Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[O:11][CH2:12][C:13](=[O:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2ccccc2OC)OCC1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2OC)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of ethyl 2-[(2-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.30 g, y. 74%).
Reaction SMILES: [NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@@H:10]([C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:5][CH:4]=1.[CH:47]([O:50][C:51](=[O:55])[O:52][CH2:53]Cl)([CH3:49])[CH3:48].C(=O)([O-])[O-].[Rb+].[Rb+].CC(N(C)C)=O>O.C(OCC)(=O)C>[NH2:1][C:2](=[N:39][C:40]([O:42][CH2:43][C:44]([CH3:46])=[CH2:45])=[O:41])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]([C:27]2[N:31]=[C:30]([O:32][CH2:53][O:52][C:51]([O:50][CH:47]([CH3:49])[CH3:48])=[O:55])[N:29]([C:33]3[N:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:28]=2)[C:11]2[C:12]([F:26])=[C:13]([CH:21]=[C:22]([O:24][CH3:25])[CH:23]=2)[O:14][CH2:15][CH2:16][O:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:8]=1
Reactant: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Reactant: CC(C)OC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [Rb+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nc(OCOC(=O)OC(C)C)n(-c3ncccn3)n2)c2cc(OC)cc(OCCOC(C)=O)c2F)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a mixture of acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester (Example 45, 250 mg), carbonic acid chloromethyl ester isopropyl ester [CAS No. 35180-01-9] (121 mg), rubidium carbonate (73.2 mg) and DMA (10 mL) was stirred at 85° C. for 90 minutes. After cooling the mixture to room temperature, ethyl acetate and water were added thereto. The organic layer was collected, the aqueous layer was reextracted with ethyl acetate, and all the organic layers were combined. The organic layer was sequentially washed with water and with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate-methanol) to obtain the acetic acid 2-{3-[(R)-(4-{amino[2-methylallyloxycarbonylimino]methyl}phenylamino)-(5-isopropoxycarbonyloxymethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxyl}ethyl ester as a solid.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:11]=2[CH:10]=[C:9]([C:19]([OH:21])=[O:20])[CH:8]=1.[CH3:22]O>>[CH3:22][O:20][C:19]([C:9]1[CH:8]=[C:7]([CH3:6])[C:12]2[N:13]=[C:14]([CH2:16][CH2:17][CH3:18])[NH:15][C:11]=2[CH:10]=1)=[O:21]
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2[nH]1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCc1nc2c(C)cc(C(=O)OC)cc2[nH]1
Yield: 92.1 %

Procedure:
Sulfuric acid (12 mL, 0.22 mol) was added to 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30 g, 136 mmol) dissolved in MeOH (670 mL, 16 mol). The mixture was refluxed for 36 hours and concentrated in vacuo. The recovered material was dissolved in 500 ml, EtOAc and washed with a saturated NaHCO3 solution. The organic layer was dried over MgSO4 and concentrated to provide Intermediate (7a) as a brown solid (29.1 g). MS m/z: [M+H+] calcd for C13H16N2O2, 233.1. found 233.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][C:18]=1[N+:19]([O-])=O)[NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:9])([O-])=O.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([C:28]2[NH:19][C:18]3[CH:17]=[CH:16][C:6]([NH:7][C:8](=[O:9])[C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccncc1
Product: CN(C)c1ccc(-c2nc3cc(NC(=O)c4ccncc4)ccc3[nH]2)cc1

