Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[C:17]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[NH2:29])=[C:24]([OH:31])[CH:23]=2)=[C:16]([F:32])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl>ClCCl.O1CCOCC1>[F:20][C:18]1[CH:19]=[C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:15]=[C:16]([F:32])[C:17]=1[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[O:30])=[C:24]([OH:31])[CH:23]=1
Reactant: CC(C)CCN(Cc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CCNCc1cc(F)c(Oc2ccc(C(N)=O)c(O)c2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
[4-(4-Carbamoyl-3-hydroxy-phenoxy)-3,5-difluoro-benzyl]-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-1e-3: 0.8 g) was dissolved in 5 mL of dichloromethane and treated with 2.5 ml of a 4.0 M hydrogen chloride solution in dioxane. After stirring 24 hours at room temperature, the volatiles were removed under reduced pressure and the resulting crude material was suspended in methanol, heated at reflux for 20 minutes, and stirred overnight at room temperature. The resulting slurry was collect via filtration, rinsing with chilled methanol, and dried under vacuum to provide the title compound (4A).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH3:13])=[CH:8][C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[CH2:21][CH3:22]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:12]([CH3:13])[CH:26]3[CH2:27][CH2:28][N:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CCCN1CCC(=O)CC1
Product: CCCN1CCC(N(C)Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 30 %

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methylamine was reacted with 1-propyl-piperidin-4-one using standard reductive amination conditions. The resulting crude solid was triturated was with diethyl ether and methanol to give (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-methyl-(1-propyl-piperidin-4-yl)amine as a solid (30% yield), which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethylether and methanol to give 344 as a solid (77% yield). NMR (CDCl3, 400 MHz), 0.92 (3H, t, J=7.3), 1.49-1.56 (2H, m), 1.64-1.72 (2H, m), 1.82-1.86 (2H, m), 1.93 (2H, t, J=11.3), 2.29 (2H, dd, J=7.7 and 7.9), 2.37 (3H, s), 2.50-2.56 (1H, m), 3.03 (2H, d, J=11.6), 3.88-3.91 (4H, m), 3.93 (2H, s), 4.03-4.06 (4H, m), 5.22 (2H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=483
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1.O.[NH3:12]>O1CCOCC1>[NH2:12][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([F:8])=[CH:6][N:7]=1
Reactant: N#Cc1nc(F)cnc1F
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1nc(F)cnc1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In a mixture of 1.5 mL of 25% aqueous ammonia and 500 mL of dioxane was dissolved 1.0 g of 3,6-difluoro-2-pyrazinecarbonitrile. The solution thus obtained was stirred at room temperature for 6 hours. Then, 20 mL of water was added to the reaction mixture and stirred for 20 minutes while cooling the mixture with ice. The deposited material was collected by filtration, washed successively with 5 mL of cold water and 5 mL of ethanol to obtain 0.84 g of 3-amino-6-fluoro-2-pyrazine-carbonitrile as a light yellow-colored solid product.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH3:39])[C:32]([C@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)=[O:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:37][CH2:38][C@H:34]([C:32]([N:31]([CH3:39])[CH3:30])=[O:33])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CN(C)C(=O)[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@H](C(=O)N(C)C)C3)n(C)c2n1
Reaction time: 18 h
Yield: 37.2 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol) and (S)-pyrrolidine-3-carboxylic acid dimethylamide (44 mg, 0.31 mmol) in DCE (5 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 398 as a cream solid (50 mg, 38%). LCMS (Method G): RT=5.90 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.28 (m, 2 H); 4.35 (m, 4 H); 3.98-3.80 (m, 9 H); 3.40-3.25 (m, 3 H); 3.20-2.78 (m, 10 H); 2.15-2.07 (m, 2 H) and 1.50-1.41 (m, 3H)
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([OH:22])=O)[CH:15]=[CH:14][CH:13]=2)=[N:3]1.ClC(OCC(C)C)=O.C([N:33](CC)CC)C.[NH4+]>C1COCC1>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][C:20]([NH2:33])=[O:22])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: O=C(O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Solvent: C1CCOC1
Product: NC(=O)CCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
3-[6-(4-Oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propionic acid (0.31 g, 1.00 mmol), isobutyl chloroformate (0.22 ml, 1.50 mmol) and triethylamine (0.22 ml, 1.50 mmol) were dissolved in THF (10 ml), and the mixture was stirred under ice cooling condition for 1 hr. 25% aqueous ammonium solution was added to the mixture, and the mixture was stirred under ice cooling condition for 0.5 hr. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.20 g, 65%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].[CH2:18](O)[CH3:19]>S(=O)(=O)(O)O>[CH2:18]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[O:5][C:4]1[CH:15]=[CH:16][CH:17]=[C:2]([OH:1])[CH:3]=1)[CH3:19]
Reactant: O=C(O)c1ccccc1Oc1cccc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1Oc1cccc(O)c1

