Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[NH:9][CH2:8][C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4].C(C1C(=O)C(Cl)=C(Cl)[C:23](=[O:24])C=1C#N)#N>C(OCC)(=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[NH:9][CH:8]([O:24][CH3:23])[C:7]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: CCCCN1N=C(c2ccc(Cl)cc2)CNC1=O
Solvent: CCOC(C)=O
Product: CCCCN1N=C(c2ccc(Cl)cc2)C(OC)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-n-Butyl-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one (2.16 g, 8.13 mmol), and DDQ (1.94 g, 8.5 mmol in 80 mL of ethyl acetate were stirred at room temperature overnight, then refluxed for 3 hours. The reaction mixture was cooled, washed twice with aqueous potassium carbonate solution, washed with brine, dried over magnesium sulfate and stripped. The product was dissolved in 15 mL of ethyl acetate and 15 mL of methanol. Alumina (7 g) was added, and the slurry was stirred for 3 hours at room temperature. The slurry was filtered, and the filtrate was stripped. The product was chromatographed on an alumina column to give 0.97 g of of 2-n-butyl-5-methoxy-6-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-3-one (Compound 3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([N:24]([C:40](=[O:42])[CH3:41])[C@H:25]([C:33]([O:35]C(C)(C)C)=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:20]2[CH:43]=[CH:44][CH:45]=[CH:46][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:53]>>[ClH:53].[CH2:1]([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([N:24]([C:40](=[O:42])[CH3:41])[C@H:25]([C:33]([OH:35])=[O:34])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:20]2[CH:43]=[CH:44][CH:45]=[CH:46][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1COc2ccccc2N(N(C(C)=O)[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1COc2ccccc2N(N(C(C)=O)[C@@H](Cc2ccccc2)C(=O)O)C1=O
Reaction time: 4 h

Procedure:
In 100 ml of hydrogen chloride-ethyl acetate (5N) solution is dissolved 0.4 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-yl-N-acetyl-L-phenylalaninate obtained in Example 24 and the solution is allowed to stand for 4 hours. The reaction solution is concentrated under reduced pressure, and 50 ml of ether is added to the residue. The resulting mixture is extracted twice with 70 ml each of saturated sodium bicarbonate solution and the aqueous layer is extracted with 50 ml of ether. The aqueous layer is neutralized with 1N hydrochloric acid and extracted with 100 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily product is dissolved in 10 ml of ether, and 0.5 ml of hydrogen chloride-ethyl acetate (5N) solution is added to the solution to give 0.2 g of 3(S)-[1(S)-ethoxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-yl-N-acetyl-L-phenylalanine hydrochloride as a colorless powder.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32](O)[CH:33]=3)[CH:28]=2)[CH2:24][O:23][C:22]([CH3:26])([CH3:25])[O:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:38])[NH:18][C:19]1([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:11][C@H:8]4[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:10][CH2:9]4)[CH:33]=3)[CH:28]=2)[CH2:20][O:21][C:22]([CH3:26])([CH3:25])[O:23][CH2:24]1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)COC(C)(C)OC1

Procedure:
The title compound was prepared from cis-4-tertbutylcyclohexanol and [5-[6-hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester in 42% yield according to the method of Example 53.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:22](O)[CH2:23][OH:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:10][CH2:22][CH2:23][O:24][CH2:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: OCCO
Reactant: CC(=O)c1ccnc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cc(C2COCCO2)ccn1

Procedure:
A mixture of 21.3 g. (0.137 mole) of 1-(2-chloro-4-pyridyl)ethanone and 0.5 g. of p-toluenesulfonic acid in 40 ml. of ethylene glycol and 300 ml. of toluene was placed in a flask fitted with a Dean-Stark trap and condenser, and was heated at reflux temperature for 16 hours. The mixture was cooled and concentrated in vacuo to give an oil which was purified by distillation under reduced pressure, 23.6 g. (86%), b.p. 65° C. (0.05 torr).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:13].[F:14][C:15]([F:29])([F:28])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.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]>[Cl:13][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:25]3[CH2:24][CH2:23][N:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:28])([F:29])[F:14])[CH:17]=4)[CH2:27][CH2:26]3)[CH:3]=2)[C:8](=[O:12])[NH:7][N:6]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cl)c2cc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)ccc12
Yield: 6.3 %

