Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:20][O-:21].[Na+].O>CO>[CH3:19][N:17]([CH3:18])[C:12]1[CH:13]=[C:14]([O:21][CH3:20])[N:15]=[C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[N:11]=1
Reactant: C[O-]
Reactant: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(N(C)C)nc(N2CCNCC2)n1
Yield: 123.9 %

Procedure:
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g) obtained in Example 109(1) and sodium methoxide (1.1 g) were refluxed under heating in methanol (10 ml) for 28 hr. The reaction mixture was poured into water (100 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (1.1 g) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18]2[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]3[CH:27]=[CH:28][C:29]([C:31]4[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=4)=[CH:30][C:20]=3[N:19]=2)[N:6]=1)=[O:4].[H-].[CH2:39]([Al+]CC(C)C)[CH:40](C)[CH3:41].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18]2[N:22]([C:23]([CH3:26])([CH3:24])[CH3:25])[C:21]3[CH:27]=[CH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=4)=[CH:30][C:20]=3[N:19]=2)[N:6]=1)=[O:4])[CH:40]([CH3:41])[CH3:39]
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)c1ncn(-c2ccc(C#N)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)c1ncn(-c2ccc(C#N)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a solution of 1-{2-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-4-cyano-phenyl}-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (example 64) (100 mg, 0.2 mmol) in dry THF (10 mL) is added Diisobutyl aluminium hydride (DIBALH) (1 M THF solution) (0.4 mL, 0.4 mmol) at 0° C. under nitrogen atmosphere. The solution is warmed to room temperature for 24 hours. Sat. NH4Cl solution (10 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The combined organic layer is dried with Mg2SO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (29 mg, 26%). LCMS (ESMS): m/z 536.40 (M++1)
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[O:11]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:12][C:10]([N:9]([CH3:13])[CH3:8])=[O:11])=[O:4]
Reactant: CN(C)C(N)=O
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)NC(=O)C(C)(C)Br
Reaction time: 4 h

Procedure:
2-Bromo-2-methylpropionyl bromide (8.9 g) in dichloromethane (20 ml) was added dropwise at 0° to a stirred suspension of 1,1-dimethylurea (3.4 g) in dichloromethane (25 ml) and triethylamine (16 ml). The mixture was stirred for 4 hr. at 22° and the solvent was evaporated. The residue was stirred with saturated sodium hydrogen carbonate solution (40 ml) and extracted with ethyl acetate (3×20 ml). The ethyl acetate solution was dried and evaporated. The residue was stirred with light petroleum (b.p. 40°-60°, 50 ml) and the remaining solid was filtered off and suspended in sodium hydrogen carbonate solution and extracted into ethyl acetate (2×20 ml). The ethyl acetate solution was dried and evaporated, leaving the urea as a pale brown solid, 1.4 g, m.p. 98°-100°, max (Nujol) 3400, 3370 (NH), 1742, 1685 cm-1 (--CONH.CON--), τ (DMSO d6) 8.06 (--C(Me)2), 7.01 (-N(Me)2), 1.6 (--CONHCO--).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=O)=[O:18])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1>>[C:1]([NH:11][CH2:12][C:13]([NH:15][CH2:16][C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:23])=[O:18])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(CNC(=O)OCc1ccccc1)NCC(=O)N1CCC[C@H]1C(=O)O
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Product: O=C(CNC(=O)OCc1ccccc1)NCC(=O)N1CCC[C@H]1C(=O)NCCc1ccc(O)c(O)c1

Procedure:
In the same manner as described in Example 1, 800 mg of carbobenzoxyglycylglycylproline and 380 mg of dopamine hydrochloride were reacted and treated to obtain N-carbobenzoxyglycylglycylprolyl dopamine. This compound was subjected to the catalytic reduction treatment in the same manner as described in Example 1. At the gel filtration, fractions Nos. 40 to 48 were collected. There was obtained 380 mg of a white powdery product, which was an acetate of the intended product. Elementary Analysis Values as C17H24N4O5.CH3COOH.1/2 H2O:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc(O)ccc1OCc1ccccc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 92.2 %

