Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[NH2:21][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH3:23].FC(F)(F)C(O)=O>>[NH2:1][C@@H:2]([C:11]([NH:21][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH3:23])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](C)NC(=O)[C@H](N)Cc1ccc(O)cc1

Procedure:
t-Boc-D-Tyr-OH was coupled with D-Ala-OMe by the N-hydroxy-succinimide ester method (The Peptides, 1, p. 105). Deprotection was carried out using trifluoroacetic acid (The Peptides, 1, p. 39) and the resulting dipeptide methyl ester salt was purified by chromatography on Sephadex G-10 using 0.2 N HOAc.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][O:16][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
2.67 g of 163 (5.73 mmol) was dissolved in 35 ml of anhydrous THF, cooled to 0° C. and added with 8.60 ml of TBAF solution (8.60 mmol, 1.5 eq., 1 M/THF). After reacting at RT overnight, 0.5 ml of water was added, followed by stirring for 30 min. Thereafter, the batch was filtered together with a small amount of MTBE over a small amount of silica gel and concentrated. Column chromatography over silica gel (EE/CH 1:3) afforded 1.28 g of alcohol 165 (5.63 mmol, 98%) as a colorless oil.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[O:13])[C:4]([CH3:23])([CH3:22])[CH2:3]1.I[Si](C)(C)C.[NH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:23][C:4]1([CH3:22])[CH2:3][CH:2]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[O:13]
Reactant: COc1cccc(C(=O)N2c3ccccc3C(O)CC2(C)C)c1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: COc1cccc(C(=O)N2c3ccccc3C(Nc3ccccc3)CC2(C)C)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To a chilled solution of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone (500 mg, 1.6 mmol) in 10 ml dichloromethane was added slowly 0.8 ml iodotrimethylsilane (5.6 mmol) at 0° C. The resulting reaction mixture was stirred at 0° C. for 6 hours. Then the mixture was concentrated under vacuum. The residue was dissolved in 12 ml TIF. BaCO3 (630 mg, 3.2 mmol) and aniline (0.17 ml, 1.92 mmol) was added. The mixture was stirred at RT overnight. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:4) to give (2,2-dimethyl-4-phenylamino-3,4-dihydro-2H-quinolin-1-yl)-(3-methoxy-phenyl)-methanone (150 mg, 24%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B5OC(C)(C)C(C)(C)O5)[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1.Br[C:54]1[CH:55]=[N:56][CH:57]=[CH:58][C:59]=1[CH3:60].O>O1CCOCC1.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>[CH3:7][O:8][CH2:9][C:10]1[C:18]2[N:17]=[C:16]([C:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:54]5[CH:55]=[N:56][CH:57]=[CH:58][C:59]=5[CH3:60])[CH:26]=4)[N:21]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:42])[CH3:43])[N:20]=3)[N:15]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:51])([CH3:52])[CH3:50])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(B4OC(C)(C)C(C)(C)O4)cc13)n2COCC[Si](C)(C)C
Reactant: Cc1ccncc1Br
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: C1COCCO1
Solvent: O
Product: COCc1cccc2c1nc(-c1nn(COCC[Si](C)(C)C)c3ncc(-c4cnccc4C)cc13)n2COCC[Si](C)(C)C
Temperature: 90 °C