Procedure:
A solution of 17.8 g of 2-(3-hydroxyphenoxy)benzoic acid in 250 ml of ethanol and 1 ml of sulfuric acid was heated at reflux for two days. After cooling, the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by high pressure liquid chromatography eluting with a 0-30% ethyl acetate in hexane gradient. The appropriate fractions were combined and concentrated in vacuo to provide 16.78 g of the desired subtitled intermediate as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]([C:26]1[O:27][C:28]([CH2:31]Cl)=[CH:29][CH:30]=1)=[O:25]>CN(C=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:31][C:28]2[O:27][C:26]([C:24]([O:23][CH3:22])=[O:25])=[CH:30][CH:29]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(C(=O)c3ccccc3)cc2)o1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.1 %

Procedure:
To a stirred solution of 4-hydroxybenzophenone (198.2 mg, 1.0 mmol) in DMF (3 mL) at 0° C. under nitrogen was added potassium carbonate (207 mg, 1.5 mmol) followed by methyl-5-chloromethyl-2-furoate (175 mg, 1.0 mmol). The reaction was allowed to warm to room temperature and the mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were washed with 10% aqueous K2CO3 solution, water, brine, dried over MgSO4, filtered and the solvent removed in vacuo to yield the title compound (330 mg, 98.2%) as a yellow oil.
Reaction SMILES: Cl[C:2]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH3:22])=[N:19][CH:18]=4)=[C:13]([O:23][CH3:24])[CH:12]=3)=[N:9][N:10]=[C:3]12.C(=O)([O-])[O-].[K+].[K+].[F:36][C:37]1[CH:38]=[C:39]([SH:44])[CH:40]=[CH:41][C:42]=1[F:43]>CN(C=O)C.C(OCC)(=O)C>[F:36][C:37]1[CH:38]=[C:39]([S:44][C:2]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7][CH2:6][CH2:5][N:4]3[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]5[O:21][C:20]([CH3:22])=[N:19][CH:18]=5)=[C:13]([O:23][CH3:24])[CH:12]=4)=[N:9][N:10]=[C:3]23)[CH:40]=[CH:41][C:42]=1[F:43]
Reactant: Fc1ccc(S)cc1F
Reactant: CCOC(=O)C1(Cl)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Sc2ccc(F)c(F)c2)CCCn2c(-c3ccc(-c4cnc(C)o4)c(OC)c3)nnc21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a mixture of ethyl 8-chloro-3-[3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (500 mg) and potassium carbonate (497 mg) in DMF (6.0 mL) was added 3,4-difluorobenzenethiol (0.133 mL), and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, the mixture was washed with saturated brine and 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) to give the title compound (491 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](Cl)=[N:16][N:15]=[CH:14]2>C1COCC1.CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([O:5][CH:3]([CH3:4])[C:2]([F:7])([F:6])[F:1])=[N:16][N:15]=[CH:14]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(Oc1nncc2cc(Br)ccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a cooled (0° C.) solution of 1,1,1,-trifluoro-2-propanol (4.0 mL, 44 mmol) in 60 mL of 5:1 THF/DMF was added sodium hydride (60% wt. dispersion in mineral oil, 0.754 g, 33 mmol) resulting in gas evolution. After 20 min, 6-bromo-1-chlorophthalazine (2.62 g, 11 mmol) was added as a solid resulting in a red solution. The reaction was allowed to warm to RT for 1 h. The mixture was quenched with saturated solution of NaHCO3, and extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (ISCO 120 g column, eluting with 25-75% EtOAc in hexanes) to give the title compound as an orange amorphous solid. MS (ESI, pos. ion) m/z: M+1=321.0, 323.0
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][C:23](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:26])[N:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:20][C:21]1[S:22][C:23]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[C:24]([CH3:26])[N:25]=1
Reactant: Cc1nc(C)c(B2OC(C)(C)C(C)(C)O2)s1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(C)c(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 2,4-dimethyl-1,3-thiazol-5-ylboronic acid pinacol ester (239 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (240 mg, 66.7%) as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20].N1C=CC=CC=1>C1COCC1>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][C:12]([C:11]1[CH:15]=[CH:16][C:8]([C:5]2[CH2:4][CH2:3][C:2](=[O:1])[NH:7][N:6]=2)=[CH:9][CH:10]=1)=[O:13]
Reactant: Nc1ccccc1F
Reactant: O=C1CCC(c2ccc(C(=O)Cl)cc2)=NN1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CCC(c2ccc(C(=O)Nc3ccccc3F)cc2)=NN1
Yield: 38.5 %