Procedure:
Compound 207 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(pyridin-4-oyl)aniline and 4-dimethylaminobenzaldehyde. 1H NMR (500 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.83 (d, J=6 Hz, 2H), 8.40 (s, 1H), 8.10 (d, J=9 Hz, 2H), 7.98 (d, J=6 Hz, 2H), 7.81 (dd, J=2, 9 Hz, 1H), 7.75 (d, J=9 Hz, 1H), 6.97 (d, J=9 Hz, 2H), 3.09 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36]O)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([CH2:36][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A solution of 3-trifluoromethylbenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (332 mg, 1.0 mmol), as prepared in the preceding step, N-(tert-butoxycarbonyl)-4-piperidinemethanol (215 mg, 1.0 mmol), as prepared in step f of Example 1, and triphenylphosphine (263 mg, 1.0 mmol) in tetrahydrofuran (10 mL at 0° C. was treated with diethyl azodicarboxylate (175 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added. The reaction mixture was extracted into ethyl acetate (3×50 mL), washed sequentially with saturated NaHCO3 (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:2 ethyl acetate:hexane) to give the title compound as a colorless liquid (375 mg, 70%). 1H-NMR (300 MHz, CDCl3) δ 1.26 (m, 2H), 1.47 (s, 9H), 1.77 (m, 2H), 1.89 (m, 1H), 2.24 (s, 3H), 2.73 (t, 2H), 3.67 (d, 2H), 4.13 (m, 2H), 6.34 (d, 1H), 6.36 (s, 1H), 6.62 (s, 1H), 7.72 (t, 1H), 7.94 (d, 1H), 8.09 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:27][CH2:28][CH2:29][OH:30])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:19])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccccc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(SCCCO)nc2c1nc(O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
Crude 6-amino-9-benzyl-8-hydroxy-2-mercaptopurine (200 mg, 0.73 mmol) was suspended in dimethylformamide (100 ml). To the suspension were added potassium carbonate (150 mg, 1.1 mmol) and 3-bromo-1-propanol (0.1 ml, 1 mmol) in order. The mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1% methanol/chloroform) to give the subject compound (149 mg, yield 62%).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl-].[NH4+:5].N.[CH2:7]([O:14][CH2:15][CH2:16][C:17](=O)[CH3:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.C(O)C.C(Cl)Cl>[NH2:5][C:17]([CH3:18])([CH2:16][CH2:15][O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]#[N:2]
Reactant: CC(=O)CCOCc1ccccc1
Reactant: [NH4+]
Reactant: [C-]#N
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CC(N)(C#N)CCOCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5.31 g (108.3 mmol) of sodium cyanide in 10 ml of water were admixed with 6.37 g (119.1 mmol) of ammonium chloride (dissolved in 15 ml of warm water) and 9 ml (216.6 mmol) of conc. ammonia in water. Subsequently, 19.3 g (108.3 mmol) of 4-(benzyloxy)butan-2-one, dissolved in 3 ml of ethanol, were added. The mixture was stirred at RT for 15 min and at 60° C. for 2 h. Another 4 g (81.6 mmol) of sodium cyanide, 4.8 g (89.7 mmol) of ammonium chloride and 6.5 ml (156.4 mmol) of conc. ammonia in water were added and the mixture was stirred at 60° C. for a further 2 h. Then the reaction solution was cooled and 300 ml each of methylene chloride and water were added thereto. After phase separation, the aqueous phase was extracted with 300 ml of methylene chloride. The combined organic phases were dried and concentrated. The crude product was purified using silica gel (cyclohexane/ethyl acetate gradient 6/4-1/1). 19.9 g of the target compound (77% purity, 69% of theory) were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:30])[CH3:9])=[CH:4][CH:3]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 6-methoxypyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.316 min, m/z=524.1; 1H NMR (CDCl3) 1.28-1.38 (m, 1H), 1.48 (d, 3H), 1.67 (m, 1H), 1.81-1.98 (m, 2H), 2.13 (m, 1H), 2.24 (m, 2H), 2.83 (m, 4H), 3.01 (m, 2H), 3.91 (s, 3H), 4.15 (m, 1H), 5.62 (m, 1H), 6.73 (d, 1H), 6.91 (d, 2H), 7.18-7.32 (m, 7H), 7.62 (dd, 1H), 8.21 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:18][CH:19]([CH2:23][CH2:24][Cl:25])[C:20](Cl)=[O:21]>C(OCC)(=O)C>[Cl:25][CH2:24][CH2:23][CH:19]([CH3:18])[C:20]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:9]=1)=[O:21]
Reactant: CC(CCCl)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)on1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(CCCl)C(=O)Nc1cc(C(C)(C)C)no1

Procedure:
To a stirred solution of 7 g of 3-(1,1-dimethylethyl)-5-aminoisoxazole dissolved in 50 ml ethyl acetate was added 5.05 g of triethylamine at room temperature. As the solution continued to stir, 8 g of 2-methyl-4-chlorobutyric acid chloride was added to the reaction mixture over a 15 minute period. The reaction was allowed to stir for about 3 days and the precipitated triethylamine hydrochloride salt was collected by filtration and washed with ethyl acetate. The solvent was evaporated from the filtrate under reduced pressure and the residue was recrystallized from diethyl ether to afford 4-chloro-N-[3-(1,1-dimethylethyl)-5-isoxazolyl]-2-methylbutanamide as a solid. mp 135°-137° C.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:28](=[O:29])[N:7]2[CH:8]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:30])[C:5]1=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=4.[CH:32]1([CH2:35][NH2:36])[CH2:34][CH2:33]1>>[CH:32]1([CH2:35][NH:36][CH2:2][CH2:3][N:4]2[C:28](=[O:29])[N:7]3[CH:8]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=4)[C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH2:18][C:6]3([CH3:30])[C:5]2=[O:31])=[CH:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=5)[CH2:34][CH2:33]1
Reactant: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: NCC1CC1
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNCC2CC2)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-10-(3-hydroxy-phenyl)-6-methoxy-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 24) and C-cyclopropyl methyl amine as starting materials. MS: m/z (MH+)=475.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:19])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[O:29])[CH:26]=1>C(O)(C)C.C(OCC)C>[ClH:19].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:21][C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=4)=[O:29])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cnn(CC(=O)Nc2cccc(F)c2)c1
Reactant: Fc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Solvent: CC(C)O
Solvent: CCOCC
Product: Cl
Product: O=C(Cn1cc(Nc2ncnc3cc(OCc4ccccc4)c(F)cc23)cn1)Nc1cccc(F)c1
Temperature: 80 °C
Yield: 95.4 %