Procedure:
An aqueous 2M sodium carbonate solution (0.11 mL, 0.23 mmol) was added to a solution of 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 12c (60 mg, 0.09 mmol), 3-bromo-4-methyl-pyridine Compound 13a (10 μl, 0.09 mmol) and tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.01 mmol) in dioxane (1 mL) in a reaction tube. The reaction tube was sealed and heated to 90° C. overnight. After cooling to room temperature, the crude mixture was poured into water (30 mL) and was extract with DCM (2×25 mL). The combined organic layer was dried over sodium sulfate and concentrated. Silica gel chromatography (10% to 50% ethyl acetate/hexanes) gave 3-[4-methoxymethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-5-(4-methyl-pyridin-3-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 13b (54 mg, 95%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 9.17 (d, 1H, J=1.5 Hz), 8.92 (d, 1H, J=1.5 Hz), 8.71 (m, 2H), 7.87 (m, 2H), 7.61 (m, 2H), 6.50 (s, 2H), 6.23 (s, 2H), 5.17 (s, 2H), 4.04 (t, 2H, J=6 Hz), 3.86 (t, 2H, J=6 Hz), 3.66 (s, 3H), 2.62 (s, 3H), 1.18 (t, 2H, J=6 Hz); 1.05 (t, 2H, J=6 Hz), 0.18 (s, 9H), 0.05 (s, 9H); MS (ESI) m/z: 631 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=[O:36].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:35](=[O:36])[CH2:34][N:18]2[CH2:19][CH2:20][C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:17]2=[O:16])[CH2:9][CH2:10]1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: Clc1cccc(Cl)c1CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C

Procedure:
To 1-(2,6-dichlorobenzyl)piperazine (0.045 g, 0.183 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.183 mmol) and 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.054 g, 0.183 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.048 mL, 0.274 mmol), and the reaction mixture was stirred at room temperature. After stirring overnight, thin layer chromatography (hexanes/ethyl acetate 1:1) indicated formation of the product. The reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 75% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.10-7.38 (m, 13H), 4.19 (s, 2H), 3.71 (s, 2H), 3.48-3.59 (m, 4H), 3.33-3.40 (m, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.50-2.58 (m, 2H), 2.41-2.49 (m, 2H); MS (DCI+) m/z 522.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH:4]([NH:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)=[O:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][N:10]=[CH:9]2.O1CCCC1.CO.[OH-].[Li+]>O>[CH3:15][C:13]1[CH:14]=[C:6]([CH2:5][CH:4]([NH:16][C:17]([N:19]2[CH2:20][CH2:21][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:23][CH2:24]2)=[O:18])[C:3]([OH:36])=[O:2])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[CH:9]2
Reactant: COC(=O)C(Cc1cc(C)c2[nH]ncc2c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Reaction time: 0.02 h
Yield: 75 %

Procedure:
A suspension of (±)-3-(7-methyl-1H-indazol-5-yl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionic acid methyl ester (240.0 mg, 0.489 mmol) in 1:1 tetrahydrofuran/methanol (20 mL) at room temperature was treated with a solution of lithium hydroxide (140.5 mg, 7 equiv) in water (10 mL). Within 1 min, the mixture became homogeneous and it was left to stand at 4° C. overnight. The solvents were evaporated at ca. 30° C. and the pH was adjusted to ca. 1 with 1N hydrochloric acid. The resulting white suspension was stored at 4° C. for several hours and the product was collected by filtration, washed with a small amount of water, and dried in vacuo (169.0 mg, 73%). Solid sodium chloride was added to the filtrate resulting in precipitation of more product (5.2 mg, total yield 75%). 1H-NMR (CD3OD, 500 MHz) δ 1.2-1.7 (4H, m), 2.58 (3H, s), 2.5-3.2 (4H, m), 3.35 (2H, m), 4.15 (2H, m), 4.36 (1H, m), 4.60 (1H, m), 6.79 (1H, d), 6.96 (1H, t), 7.18 (3H, m), 7.49 (1H, s), 8.00 (1H, s). Mass spec.: 477.13 (MH)+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7].CN(C)C=O.Cl[CH2:34][C:35]#[CH:36].[H-].[Na+]>O>[F:1][CH:2]([F:27])[O:3][CH:4]=[C:5]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:36][C:35]#[CH:34])=[C:13]([O:18][CH3:19])[CH:12]=1)=[O:7]
Reactant: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)ccc1O
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1ccc(CCNC(=O)C(=COC(F)F)c2ccc(C)cc2)cc1OC
Yield: 43.8 %