Procedure:
120 mg (0.5 mmol) of 4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoyl chloride from example I are stirred, at 60° C. for 2 hours, in 5 ml of THF together with 56 mg (0.5 mmol) of 2-fluoroaniline and 0.1 ml of pyridine. The mixture is cooled down and inspissated. The inspissation residue is purified on a silica gel column. The clean fractions are combined, inspissated, crystallized using methanol, filtered-off with suction and washed with methanol. This results in 60 mg of colorless crystals having a melting point of 242-244° C.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C@H:7]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)[C:8](OC)=[O:9])=[O:5].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:3]=1[C:4]([NH:6][C@@H:7]([CH2:8][OH:9])[CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:30])[CH:17]=[CH:16]2)=[O:5]
Reactant: COC(=O)[C@@H](Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CO)Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To methyl (2R)-2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 36 (0,222 g) in THF (1 ml) is added, at 0° C., LiAlH4 (1.5 equ.). The solution is stirred at 0° C. for 1 hour. The reaction is quenched at −25° C. by successive additions of water (25 μl), 15% NaOH (25 μl) and water (75 μl). After evaporation of THF under vacuum, AcOEt is added. The organic phases are washed with water, brine, dried over MgSO4 and evaporated. The resulting residue is purified over silica gel using CH2Cl2/CH3OH/NH4OH (99/1/0.1) as eluent to give 2,6-dichloro-N-[(1R)-2-[2-(2,6-dichlorophenyl)-6-quinolinyl]-1-(hydroxymethyl)ethyl]benzamide 60.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([O:24]C)=[O:23])[CH:10]([CH3:21])[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[CH2:14]([O:13][C:11](=[O:12])[CH:10]([CH3:21])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C(=O)OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 35.5 %

Procedure:
To a solution of 4-benzyl 1-methyl N-(tert-butoxycarbonyl)-3-methyl-L-aspartate (Preparation 68, 0.5 g, 1.52 mmol) in THF/water (50 mL/10 mL) was added lithium hydroxide (34 mg, 1.42 mmol) at 0° C. and the reaction stirred warming slowly to room temperature for 18 hours. The reaction was extracted with heptane and the aqueous was acidified with 10% aqueous KHSO4 solution. The solution was extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-60% MeCN in 0.1% formic acid in water to afford the title compound (182 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[NH:1][CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14])#[N:5]
Reactant: N#Cc1ccc(F)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cc(F)ccc1C#N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 43.1 %