Procedure:
A mixture of 2-benzyloxy-5-hydroxybenzaldehyde (8.93 g), ethyl iodide (7.31 g), anhydrous potassium carbonate (5.40 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give 2-benzyloxy-5-ethoxybenzaldehyde as a colorless oil (9.25 g, 92%) from a fraction eluted with ethyl acetate-hexane (1:9, v/v).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH2:5])=[O:4].C(N(CC)CC)C.[C:16]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[C:16]1([CH2:22][S:23]([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([NH2:5])=[O:4])(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCN1S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a solution of L-prolinamide (2.28 g, 20 mmol) and triethylamine (5.76 ml, 42 mmol) in 40 ml methylene chloride was added 3.92 g (20 mmol) α-toluenesulfonyl chloride at 0° C. with stirring. The reaction was gradually warmed up to room temperature and stirred overnight. The mixture was diluted with water, and extracted into 200 ml methylene chloride. The organic extract was concentrated and further purified by silica gel to give 3.0 g product as a white solid (55.7% yield). 1H NMR (CDCl3): d 01.89 (m, 3H); 2.25 (m, 1H); 3.40 (m, 1H); 3.50 (m, 1H); 3.96 (m, 1H); 4.35 (s, 2H); 7.39-7.45 (m, 5H, aromatic).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](OC)=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19](F)=[C:18](Cl)[CH:17]=3)[N:12]=[CH:11][N:10]=2)C=1.[NH2:26]C1C=CC=CC=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:26][C:2]1[N:1]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(N)cc1Nc1cc(Nc2ccc(F)c(Cl)c2)ncn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
The preparation of N4-(5-amino-2-methoxyphenyl)-N6-(3-chloro-4-fluorophenyl)pyrimidine-4,6-diamine (1) is described in Example 7 (Int-G). To a stirred solution of 1 (150 mg, 0.41 mmol) in DMF (8 mL) was added 2 (137 mg, 0.83 mmol), HATU (317 mg, 0.83 mmol) and DIPEA (215 mg, 1.67 mmol) at 0° C. The reaction mixture was stirred for 18 h at RT. After the completion of reaction (monitored by TLC), the crude mixture was diluted with water and extracted with EtOAc (4×100 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuo to afford 3 (100 mg, 47.3%) as off-white solid, which was used in the next step without further purification. 1H NMR (CDCl3, 500 MHz): δ 8.35 (s, 1H), 8.12 (s, 1H), 7.48-7.43 (m, 1H), 7.24 (s, 1H), 7.16-7.10 (m, 2H), 7.03 (s, 1H), 6.84 (t, J=9.0 Hz, 2H), 6.49 (s, 1H), 6.15 (s, 1H), 5.29 (s, 1H), 3.85 (s, 3H), 3.33 (d, J=5.0 Hz, 2H), 2.80 (s, 3H). Mass: m/z 506 (M++1).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C[C:15]([CH3:18])([O-])[CH3:16].[K+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CS(C)=O>[CH2:21]([C:12]1([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH2:13][CH2:12][CH2:16][CH2:15][CH3:18])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Reactant: CCCCCCCCCCCCCCBr
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCC1(CCCCCCCCCCCCCC)c2ccccc2-c2ccccc21
Temperature: 10 °C
Reaction time: 24 h
Yield: 166.5 %

Procedure:
A 2000 mL round flask was charged with 9H-fluorene (15 g, 90.24 mmol) and potassium tert-butoxide (21.2 g, 198.5 mmol), and then 300 mL of DMSO was slowly injected thereto. Under nitrogen atmosphere, 1-bromotetradecane (54 g, 198.5 mmol) was slowly dropped through a dropping funnel while the reactor temperature was maintained at 10° C. or lower. The mixture was stirred at room temperature for 24 hours, and the reaction was terminated by addition of 500 mL of distilled water. The organic layer collected by extraction with n-hexane was dried over magnesium sulfate, followed by removal of volatile materials, and then purified with n-hexane by using silica gel column chromatography tube, followed by drying, to thereby obtain 42.0 g of 9,9-ditetradecyl-9H-fluorene (yield: 83.26%) as white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C(N(CC)CC)C.CO>ClC(Cl)C>[O:26]=[C:25]1[C:24]2[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:22](=[O:27])[N:2]1[CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C:4]1=[O:21]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)C(N)C(=O)N2c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)C(N1C(=O)c3ccccc3C1=O)C(=O)N2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
In one portion of 4.00 g (0.013 mole) of 3-amino-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one hydrochloride in 80 ml of anhydrous dichloroethane, 2.69 g (0.0182 mole, 1.4 equivalent) of phthalic anhydride was added to a stirred suspension under argon atmosphere. 2 ml (0.0143 mole) of triethylamine was added dropwise to this mixture over 10 minutes. Then, after the whole was stirred at room temperature for 10 minutes, it was further refluxed over an oil bath overnight. Excessive phthalic anhydride was decomposed by adding a mixture of 2 ml of triethylamine and 2 ml of methanol and refluxing the resulting mixture for 20 minutes. The reaction mixture was concentrated under reduced pressure and then extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried. The residue obtained by removing ethyl acetate by evaporation was recrystallized from hexane-ethyl acetate to afford 4.50 g of 3-(1,2-dihydro-1,3-dioxoisoindol-2-yl)-1-(4-fluorophenyl)-2,3-dihydro-5-methoxy-1H-indol-2-one as colorless crystals. Melting point: 208.5° to 210.0° C., IR (Nujol) (cm-1): 1730, 1715, 1495, 1400, 1225, 1210, 750, 715, MS (DI, m/e): 402 (M+, base), 227, 184, 76.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH2:19]([NH2:22])[C:20]#[CH:21]>>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=1[C:11]([NH:22][CH2:19][C:20]#[CH:21])=[O:12]
Reactant: C#CCN
Reactant: O=c1[nH]c2c(F)cccc2c(=O)o1
Solvent: C1CCOC1
Product: C#CCNC(=O)c1cccc(F)c1N
Reaction time: 2 h
Yield: 79 %