Procedure:
Five hundred milligrams (500 mg) of 3-difluoromethoxy-N-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2-(4-methylphenyl)acrylamide (1.33 mmol), 5 ml of anhydrous N,N-dimethylformamide, 196 mg (2.65 mmol) of 3-chloropropyne and 60 mg (1.46 mmol) of 60% sodium hydride were stirred at room temperature for 2 hours. Water was added to to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 242 mg of 3-difluoromethoxy-N-[2-{3-methoxy-4-(2-propynyloxy)phenyl}ethyl]-2-(4-methylphenyl)acrylamide (the present compound 1353).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=O)[N:19]=[N:18]2)[CH:14]=[CH:15][CH:16]=1.FC1C=C(C=CC=1)N.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:55][CH2:56][C:57]([N:59]1[CH2:64][CH2:63][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:74])[F:73])[CH:67]=2)[CH2:61][CH2:60]1)=[O:58]>CN(C=O)C.O>[O:58]=[C:57]([N:59]1[CH2:60][CH2:61][CH:62]([O:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([C:72]([F:75])([F:73])[F:74])[CH:67]=2)[CH2:63][CH2:64]1)[CH2:56][NH:55][C:22]([C:20]1[N:19]=[N:18][N:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([F:10])[CH:12]=2)[CH:21]=1)=[O:24]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cn(-c2cccc(F)c2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccc(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(-c2cccc(F)c2)nn1
Reaction time: 0.03 h
Yield: 77.46 %

Procedure:
DIPEA (168 mg, 1.3 mmol) was added to a stirred solution of 1-(3-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid (prepared by the method used for the synthesis of Intermediate 64, starting from 3-fluoroaniline) (60 mg, 0.29 mmol) in DMF (5 mL) followed by, HOBt (43 mg, 0.32 mmol) and EDCI (139 mg, 0.72 mmol). After 2 minutes of stirring, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride salt (prepared according to Step 1 and 5 of the General Scheme) (108 mg, 0.32 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the precipitate formed was collected to afford 110 mg (77.46% Yield) of 1-(3-fluoro-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 492.16, 90.71%. 1H NMR (300 MHz, DMSO-d6): δ 9.4 (s, 1H), 8.56 (t, 1H), 8.0 (q, 2H), 7.74 (q, 1H), 7.58 (t, 1H), 7.46-7.24 (m, 4H), 4.9 (m, 1H), 4.3 (d, 2H), 4.0 (bs, 1H), 3.8 (bs, 1H), 3.5 (bs, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39])(=O)=O.[CH3:42][NH:43][CH2:44][C:45]#[CH:46]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:42][NH:43][CH2:44][C:45]#[C:46][C:7]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:12]2[C:8]=1[CH2:9][NH:10][C:11]2=[O:39]
Reactant: C#CCNC
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)C(F)(F)F)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCNCC
Product: CNCC#Cc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 47.1 %

Procedure:
In a similar manner to Step 2 of Example 161, 4-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.0 mg, 0.135 mmol) was dissolved in diethylamine (4.0 mL), and the solution was treated with bis(triphenylphosphine)dichloropalladium (14.3 mg, 0.203 mmol), copper iodide (11.6 mg, 0.0608 mmol) and N-methylpropargylamine (0.114 mL, 1.35 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=5/1 to 3/1) to obtain 4-(3-methylamino-1-propinyl)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (32.6 mg, yield 47%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]2[CH:12]=[CH:13][CH:14]=[CH:15][C:5]=2[NH:4][C:3]1=O.[H-].[Na+].C(O)(=O)C>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:3]2[NH:4][C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=3[C:7](=[O:11])[C:8]=2[CH2:9][O:10]1
Reactant: CC1(C)OCCC(=O)c2ccccc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)OCc2c1[nH]c1ccccc1c2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound of formula V, 5,6-dihydro-3,3-dimethyl-4,1-benzoxazonine-2,7(1H,3H)-dione (11.66 g, described in Example 1), in tetrahydrofuran (250 ml) is added to a stirred mixture of sodium hydride (4.8 g, 55% dispersion) in tetrahydrofuran (220 ml). The mixture is stirred at room temperature for 30 minutes and acetic acid is added until the mixture is neutral. The precipitate is collected and washed with a small amount of tetrahydrofuran and water. The precipitate is dried and crystallized from methanol to give the title compound, mp 335°-340° C. (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1CN([P+](O[N:34]2N=[N:41][C:36]3C=CC=C[C:35]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.NCC#N.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][CH:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C:14]([NH:41][CH2:36][C:35]#[N:34])=[O:16])=[N:4][CH:3]=1
Reactant: CC(C)C[C@H](Nc1ncc(Br)cn1)C(=O)O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(Nc1ncc(Br)cn1)C(=O)NCC#N
Reaction time: 8 h