Procedure:
A mixture 6-bromo-4-chloro-2H-phthalazin-1-one (150 mg, 0.578 mmol), 1-(α,α,α-trifluoro-m-tolyl)piperazine (0.12 mL, 0.639 mmol), Pd2(dba)3 (53 mg, 0.0578 mmol), rac-BINAP (123 mg, 0.198 mmol) and NaOtBu (176 mg, 1.831 mmol) in DMA (5 mL) was heated at 85° C. for 1 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography on silica (EtOAc/hexanes) afforded 4-chloro-6-[4-(3-trifluoromethyl-phenyl)-piperazin-1-yl]-2H-phthalazin-1-one (15 mg) as a beige solid, 1H (400 MHz, d6-DMSO) δ: 3.21 (m, 4H), 3.40 (m, 4H), 6.86 (d, 1H), 6.91 (d, 1H), 6.98 (s, 1H), 7.05 (m, 1H), 7.22 (t, 1H), 7.38 (dd, 1H), 7.85 (d, 1H), 12.28 (s, 1H) ppm; m/z (M+1) 408.82.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][CH:24]1[CH:29]([CH3:30])[CH2:28][CH2:27][CH2:26][CH:25]1[NH2:31]>>[CH3:23][CH:24]1[CH:29]([CH3:30])[CH2:28][CH2:27][CH2:26][CH:25]1[NH:31][C:7]1[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[N:8]=1
Reactant: CC1CCCC(N)C1C
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCC(C)C2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2,3-dimethylcyclohexanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.75-0.76 (m, 3H), 0.85-0.95 (m, 3H), 1.55-1.74 (m, 8H), 1.86-1.97 (m, 4H), 2.07 (s, 3H), 3.10-3.18 (m, 1H), 4.43 (bs, 2H), 7.20-7.26 (m, 1H), 7.50-7.57 (m, 1H), 7.67-7.73 (m, 1H), 8.60-7.68 (m, 1H); MS (ESI) m/z 340.4 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Product: O=C(Cl)Cc1ccc(Cl)c(Cl)c1

Procedure:
A solution of 3,4-dichlorophenylacetic acid (23.59 g, 115 mmol) in thionyl chloride (66 mL, 905 mmol) was heated at 76° C. for 2.5 h and then evaporated under reduced pressure to yield 3,4-dichlorophenylacetyl chloride. A solution of 3,4-dichlorophenylacetyl chloride in cold, dry CH2Cl2 (90 mL) was added dropwise to an ice-cold solution of 13 (26.025 g, 104 mmol) and Et3N (16 mL, 115 mmol) in dry CH2 Cl2 (150 mL) with stirring under argon and ice-cooling over 30 min. The mixture was stirred at 25° C. for 21 h before the solvent was removed under reduced pressure. The residue was then dissolved in EtOAc and washed with 3N NaOH. The organic fraction was dried (MgSO4), filtered, and evaporated to yield 43.5 g (95%) of crude product. Two crystallizations from boiling MeOH yielded 14.HCl (10.24 g, 21%): mp (14.HCl)>260° C.; [α]D25°C. +137° (c=0.2, 14.HCl:, MeOH); 1H NMR (14.HCl, DMSO-d6) δ 1.89-2.01 (m, 4H, --CH2CH2 --), δ 2.83 (s, 3H, NCH3), δ 3.15-4.19 (complex, 6H, 3 --CH2N), δ 3.85 (d, J=17 Hz, 1H, ArCH2CO), δ 3.99 (d, J=16 Hz, 1H, ArCH2 CO), δ 6.21 (m, 1H, CH), δ 7.28-7.30 (m, 1H, Cl2C6 H3 --), δ 7.56-7.57 (m, 2H, Cl2C6H3 --), δ 7.71-7.72 (m, 2H, m-NO2C6H4), δ 8.08 (s, 1H, m-NO2C6H4), δ 8.21-8.22 (m, 1H, m-NO2 C6H4). MS (FAB) m/z 436.1. Anal. (C21H23N3 O3Cl2.HCl.0.5 H2O) calcd.: C 52.35, H 5.23, N 8.72, Cl 22.08; found: C 52.18, H 5.22, N 8.58, Cl 22.00.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:4]1.[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH:34]=O)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21].Cl.Cl.N1CC(N2CCSCC2)C1.FC1C=CC(C(CC=O)CN(C)C(=O)OC(C)(C)C)=CC=1>>[Cl:14][C:15]1[CH:16]=[C:17]([C@H:22]([CH2:33][CH2:34][N:3]2[CH2:6][CH:5]([N:7]3[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]3)[CH2:4]2)[CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Reactant: OC1CCN(C2CNC2)CC1
Agent: C1CN(C2CNC2)CCS1
Agent: CN(CC(CC=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Agent: Cl
Product: CN(C[C@@H](CCN1CC(N2CCC(O)CC2)C1)c1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C