Procedure:
8-Fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.00 g, 16.6 mmol) was dissolved in tetrahydrofuran (100 mL, 1.23 mol) and prop-2-ynylamine (1.70 mL, 24.8 mmol) was added. The reaction was stirred for 2 hours and then concentrated under reduced pressure onto silica gel. Purification by silica gel chromatography (dry loaded) using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain 2-amino-3-fluoro-N-prop-2-ynyl-benzamide as a white solid (2.52 g, 79%). m.p.=89-91° C.; LCMS (m/e) 138 (M-NHCH2CCH); 1H-NMR (CDCl3, 400 MHz) δ 7.14 (d, 1H, J=8.0 Hz), 7.12-7.05 (m, 1H), 6.64-6.56 (m, 1H), 6.28-6.14 (m, 1H), 5.67 (bs, 2H), 4.27-4.19 (m, 2H), 2.34-2.27 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([NH:20][C:21](=[O:40])[NH:22][C@@H:23]([CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:8][CH2:9][C:10](ON1C(=O)CCC1=O)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:42][C@@H:43]([CH2:47][CH2:48][CH2:49][CH2:50][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73]([O:75][C:76]([CH3:79])([CH3:78])[CH3:77])=[O:74])[CH:69]=[CH:70][N:71]=1)[CH2:52][C:53]1[N:54]([CH2:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:55]=[CH:56][N:57]=1)[C:44]([OH:46])=[O:45].CCN(C(C)C)C(C)C>CN(C=O)C>[C:61]([O:60][C:59](=[O:65])[CH2:58][N:54]1[CH:55]=[CH:56][N:57]=[C:53]1[CH2:52][N:51]([CH2:66][C:67]1[N:68]([CH2:72][C:73](=[O:74])[O:75][C:76]([CH3:79])([CH3:78])[CH3:77])[CH:69]=[CH:70][N:71]=1)[CH2:50][CH2:49][CH2:48][CH2:47][C@H:43]([NH:42][C:10](=[O:11])[CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:41])[NH:20][C:21](=[O:40])[NH:22][C@H:23]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:31][CH2:32][C:33](=[O:34])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C:44]([OH:46])=[O:45])([CH3:62])([CH3:64])[CH3:63]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](N)C(=O)O)Cc1nccn1CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCC(=O)N[C@@H](CCCCN(Cc1nccn1CC(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 85.6 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-5-(2,5-dioxopyrrolidin-1-yloxy)-1,5-dioxopentan-2-yl)ureido)pentanedioate (138 mg, 0.236 mmol), (S)-2-amino-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)hexanoic acid (127 mg, 0.237 mmol) and DIPEA (0.50 mL) in DMF (1.0 mL) was stirred at rt for overnight. The Solvent was removed under reduced pressure to give a residue, which was purified by biotage eluting with 1% to 50% MeOH in DCM to afford (2S,7S,11S)-2-(4-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-16,16-dimethyl-4,9,14-trioxo-15-oxa-3,8,10-triazaheptadecan-1-oic acid (203 mg, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.40 (brs, 1H), 6.99 (s, 2H), 6.79 (s, 2H), 6.12 (brs, 1H), 5.62 (brs, 1H), 4.67-4.28 (m, 7H), 3.68 (d, J=14.0 Hz, 2H), 3.62 (d, J=14.0 Hz, 2H), 2.62-2.53 (m, 2H), 2.34-2.02 (m, 8H), 1.83-1.42 (m, 51H); MS (ESI), 503.5 (M/2+H)+.
Reaction SMILES: NC1C=CC(C2C3C(=NC=NC=3N)N([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)N=2)=CC=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[OH:39].[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4OC5C=CC=C(C)C=5N=4)=[CH:52][CH:51]=3)[C:42]=12>>[NH2:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C@H:67]3[CH2:72][CH2:71][C@@H:70]([N:73]4[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]4)[CH2:69][CH2:68]3)[N:48]=[C:49]([C:50]3[CH:55]=[CH:54][C:53]([NH:56][C:57]4[O:39][C:33]5[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=4)=[CH:52][CH:51]=3)[C:42]=12
Reactant: Nc1cccc(Cl)c1O
Reactant: Cc1cccc2oc(Nc3ccc(-c4nn([C@H]5CC[C@@H](N6CCN(C)CC6)CC5)c5ncnc(N)c45)cc3)nc12
Agent: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(N)cc4)c4c(N)ncnc43)CC2)CC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6cccc(Cl)c6o5)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-chlorophenol (0.053 g, 0.367 mmol) in a manner similar to that used in the synthesis of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine (PH4052419F). The compound was formed as an off-white solid (0.018 g, 13%): RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=7.78 min., 94%; m/z 558 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH2:11][CH2:10]1)[CH3:2].[NH2:28][CH2:29][CH2:30][CH2:31][OH:32]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])[C:12]=2[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCc1ccccc1N1CCc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Reactant: NCCCO
Product: CCc1ccccc1N1CCc2c(NCCCO)nc3c(OC(F)(F)F)cccc3c21