Procedure:
To the crude N-(5-bromo-2-pyrimidinyl)leucine (1.3 g, 4.2 mmol), PyBOP (2.62 g, 5.04 mmol), aminoacetonitrile hydrochloride (930 mg, 10.08 mmol) in dry DMF (50 mL) under dry nitrogen was added triethylamine (2.4 mL, 16.8 mmol) dropwise and the reaction was stirred overnight. Aqueous Sat. NaHCO3 was added and the product extracted with Et2O (2×), dried on Na2SO4, concentrated in vacuo, and purified by flash chromatography over silica gel (EtOAc/Hex, 1/1) to afford 2-[(5-bromo-2-pyrimidinyl)amino]-N-(cyanomethyl)-4-methylpentanamide.
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[N:6]=[CH:7][NH:8][C:9](=O)[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18].C(=O)(O)[O-].[Na+]>CN(C=O)C.CC(N(C)C)=O>[C:17]([C:19]1[CH:20]=[C:21]([NH:22][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:23]=[CH:24][CH:25]=1)#[CH:18]
Reactant: C#Cc1cccc(N)c1
Reactant: O=c1[nH]cnc2cnc(F)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cnc(F)cc23)c1
Yield: 98.8 %

Procedure:
A suspension of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (93) (6.64 g, 40.2 mmol), thionyl chloride (150 mL) and a catalytic amount of DMF (5 drops) was stirred under reflux for 30 min to give a homogeneous mixture which was evaporated under reduced pressure at 45° C. (bath temperature) to give a light brown solid. To this solid was added a mixture of 3-ethynylaniline (6.56 g, 44.2 mmol) and dry DMA (40 mL). The reaction mixture was then stirred at room temperature for 40 min before a 5% solution of sodium bicarbonate (500 mL) was added and the resultant mixture was stirred at room temperature for 15 min. The solid was collected by filtration and washed several times with water and then hexane, respectively. The solid was then dried under vacuum over silica gel to give N-(3-ethynylphenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (164) (10.5 g, 99%), mp 225-227° C.; 1H NMR δ [(CD3)2SO] 10.06 (s, 1H), 8.96 (s, 1H), 8.74 (s, 1H), 8.28 (poorly resolved d, J=0.6 Hz, 1H), 8.10 (t, J=1.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.46 (t, J=7.9 Hz, 1H), 7.32-7.27 (m, 1H), 4.22 (s, 1H). Anal. Calcd for C15H9BrFN4: C, 68.18; H, 3.43; N, 21.20%. Found C, 67.80; H, 3.50; N, 20.81%.
Reaction SMILES: CC([O-])(C)C.[K+].CCO[CH2:10][CH3:11].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3=[N:24][C:25]4[CH2:26][CH2:27][CH2:28]C(=O)[C:30]=4[CH:31]=[C:22]3[CH:21]=[N:20]2)=[CH:15][CH:14]=1.O1CCOCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCCCCCC.CCOC(C)=O>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[C:23]3=[N:24][C:25]4[CH2:26][CH2:27][CH2:28][C:10](=[CH2:11])[C:30]=4[CH:31]=[C:22]3[CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Reactant: CCOCC