Procedure:
A mixture of 7-(benzyloxy)-4chloro-6-fluoroquinazoline (0.288 g, 1.0 mmol) and 2-(4-amino-1H-pyrazol-1-yl)-N-(3-fluorophenyl)acetamide (0.234 g, 1.0 mmol) in isopropanol (5 ml) was heated at 80° C. for 10 minutes. The mixture was allowed to cool to room temperature and then diluted with diethyl ether. The resultant solid was filtered to give 2-(4-{[7-(benzyloxy)-6-fluoroquinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(3-fluorophenyl)acetamide hydrochloride (0.499 g, 95% yield) as a yellow solid:
Reaction SMILES: P([O-])(OCC)OCC.[H-].[Na+].Cl[CH2:12][C:13]([OH:15])=[O:14].[H][H].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>COCCOC>[C:18]1(=[CH:12][C:13]([OH:15])=[O:14])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(O)CCl
Reactant: [H][H]
Reactant: O=C1CCCCC1
Agent: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(O)C=C1CCCCC1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of 4.0 ml (0.031 mole) of diethyl phosphite and 4.46 g (0.093 mole) of 50% sodium hydride in mineral oil in 100 ml of 1,2-dimethoxyethane under nitrogen was treated with a solution of 2.93 g (0.031 mole) of chloroacetic acid in 30 ml of 1,2-dimethoxyethane, and the mixture was stirred until hydrogen gas evolution ceased. Then 3.20 ml (0.031 mole) of cyclohexanone was added and the mixture was stirred for 1 h, after which it was quenched by the addition of 5 ml of ethanol and then poured into 500 ml of water. The strongly basic solution was washed with ether to remove mineral oil (ether extract discarded), then acidified to pH 4 with conc hydrochloric acid and extracted with ether. The ether extract was dried (over MgSO4) and evaporated in vacuo to yield 2.35 g (54%) of cyclohexylideneacetic acid which was recrystallized from methanol/water; mp 90°-91.5° (literature mp 90°-92°, Beesley, Thorpe, and Ingold, J. Chem. Soc., 107, 1099 (1915)); Ir (CHCl3) 3600-2400 (--OH), 1700 (C=O), and 1650 (C=C) cm-1 ; 1H NMR (CDCl3) δ 1.60 (6, s, CH2CH2CH2CH 2 CH2C=), ##STR8## 5.50 (1, s, =CHCO2H), and 11.40 (1, s, --CO2H); Anal Calcd for C8H12O2 : C, 68.55; H, 8.63; Found: C, 68.45; H, 8.61.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(F)c1
Temperature: -30 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
To a suspension of 3-fluoro-4-hydroxy-5-methoxy-benzaldehyde (1.35 g, 7.94 mmol) in dichloromethane (100 mL) was added BBr3 (1.5 mL, 16 mmol) dropwise at −78° C. under N2 After addition, the mixture was warmed to −30° C. and it was stirred at this temperature for 5 h. The reaction mixture was poured into ice water. The precipitated solid was collected by filtration and washed with dichloromethane to afford 3-fluoro-4,5-dihydroxy-benzaldehyde (1.1 g, 89%), which was directly used in the next step.
Reaction SMILES: [NH2:1][CH:2]([OH:29])[C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17](Cl)[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][C:31]1[O:32][C:33]2[CH:48]=[CH:47][CH:46]=[CH:45][C:34]=2[C:35]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][C:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[S:14][C:15]3[N:16]=[C:17]([C:35]4[C:34]5[CH:45]=[CH:46][CH:47]=[CH:48][C:33]=5[O:32][C:31]=4[CH3:30])[N:18]=[C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:20]=3[N:21]=2)[CH2:8][CH2:7]1)([CH3:5])[C:2]([NH2:1])=[O:29]
Reactant: Cc1oc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C(N)O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C(N)=O)CC3)sc2n1
Temperature: 140 °C
Yield: 60.9 %