Procedure:
1-(2-Ethylphenyl)-4-chloro-6-trifluoromethoxy-2,3-dihydropyrrolo[3,2-c]quinoline(801 mg, 2.0 mmol) was dissolved in 3-amino-1-propanol(10 ml) in the pressure tube, then reacted at the same condition of Step 3 in the Example 10 to obtain 560 mg of desired compound as solid in 62% of yield.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:19][C:18]=2[CH:28]=1>>[CH3:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)=[N:19][C:18]=2[CH:28]=1)=[O:5]
Reactant: Nc1ccc2oc(-c3ccncc3)nc2c1
Reactant: CC(Cc1ccccc1)C(=O)O
Product: CC(Cc1ccccc1)C(=O)Nc1ccc2oc(-c3ccncc3)nc2c1
Yield: 75 %

Procedure:
Similarly prepared as per compound 8 procedure, using starting materials 2-methyl-3-phenylpropanoic acid and compound 4 to obtained title compound as white solid (75%). 1H NMR (CDCl3, 400 MHz) δ 1.29 (d, J=6 Hz, 3H), 2.63 (q, J=6.4 Hz, 1H), 2.77 (dd, J1=16 Hz, J2=5.6 Hz, 1H), 3.02 (dd, J1=16 Hz, J2=9.2 Hz, 1H), 7.17-7.25 (m, 5H), 7.34-7.44 (m, 3H), 7.75 (s, 1H), 7.99 (d, J=4 Hz, 2H), 8.75 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 18.0, 40.9, 44.9, 110.9, 112.5, 120.0, 121.2, 126.7, 128.8, 129.1, 134.4, 135.3, 139.8, 142.1, 147.8, 150.8, 174.3; ESI-HRMS for C22H20N3O2 (M+H)+ calcd. 358.1556 found 358.1556.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN([CH:66]=[O:67])C.[CH3:68][OH:69]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:68]([O:67][CH3:66])=[O:69])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[F:24]
Reactant: CN(C)C=O
Reactant: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Reactant: CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1nccc2c1CN(C(C)c1cnc(OCC(F)(F)F)c(C)c1)C2=O
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 4-chloro-2-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (540 mg, 1.40 mmol, Intermediate-2, single enantiomer), palladium(II) acetate (190 mg, 0.84 mmol), 1,3-bis(diphenylphosphino)propane (115 mg, 0.28 mmol), and triethylamine (0.58 mL, 4.20 mmol) in DMF/MeOH (2.5:1, 14 mL) is heated at 100° C. under carbon monoxide atmosphere for 18 hours. The reaction mixture is cooled to rt and dilute with water. The mixture is filtered through a pad of Celite™ and the filtrate is extracted with n-hexane/EtOAc (1:1) mixed solvent. The combined extracts are washed with water, and brine. The organic extract is dried over sodium sulfate, filtrate, and volatiles are removed. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:1 to 1:4) to give 300 mg (52% yield) of the title compound as brown amorphous solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[OH:10])[CH3:3].[C:14](Cl)([Cl:16])=[O:15].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH:11]([C:8]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:2]([CH3:1])[CH3:3])[C:9]=1[O:10][C:14]([Cl:16])=[O:15])([CH3:13])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0° C.) solution of propofol (20.0 g, 112 mmol) in toluene (40 mL) was added phosgene (82 mL, 20% in toluene) under a nitrogen atmosphere. The reaction mixture was stirred for 5 min, and then N,N-dimethylaniline (15 mL, 118 mmol) was added dropwise. The mixture was allowed to warm to room temperature slowly and stirred for 14 h. The suspended mixture was then filtered. The filtrate was collected and the solvent was removed in vacuo. The remaining crude product (9) was carried to the next step without further purification. 1H-NMR (400 MHz, CDCl3): δ 7.18-7.29 (m, 3H), 3.00-3.07 (m, 2H), 1.25-1.27 (d, J=6.8 Hz, 12H).