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A flask was charged with potassium 2-methylpropan-2-olate (45.4 g, 404 mmol), Et2O (1000 mL) and methyltriphenylphosphonium bromide (141 g, 395 mmol). The mixture was stirred for about 2 h at rt then 1-(4-fluorophenyl)-7,8-dihydro-1H-pyrazolo[3,4-b]quinolin-5(6H)-one (112, R1=4-Fluorophenyl) (55.5 g, 197 mmol) was added over about 15 min. The mixture was stirred at rt for about 15 h. 1,4-Dioxane (100 mL) was added to the reaction mixture and stirring was continued for about 4 h. Solids were removed by filtration and the pad was washed with 600 mL Et2O. The filtrate was concentrated under reduced pressure then EtOAc (250 mL) and heptane (750 mL) was added. The solids were removed by filtration then the pad was washed with 3 portions of 3:1 heptane/EtOAc (100 mL). The filtrate was concentrated under reduced pressure to yield a slurry. A mixture of 3:1 heptane/EtOAc (100 mL) was added to the material then the slurry was poured onto a pad of 600 grams of silica pre-gelled with 3:1 Heptane/EtOAc. The pad was washed with 3:1 Heptane/EtOAc (6 L) until TLC (3:1 Heptane/EtOAc, visualized by UV) showed essentially no more desired product in the filtrate. The filtrate was concentrated under reduced pressure to yield 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline (113, R1=4-Fluorophenyl) (44.0 g, 80%): LC/MS, method 3, Rt=2.87 min, MS m/z 280 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 8.37 (s, 1H), 8.34-8.27 (m, 2H), 7.45-7.38 (m, 2H), 5.67 (d, J=0.8 Hz, 1H), 5.09 (d, J=0.9 Hz, 1H), 3.10 (t, J=6.4 Hz, 2H), 2.63-2.56 (m, 2H), 1.97-1.87 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:13]([C:16](C2C=CC=CC=2)(C2C=CC=CC=2)[O:17][SiH2]C(C)(C)C)([CH:14]=[CH2:15])[O:12][CH:11]([N:35]2[CH:43]=[N:42][C:41]3[C:36]2=[N:37][CH:38]=[N:39][C:40]=3[NH2:44])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[NH2:44][C:40]1[N:39]=[CH:38][N:37]=[C:36]2[C:41]=1[N:42]=[CH:43][N:35]2[CH:11]1[O:12][C:13]([CH2:16][OH:17])([CH:14]=[CH2:15])[CH:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10]1
Reactant: C=CC1(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)OC(n2cnc3c(N)ncnc32)CC1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC1(CO)OC(n2cnc3c(N)ncnc32)CC1OCc1ccccc1
Yield: 68 %

Procedure:
9-[4-Benzyloxy-5-(tert-butyl-diphenyl-silanyloxymethyl)-5-vinyl-tetrahydro-furan-2-yl]-9H-purin-6-ylamine, THF, and TBAF were added to a flask and allowed to stir. The reaction was extracted, and the solvent removed to provide the titled compound in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:33])=[O:32])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:23])[CH:11]=2)[CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(N)cc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of [4-(4-amino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (100 mg, 0.29 mmol) and benzenesulfonyl chloride (105 mg, 0.59 mmol) in THF (5.5 mL) was added diisopropylethylamine (0.15 ml, 0.85 mmol) at 0° C. under nitrogen. After addition, the reaction mixture was warmed to room temperature and stirred for 3 hours. The solvent was removed under vacuum and the residue was diluted with water (10 mL). Then, the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (30 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum gave the crude residue which was purified using an ISCO (40 g) column, eluting with 5-25% ethyl acetate in hexanes, to afford [4-(4-benzenesulfonylamino-phenyl)-6-chloro-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (108 mg, 76%) as a white foam. HRMS calcd. for C26H21ClNO4S [(M−H)−] 478.0885, obsd. 478.0884.