Procedure:
A mixture of 1-amino-2-[4-(5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl)piperazin-1-yl]-2-methylpropan-1-ol (100 mg, 0.23 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzofuran (88 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium (26 mg, 0.02 mmol) and Cs2CO3 (148 mg, 0.45 mmol) in dioxane (6 mL) and H2O (3 mL) was purged with argon then heated at 140° C. for 30 min in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM/MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, EtOAc:cyclohexane, 50-100%) to afford 211 as a cream solid (75 mg, 61%). LCMS (Method G): RT 10.35 min, [M+H]+ 536.4. 1H NMR (CDCl3, 400 MHz): δ 8.40-8.37 (m, 1 H); 7.46-7.42 (m, 1 H); 7.32-7.23 (m, 2 H); 7.10 (d, J=5.3 Hz, 1 H); 5.22 (d, J=5.3 Hz, 1 H); 4.40 (m, 4 H); 3.93-3.87 (m, 6 H); 2.92 (s, 3 H); 2.69 (m, 4 H); 2.62 (m, 4 H) and 1.26 (s, 6 H)
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@H:23]([C:34](O)=[O:35])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C[CH2:38][N:39]=[C:40]=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CNC>C(Cl)Cl.CCOC(C)=O>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C@H:23]([C:34](=[O:35])[N:39]([CH3:40])[CH3:38])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)C[C@H]1C(=O)O
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.9 %

Procedure:
(2S,4S)-4-(2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yloxy)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (Example 53; 0.100 g, 0.204 mmol), EDCI (0.0548 g, 0.286 mmol) and HOBT (0.0373 g, 0.276 mmol) were mixed in CH2Cl2 (2.5 mL) and the mixture was cooled to 0° C. Triethylamine (0.0712 mL, 0.511 mmol) was added and the mixture stirred for 15 minutes. Dimethylamine (0.153 mL, 0.306 mmol, 2.0M in THF) was added, and the mixture was warmed to ambient temperature and stirred for 5.0 hours. The mixture was diluted with EtOAc (20 mL) and washed with 1N KHSO4 (2×10 mL), followed by saturated aqueous NaHCO3, and brine. The organics were dried over MgSO4, filtered and concentrated, then purified by column chromatography (1 to 5% MeOH/CH2Cl2) to afford 0.080 g (75%) of the desired product.
Reaction SMILES: [C:1]12([OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1.[CH3:19][O:20][C:21](Cl)=[O:22]>CN(C=O)C>[CH3:19][O:20][C:21]([O:12][C:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][C:3]([OH:11])([CH2:4]3)[CH2:2]1)[CH2:8]2)=[O:22]
Reactant: OC12CC3CC(C1)CC(O)(C3)C2
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Temperature: 25 °C
Yield: 85 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-adamantanediol and 12 mmole of pyridine was dissolved in 10 ml of DMF. To the mixture, 11 mmole of methoxycarbonyl chloride was added dropwise with stirring at room temperature. Cooling of the resultant mixture with ice was started at about the time exothermic reaction began. When the exothermic reaction is completed, the mixture was heated to 60° C. and then stirred for one hour. As a result, the conversion of 1,3-adamantanediol was 99% and 1-methoxycarbonyloxy-3-adamantanol (yield 85%) was formed.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]OC(C1CCCC1)=O>CCOCC>[CH3:16][O:14][C:13]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:15]
Reactant: COC(=O)C1CCCC1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Solvent: CCOCC
Product: COC(=O)C1(c2ccccc2)CCCCC1

Procedure:
This compound was prepared (1.91 g, 8.76 mmol, 89%) from the product of Step A (2.00 g, 9.8 mmol) following the procedure for synthesis of methyl-1-cyclopentanecarboxylate as set forth in Step A, Example 1. The product of this step was homogeneous by TLC (ether:C2Cl2, 2:1) and used in the next step without further purification. CIMS 219 m/z (M+1).
Reaction SMILES: [CH2:1]([NH:3][C@H:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>>[CH2:1]([N:3]([C@H:4]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[C:18](=[O:20])[CH3:19])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCN[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: c1ccncc1
Product: CCN(C(C)=O)[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Yield: 26.4 %

Procedure:
A solution of product from Example 122A (0.267 g, 1.135 mmol) in acetic anhydride (1.073 mL, 11.35 mmol) and pyridine (0.918 mL, 11.35 mmol) was stirred at 98° C. for 2 hrs. The mixture was partitioned between CH2Cl2 and 1N HCl solution, and the organic extract was separated, dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 1-35% ethyl acetate in hexane to give the title compound (0.083 g, 27%).