Procedure:
The compound was synthesized in an analogous way to that of Method 3d but using 1-azetidin-3-ylpiperidin-4-ol dihydrochloride (see Meth 15) and tert-butyl [(2S)-2-(3,4-dichlorophenyl)-4-oxobutyl]methylcarbamate (see WO 95/05377) rather than 4-azetidin-3-ylthiomorpholine dihydrochloride and tert-butyl [2-(4-fluorophenyl)-4-oxobutyl]methylcarbamate (yield, 35%). 1H NMR (500 MHz, CDCl3): 1.3 (m, 2H), 1.4 (s, 9H), 1.5-3.8 (cm, 23H), 7.0 (dd, 1H), 7.2-7.4 (m, 2H), LCMS: m/z 487 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH:17]1([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:28]1[CH2:27][CH2:26][CH:25]([C:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:24])[CH2:30][CH2:29]1)=[O:8]
Reactant: O=C(C1CCCCC1)C1CCNCC1
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(C(=O)C3CCCCC3)CC2)c([N+](=O)[O-])cc1OC

Procedure:
10.3 g of 3,4-dimethoxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 8.83 g of 4-cyclohexylcarbonylpiperidine and 4.58 g of triethylamine in 300 ml of dichloromethane. Yield 16.4 g (90%), m.p. 120°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2I)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[C:27]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CCO.O1CCOCC1.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([NH:16][C:17](=[O:26])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=2[C:27]2[CH2:31][CH2:30][CH2:29][CH:28]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:15])[CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)C1=CCCC1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2ccc(F)cc2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C2=CCCC2)Cc2ccc(F)cc2C1
Yield: 69.3 %

Procedure:
To a solution of 5-fluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (400 mg, 0.85 mmol) and cyclopenten-1-ylboronic acid (383 mg, 3.42 mmol) in EtOH (10 mL) and dioxane (5 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 186 mg, 8.5% mmol) and 2M aqueous solution of K2SO4 (1.71 mL, 3.42 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 8 h. After concentration in vacuo, the residue is purified HPLC to give a pure product (151) as white solid (240 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[CH3:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([N:33]3[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]3[CH3:31])[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Cc1c(CN2CCC(N3CCOCC3)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCC(N3CCOCC3)CC2)sc2c(N3CCOCC3)nc(-n3c(C)nc4ccccc43)nc12

Procedure:
Following General Procedure I for Buchwald coupling, 4-(1-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)morpholine and 2-methyl-1H-benzo[d]imidazole were reacted to give 232. LCMS: M+H+=548.3
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[F:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccccc4F)c3O2)cc1
Yield: 81.2 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with 2-fluorophenylboronic acid (0.274 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.051 g, 0.065 mmol), and potassium carbonate (0.45 g, 3.26 mmol) generally according to the procedure described for Intermediate 37 provided 0.422 g (81%) of (±)-[7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. mp 99-101° C.; Anal. calcd. for C22H19FO4S: C, 66.32; H, 4.81. Found: C, 65.16; H, 4.86.
Reaction SMILES: [CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH3:34]>C1COCC1>[CH:1]1([N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([N:33]([CH3:34])[CH3:32])(=[O:25])=[O:24])=[CH:19][C:18]=3[CH3:27])=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CNC
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)N(C)C)ccc1NC(=O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]-3-methylbenzenesulfonyl chloride (Intermediate 20, 50 mg; 0.11 mmol) in THF (5 ml) was treated with polymer-supported-diisopropylethylamine (60.7 mg; 0.22 mmol) and dimethylamine (8 μl; 0.13 mmol, Aldrich) and the reaction mixture was stirred at room temperature for three hours. The resin was filtered and the solvents were evaporated to give a residue, which was purified by column chromatography (silica) using as eluent petroleum ether/EtOAc to afford the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:10]2[C:11]([NH:13][C:14](=[O:15])[C:9]=12)=[O:12].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)C>[N:19]1([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:18]=[CH:17][CH:16]=[C:10]3[C:11]([NH:13][C:14](=[O:15])[C:9]=23)=[O:12])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=C1NC(=O)c2c(CCCCCCBr)cccc21
Reactant: C1COCCN1
Solvent: CCOCC
Product: O=C1NC(=O)c2c(CCCCCCN3CCOCC3)cccc21