Procedure:
2-amino-4-fluorobenzonitrile (111 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(2-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (40 mg, 42%) as a white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[O:12]1[CH:16]=[N:15][N:14]=[C:13]1[C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1.C(N(CC)CC)C.O=O>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[O:12][CH:16]=[N:15][N:14]=3)=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1ccc(-c2nnco2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Yield: 72.1 %

Procedure:
A mixture of 4-methoxybenzeneboronic acid (1.9 g, 12 mmol), 4-(1,3,4)oxadiazol-2-yl-phenol (1.0 g, 6.2 mmol), copper(II)acetate (1.1 g, 6.2 mmol), crushed 4-Angstrom molecular sieves (0.65 g), triethylamine (4.2 mL) and methylene chloride (22.7 mL) was stirred under 1 atm of oxygen gas for 48 hours. The mixture was filtered through a pad of Celite®, concentrated in vacuo and purified by radial chromatography (2:1 hexane-ethyl acetate), affording 1.2 g of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1.[OH-].[NH4+:14]>C(Cl)Cl>[NH2:14][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[CH:3]=1
Reactant: [NH4+]
Reactant: Clc1cc(-n2cccn2)ncn1
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cc(-n2cccn2)ncn1

Procedure:
In sealed tube, 180 mg of 6-chloro-4-(1-pyrazolyl)pyrimidine and 2.5 ml of concentrated ammonium hydroxide were warmed at 140° C. for 30 hours. The reaction mixture was dissolved in methylene chloride, and washed with water. The organic fraction was dried over anhydrous sodium sulfute, and distilled off. A residue was recrystallized from methanol to yield 148 mg of 6-amino-4-(1-pyrazolyl)pyrimidine, a flaking crystal having a melting point of 236.5°-237° C.,
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:4]2[CH:3]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CN1CCCC1=O>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[CH:7]=[C:6]([NH2:8])[N:5]3[N:9]=[C:10]([C:12]4[O:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:4]3[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Br)cc1
Reactant: Nc1cc(Br)cc2nc(-c3ccco3)nn12
Solvent: CN1CCCC1=O
Product: Nc1cc(Oc2ccc(Br)cc2)cc2nc(-c3ccco3)nn12

Procedure:
A mixture of 1 eq. 7-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine, 5 eq. p-bromo-phenol and a catalytic amount of CS2CO3 in 200 μl N-methyl-pyrrolidon was heated for 2 h to 160°. The mixture was, after filtration, purified with reversed phase column chromatography eluting with an acetonitrile/water gradient yielding the title compound, MS m/e (%): 371 M+ (100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][CH2:11][Cl:12])=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(C)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][CH2:11][Cl:12])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C=CCCCl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Yield: 92.8 %

Procedure:
A suspension of 150 g of 4,4-bis-(4-fluorophenyl-3-butenylchloride, 1 l isopropyl alcohol, and 10 g of 10% palladium-on-charcoal was shaken at room temperature under 40 psi of hydrogen. The uptake of hydrogen ceased after about 5 hrs. The mixture was filtered and the solvent was evaporated to provide an oil. Distillation provided 140.2 g (92.8%) of 4,4-bis-(4-fluorophenyl)butylchloride, bp 155°-158° (1.3 mm).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]1([CH3:45])[CH:38]=[CH:37][C:36]([N:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:42]1[CH2:41][CH2:40][N:39]([C:36]2[CH:35]=[CH:34][C:33]([CH3:45])=[CH:38][CH:37]=2)[CH2:44][CH2:43]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: Cc1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 2.6 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-p-tolyl-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (1.8 mg, 2.6%) as light yellow oil. MS m/e=505.4 [M+H]+.