Cl)(Cl)Cl.C(O)C.CCCCCC>[CH:1]1([NH:4][CH:8]=[C:9]([C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])[C:10]#[N:11])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCOC=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCO
Product: N#CC(=CNC1CC1)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A solution of cyclopropylamine (3.3 g) in chloroform (20 ml) is added dropwise to a solution of 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (14.0 g) in chloroform (50 ml) with maintaining the internal temperature between 6° C. and 8° C. by using an ice bath. The mixture is allowed to stand overnight at room temperature and then concentrated under vacuum to yield an orange oily residue. The oily residue is dissolved in ethanol and the ethanol is removed in vacuum to afford a crystalline residue. The residue is dissolved in hexane and washed with a 20:1 mixture of hexane and ethanol to yield 3-cyclopropylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile (12.6 g) as pale yellow prisms, m.p. 88°-89° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].C(OC(C)C)(C)C>O1CCCC1.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(N)c(N)c1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: Cc1ccc2[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 81.1 %

Procedure:
To a solution of 4-methyl-1,2-phenylenediamine (1) (25 g) in tetrahydrofuran (375 mL) was added dropwise a solution of 1,1′-carbonyldiimidazole (36.5 g) in dichloromethane (375 mL). After stirring at room temperature for 6.5 hr, diisopropylether (375 mL) was added to the reaction mixture. After stirring at room temperature, the resulting precipitate was collected by filtration. The precipitate was washed with diisopropyl ether, and dried under reduced pressure to give 5-methyl-1,3-dihydrobenzimidazol-2-one (2) (24.6 g).
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][C:17](O)=[O:18])=[N:14][N:13]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:12](=[O:26])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>O>[Br:1][C:2]1[C:3]2[C:4]3[C:15]([CH2:16][C:17]([N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[O:18])=[N:14][N:13]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:12](=[O:26])[C:5]=3[N:6]([CH3:11])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: C1CCNC1
Reactant: Cn1c2cccc(Br)c2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Product: Cn1c2cccc(Br)c2c2c(CC(=O)N3CCCC3)nn(-c3ccccc3)c(=O)c21

Procedure:
The preparation is carried out as in Example 3.2, from 3.1 g (7.5 mmol) of 9-bromo-5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid, from 1.4 g of 1,1′-carbonylbis-1H-imidazole and from 0.7 ml of pyrrolidine. After reaction, water is added and the precipitate is collected by filtration and dried under reduced pressure. It is recrystallized from propan-2-ol and washed with ether and pentane. It is dried under reduced pressure. 2.3 g (4.9 mmol) of solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH:7]=[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[O:9]2)=[CH:5][C:4]=1[N+:20]([O-])=O.[Cl-].[NH4+]>[Fe].O>[NH2:20][C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][C:3]=1[O:2][CH3:1])[CH:7]=[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:17])[O:9]1
Reactant: COc1ccc(C=C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccc(C=C2OC(=O)c3ccccc32)cc1N
Temperature: 70 °C
Yield: 65.6 %

Procedure:
A stirred mixture of the above crude 3-(4-methoxy-3-nitrobenzylidene)-3H-isobenzofuran-1-one (2.5 g, 0.0085 mol), industrial methylated spirit (40 ml), water (30 ml) and ammonium chloride (0.91 g, 0.017 mol) was heated to 70° C., and iron powder (4.76 g, 0.085 gatom) was added in portions. When the addition was complete, the stirred mixture was heated under reflux for a further 2 hours, then it was filtered while hot through Celite. The collected inorganic solids were washed with hot industrial methylated spirit (3×80 ml), then the filtrate and washings were combined and the solvent was removed in vacuo. The residue was triturated with water (50 ml) and the resulting solid was collected by filtration and dissolved in ethyl acetate (300 ml). The solution was filtered, the filtrate was concentrated in vacuo and the residue was triturated with industrial methylated spirit (10 ml). The resulting solid was collected by filtration and dried in vacuo for 24 hours to give 3-(3-amino-4-methoxybenzylidene)-3H-isobenzofuran-1-one (1.49 g) as a yellow solid, m.pt. 148–153° C.; m/z (M+H)+. 268, 100% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[O:22])[CH:17]=[CH:18][C:19]=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[C:6]([O:8][C:19]2[CH:18]=[CH:17][C:16]([C:21](=[O:22])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:15][C:14]=2[Cl:13])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)c(Cl)c1
Product: O=C(O)Cc1cc(Cl)cc(Oc2ccc(C(=O)c3ccc(F)cc3)cc2Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the is product from example 18 step (iv) and the product from step (i).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[O:8]C)(=[O:3])[CH3:2].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17])=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCCCC(=O)Cl
Reactant: COc1cccc(NC(C)=O)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(=O)c1ccc(NC(C)=O)cc1O
Temperature: 0 °C