Procedure:
6-Bromohexylphthalimide (633 mg; 2.0 mmoles) and morpholine (0.35 mg; 4.0 mmoles) were dissolved in anhydrous ethyl ether (5 ml). Reaction times and process as per Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:17]([CH3:23])=[CH:18][CH:19]=[N:20][C:21]=4[CH:22]=3)[N:9]=[C:10](I)[C:3]=12.[OH:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C(O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[N:14]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])[C:15](=[O:24])[C:16]4[C:17]([CH3:23])=[CH:18][CH:19]=[N:20][C:21]=4[CH:22]=3)[N:9]=[C:10]([C:37]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:32])[CH:38]=3)[C:3]=12
Reactant: Cc1ccccc1-n1c(Cn2nc(I)c3c(N)ncnc32)cc2nccc(C)c2c1=O
Reactant: OB(O)c1cccc(O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1-n1c(Cn2nc(-c3cccc(O)c3)c3c(N)ncnc32)cc2nccc(C)c2c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
To a stirred mixture of 7-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthyridin-5(6H)-one (2114) (1.05 g, 2.0 mmol) and 3-hydroxyphenylboronic acid (0.33 g, 2.4 mmol) in DMF-EtOH—H2O (3:1:1, 50 mL), Pd(OAc)2 (0.14 g, 0.60 mmol), PPh3 (0.31 g, 1.2 mmol) and Na2CO3 (1.06 g, 10.0 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon three times and then stirred at 80° C. for 1 h. The mixture was allowed to cool to RT, filtered through silica gel (5 g) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (2-5% MeOH/DCM) to afford the desired product, 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthyridin-5(6H)-one (2115) (0.68 g, 69% yield) as a slight yellow solid. Then the product was dissolved in EtOH (5 mL), and stirred at reflux for 30 min. The solution was allowed to cool to RT and the solid was collected by filtration. The solid was then suspended in ethyl acetate (5 mL), and stirred at RT for 16 h. The precipitate was collected by filtration and further dried in vacuo to afford the desired product, 7-((4-amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-methyl-6-o-tolyl-1,6-naphthyridin-5(6H)-one (2115) (0.59 g, 60% yield) as a white solid.
Reaction SMILES: C([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1)[CH3:6])(=O)C.[OH-].[K+]>O1CCOCC1.C(OCC)(=O)C>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][N:16]1[CH2:15][CH2:14][N:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([C@H:5]([OH:4])[CH3:6])[N:12]=2)[CH2:18][CH2:17]1
Reactant: CC(=O)O[C@H](C)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](O)c1nccc(N2CCN(Cc3ccccn3)CC2)n1
Reaction time: 3 h

Procedure:
To a solution of (R)-1-[4-(4-pyridin-2-ylmethyl-piperazin-1-yl)-pyrimidin-2-yl]-ethyl acetate (prepared according to the method of Example 182, Step A, 0.14 g, 0.33 mmol) in dioxane (6 mL) was added at ambient temperature 6 N aqueous potassium hydroxide (0.5 mL). After stirring for 3 h the solution was diluted with ethyl acetate and washed twice with water. The organic layer was separated, dried over magnesium sulfate, filtered, and the filtrate was concentrated to give the title compound as a white solid, 0.09 g (69%). 1H NMR (CDCl3, 300 MHz) δ1.52 (d, 3H), 2.38-2.59 (m, 4H), 3.72-3.77 (m, 6H), 4.69 (q, 1H), 6.37 (d, 1H), 7.22 (d, 1H), 7.41 (d, 1H), 7.69 (m, 1H), 8.21 (d, 1H) 8.58, (d, 1H); mp: 68-70° C.; MS (CI) 300 (MH+); [α]D +16.2 (c 1.0, MeOH).
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)([O-:15])=[O:14]>CC(=O)CC>[N+:13]([C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:2][C:1]([OH:11])=[O:10])=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CCC(C)=O
Product: O=C(O)CC(Nc1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
A mixture of trans-cinnamic acid (2 g, 13 mmol) and HBr (30% solution in AcOH, 40 mL) was stirred at room temperature for 18 h and then evaporated to dryness. The resulting solid was taken upin 2-butanone (100 mL) and p-nitroaniline (5 g, 36 mmol) was added. The reaction mixture was refluxed for 18 h, allowed to cool and partitioned between CHCl3 and 1N HCl. The organic phase was dried and concentrated to a residue. This was purified by chromatography on silica gel (hexane: EtOAc, 50%), to afford the title compound as a yellow solid (0.78 g, 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:33]([OH:35])=[O:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:42]([O:34][C:33](=[O:35])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:28])([F:29])[F:27])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:10])[CH3:43]
Reactant: CCI
Reactant: Cc1cc(C(F)(F)F)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.5 %

Procedure:
To a suspension of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (145 mg, 0.275 mmol) and sodium bicarbonate (185 mg, 2.2 mmol) in DMF (2 mL) was added iodoethane (343 mg, 2.2 mmol) at room temperature. The mixture was stirred for 72 h at room temperature. Then, the reaction mixture was poured into water (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed with brine solution (60 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the filtrate gave 129 mg (85% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine ethyl ester as a crystalline white solid: mp 86-91° C. ES-HRMS m/e calcd for C26H23Cl2F3N2O4 (M+Na) 577.0876, found 577.0887.