Procedure:
The mixture consisting of 49.5 g of N-acetyl-m-anisidine, 72.3 cc of valeric acid chloride and 200 cc of methylene chloride is cooled to 0° C. 120 g of aluminum chloride are added little by little. The reaction mixture is refluxed for 2 hours with stirring, cooled, then poured in ice water. The resulting oily product is extracted with chloroform. The chloroform phase in turn is extracted with 2N sodium hydroxide solution which is then acidified. Thus, 24 g of 5-acetamido-2-valeryl phenol (MP 113° C.) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Br:10])[C:7]([OH:11])=[C:6]([Br:12])[CH:5]=1.[CH3:14]I>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:5]=[C:6]([Br:12])[C:7]([O:11][CH3:14])=[C:8]([Br:10])[CH:9]=1
Reactant: COC(=O)c1cc(Br)c(O)c(Br)c1
Reactant: CI
Product: COC(=O)c1cc(Br)c(OC)c(Br)c1

Procedure:
3,5-Dibromo-4-methoxybenzoic acid methyl ester was prepared from 3,5-dibromo-4-hydroxybenzoic acid methyl ester by following Method C using methyl iodide as an alkylating agent in quantitative yield. The product was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[OH:6])=[N+]=[N-].[N-]=[N+]=[N-]>[Pd].CCO>[NH2:1][CH2:4][C@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[N:8]=1)[OH:6]
Reactant: Cc1cccc([C@H](O)CN=[N+]=[N-])n1
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCO
Product: Cc1cccc([C@H](O)CN)n1
Reaction time: 12 h
Yield: 94.7 %

Procedure:
Suspended 10% Pd/C (0.50g) into 100 mL EtOH under Ar. To this was added (R)-2-azido-1-(6-methyl-pyridin-2-yl)-ethanol (3.57 g, 20.74 mmol). The reaction was placed under atm. H2 for 12 h. LC-MS analysis indicted some remaining azide. Recharge with H2 atmospher and stir an additional 12 h. LC-MS analysis indicated complete reaction. The mixture was filtered through a bed of celite. The celite was rinsed with 100 mL of EtOH. The filtrate was concentrated to give 2.99 g of (R)-2-amino-1-(6-methyl-pyridin-2-yl)-ethanol.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][CH2:30][OH:31])[C:9](=[O:28])[CH:10](Br)[CH2:11][C:12]12[CH2:26][CH:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=31)[C:18]1[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:29][CH2:30][O:31][CH:10]([CH2:11][C:12]23[CH2:26][CH:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=42)[C:18]2[C:13]3=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C(Br)CC12CC(c3ccccc31)c1ccccc12)N(CCO)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: O=C1C(CC23CC(c4ccccc42)c2ccccc23)OCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A mixture of α-bromo-β(9,10-dihydro-9,10-methano-9-anthryl)propionic acid N-benzyl-N-hydroxyethylamide (1.25 g) and 65.4% sodium hydride (oily dispersion, 0.19 g) in dry benzene was stirred at room temperature for 7 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(4-benzyl-3-oxo-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 155° - 156° C.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22][CH:23]([C:27](O)=[O:28])[C:24](O)=[O:25]>>[OH:28][C:27]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:24](=[O:25])[C:23]=1[S:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH3:14]
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Reactant: COc1ccccc1SC(C(=O)O)C(=O)O
Product: COc1ccccc1Sc1c(O)cc(-c2ccccc2)oc1=O

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (1.95 g, 10.14 mmol) and diethyl ester of [(2-methoxyphenyl)thio]propanedioic acid (1.51 g, 5.07 mmol). m.p.208-209° C.; 1H NMR (400 MHz, DMSO-d6) δ3.83 (s, 3H), 6.74 (dd, 1H), 6.82 (d, 1H), 6.86 (s, 1H), 6.97 (d, 1H), 7.08 (t, 1H), 7.56 (m, 3H), 7.86 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH2:3][C:2]1=[O:10].[H-].[Na+].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>C1COCC1.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[C:2]1=[O:10]
Reactant: O=C1Cc2cccnc2N1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ncccc43)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 151.3 %

Procedure:
A solution of 7-azaoxindole (268 mg, 2 mmol) in THF (3 ml) was added to a suspension of sodium hydride (80 mg, 2 mmol, prewashed with THF) in THF (4 ml). After stirring for 20 minutes at ambient temperature a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (180 mg, 0.7 mmol) in a mixture of THF (3 ml) and DMF (1 ml) was added. After stirring for 30 minutes at ambient temperature followed by 1 hour at 65° C., the volatiles were removed by evaporation. The residue was partitioned between water and ether. The aqueous layer was separated and adjusted to pH4 with 2M hydrochloric acid. The precipitate was collected by filtration and dried under vacuum, it was then suspended in methylene chloride/methanol (1/1) and 3M hydrogen chloride in ether was added. The solid was collected by filtration, washed with methanol followed by ether and dried under vacuum to give 4-(7-azaoxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (388 mg, 68%).
Reaction SMILES: Cl.[S:2]1[C:6]([C:7]2[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=[C:9]([C:24]3[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=3)[CH:8]=2)=[CH:5][C:4]2[CH:31]=[CH:32][CH:33]=[CH:34][C:3]1=2>CO>[S:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:24]3[CH:29]=[N:28][C:27]([NH2:30])=[N:26][CH:25]=3)[CH:10]=[C:11]3[C:15]=2[NH:14][N:13]=[CH:12]3)=[CH:5][C:4]2[CH:31]=[CH:32][CH:33]=[CH:34][C:3]1=2
Reactant: C[Si](C)(C)CCOCn1cc2cc(-c3cnc(N)nc3)cc(-c3cc4ccccc4s3)c2n1
Agent: Cl
Solvent: CO
Product: Nc1ncc(-c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)cn1
Temperature: 65 °C
Yield: 59.1 %

Procedure:
A mixture of 6N HCl (1 mL) and 5-[7-benzo[b]thiophen-2-yl-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazol-5-yl]-pyrimidin-2-ylamine (0.063 g, 0.133 mmol) (prepared from 7-Benzo[b]thiophen-2-yl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-indazole (Preparation #23, E) and 5-iodo-pyrimidin-2-ylamine according to general procedure F) in MeOH (2 mL) was heated to about 65° C. for about 1 hour. The solvents were removed under reduced pressure and the residue treated with NaHCO3 (4 mL) and EtOAc (2 mL). The insoluble product was collected by filtration then dried to give 5-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-pyrimidin-2-ylamine (27 mg, 60%) as an off white solid; (DMSO-d6, 400 MHz) 13.56 (bs, 1H), 8.66 (s, 2H), 8.29 (s, 1H), 8.15 (s, 1H), 8.04 (m, 2H), 7.93 (m, 1H), 7.79 (d, 1H), 7.43 (m, 2H), 7.76 (bs, 2H); RP-HPLC (Table 1, Method e) Rt=2.03 MS m/z: (M−H)− 341.7.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2C(Cl)=CC(Cl)=C[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=C[C:30]=2[C:35]2[C:40](OC)=C[CH:38]=[CH:37][C:36]=2OC)CCCCC1.[F-].[K+].CB(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[C:37]([CH3:38])=[CH:36][C:35]([CH3:30])=[CH:40][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Cl)cc2Cl)CC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 449 %

Procedure:
To 2,3,5-trichloropyridine (25 g) were added 1-BOC-piperazine (28.13 g), potassium carbonate (37.86 g), N,N-dimethylformamide (25 mL) and toluene (50 mL), and the mixture was stirred at 100° C. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (39.13 g). To 4-(3,5-dichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (6.35 g) were added palladium (II) acetate (0.46 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.71 g), potassium fluoride (9.556 g), methylboronic acid (5 g) and tetrahydrofuran (202 mL), and the mixture was refluxed under a nitrogen stream for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g). To 4-(3,5-dimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (5.45 g) were added 4N hydrogen chloride/ethyl acetate (18.2 mL) and chloroform (45.5 mL), and the mixture was stirred at room temperature. After completion of the reaction, to the reaction mixture were added water and potassium carbonate, and the mixture was extracted with ethyl acetate. The solvent was evaporated to give the title compound (3.3 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:14][CH:12]([S:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:2]1=[O:1])(=[O:11])=[O:10])[CH3:13]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCCCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
Into a 500 mL single neck flask (2-hydroxycyclohexy)[(methylethyl)sulfonyl]amine (6.78 g, 30.6 mmol) was combined with pyridinium chlorochromate (7.92 g, 1.2 eq) in methylene chloride (300 mL) and stirred at room temperature under a nitrogen atmosphere for 4 hours. The solution was then filtered over a Celite® mat and the organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield 13.42 g as a dark oil. This material was purified via silica gel chromatography employing the Water's Prep. 2000 and eluting with a solvent of methylene chloride/ethyl acetate 19:1 to yield the intermediate title compound (3.95 g, 59%). as a white solid. Ion Spray M.S. 218 (M*−1). Calculated for C9H17NO3S: Theory: C 49.29, H 7.81, N 6.39. Found: C 49.25, H 7.58, N 6.32.