Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:28]([OH:30])=O)[O:3]1.[NH4+].[OH-].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:37]=1.O>C(O)(C)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24]([F:25])([F:26])[F:27])[NH:13][C:14]3=[O:17])=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:28]([NH2:37])=[O:30])[O:3]1
Reactant: O=C(O)C1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: NC(=O)C1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 78.3 %

Procedure:
The 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-carboxylic acid (12.5 mg, 0.03 mmol) obtained in Example 2-4 and a 25% ammonia aqueous solution (3.06 μl, 0.045 mmol) were dissolved in isopropanol (0.3 ml). Thereafter, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (13.3 mg, 0.045 mmol) was added to the solution, and the obtained mixture was then stirred at a room temperature for 3.5 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=30:1), so as to obtain 2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-carboxylic amide (9.8 mg, 78%) in the form of a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:45]2[CH:44]=[CH:43][C:42]([N:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:41][CH2:40]3)=[CH:47][CH:46]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) in dioxane (2 ml) was added (4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)boronic acid (73 mg, 0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) and 159 μl of a 2M aqueous solution of cesium carbonate. The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 75 mg (74% yield) as a white solid. Purity 99%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([N:12]=[N+]=[N-])[CH3:11])[CH:5]=1)([O-:3])=[O:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH:10]([NH2:12])[CH3:11])([O-:3])=[O:2]
Reactant: CC(N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(N)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.9 %

Procedure:
1-Nitro-3-(1-azidoethyl)benzene (1.3 g, 6.76 mmol) was dissolved in tetrahydrofuran and triphenylphosphine (1.9 g, 7.4 mmol) was added. The resulting solution was stirred at ambient temperature for 18 hours. 1M aqueous sodium hydroxide (1 ml) was then added and the stirring continued for 48 hours. The reaction was diluted with ethyl acetate, washed with brine several times, dried over magnesium sulfate, filtered, and evaporated. The residue was chromatographed (silica gel, 2:1 hexane:ethyl acetate) to provide 1.1 g of the title compound. (99%). 1H NMR(CDCl3)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[NH:21][C:20]1=[O:35]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)[NH:21][C:20]2=[O:35])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: NC1C(=O)NC(c2ccncc2)c2ccccc21
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NC(c2ccncc2)c2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-1-(pyrid-4-yl)-1,2,3,4-tetrahydroisoquinoline-3-one (Example 5-B), the title compound was prepared as a solid having a melting point of 100° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][CH:44]([CH2:43][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:14]=[C:15]5[C:19](=[CH:20][CH:21]=4)[NH:18][C:17]([CH3:22])=[CH:16]5)=[N:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCC5CCN(C(=O)OC(C)(C)C)CC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (423 mg, 1.45 mol), (prepared as described for the starting material in Example 82), triphenylphosphine (685 mg, 2.61 mmol), 4-hydroxymethyl-1-tert-butoxycarbonylpiperidine (500 mg, 2.32 mmol), (prepared as described for the starting material in Example 10), and diisopropyl azodicarboxylate (528 mg, 2.61 mmol) in methylene chloride (18 ml) was stirred overnight at ambient temperature. The mixture was then poured onto a column of silica and eluted with ethyl acetate. After evaporation of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 7-(1-tert-butoxycarbonylpiperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (478 mg, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Br[CH2:25][C:26]([NH2:28])=[O:27].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[NH2:28][C:26](=[O:27])[CH2:25][N:19]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:3]=1[O:2][CH3:1])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: NC(=O)CBr
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N(CC(N)=O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Benzyl 4-methoxy-3-(methylsulfonamido)benzoate (200 mg, 0.596 mmol) was dissolved in DMF (2 ml). 2-bromoacetamide (247 mg, 1.789 mmol) and K2CO3 (165 mg, 1.193 mmol) were added, and the reaction was stirred at RT overnight. The reaction mixture was diluted with water and filtered. The precipitate was washed with water and dried in the vacuum oven to give benzyl 3-(N-(2-amino-2-oxoethyl)methylsulfonamido)-4-methoxybenzoate (220 mg, 94% yield).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(C(C)C)CC)(C)C.[C:33]([O:37][C:38]([NH:40][CH2:41][CH2:42][N:43]([CH2:60][CH2:61][NH:62][C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:44](=[O:59])[CH2:45][CH2:46][C@H:47]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:48](O)=[O:49])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:55]([O:54][C:52]([NH:51][C@H:47]([C:48](=[O:49])[NH:1][C@H:2]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4])[CH2:46][CH2:45][C:44](=[O:59])[N:43]([CH2:42][CH2:41][NH:40][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:60][CH2:61][NH:62][C:63](=[O:64])[O:65][C:66]([CH3:69])([CH3:67])[CH3:68])=[O:53])([CH3:56])([CH3:57])[CH3:58]
Reactant: N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a suspension of (R)-benzyl 2-amino-3-(4-(trifluoromethyl)phenyl)propanoate (CLXV) (3 g, 8.33 mmol) in DCM (25 mL) was added diisopropylethylamine (3.57 mL, 20.83 mmol). To this solution was added (S)-5-(bis(2-(tert-butoxycarbonylamino)ethyl)amino)-2-(tert-butoxycarbonylamino)-5-oxopentanoic acid (XVI) (4.88 g, 9.16 mmol) and TBTU (2.94 g, 9.16 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was then diluted with DCM (50 mL) and washed with 2 N aqueous HCl, 1 N aqueous NaOH, brine, dried over MgSO4 and concentrated under vacuum to dryness. The residue was purified on a silica gel column using DCM:MeOH (100:1) to yield (12S,15R)-benzyl 12-(tert-butoxycarbonylamino)-8-(2-(tert-butoxycarbonylamino)ethyl)-2,2-dimethyl-4,9,13-trioxo-15-(4-(trifluoromethyl)benzyl)-3-oxa-5,8,14-triazahexadecan-16-oate (6.1 g, 7.28 mmol, 88% yield). 1H NMR (DMSO-d6) δ ppm 1.41 (s, 27H), 1.78-1.96 (m, 2H), 2.17 (brs, 1H), 2.59 (brs, 1H), 3.09-3.15 (m, 1H), 3.16-3.27 (m, 2H), 3.28-3.39 (m, 2H), 3.42-3.52 (m, 1H), 3.62 (brs, 1H), 4.06-4.14 (m, 1H), 4.83-4.91 (m, 1H), 5.08 (d, J=12 Hz, 1H), 5.17 (d, J=12 Hz, 1H), 5.76 (brs, 1H), 7.19 (d, J=8 Hz, 1H), 7.23-7.29 (m, 3H), 7.3-7.39 (m, 3H), 7.44 (d, J=8 Hz, 2H), 7.62 (brs, 1H); 19F NMR (DMSO-d6) δ ppm −61.84 (s, 3F); ESIMS found for C41H58F3N5O10 m/z 838.9 (M+H).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=O)=[CH:30][C:25]=2[O:24][CH2:23]1.O>C1COCC1>[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)=[CH:9][C:10]#[N:11])=[CH:30][C:25]=2[O:24][CH2:23]1
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCO3)cc1
Reactant: CCOP(=O)(CC#N)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (3.0 mL, 18.7 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 18.7 mL, 18.7 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of benzo[1,3]dioxol-5-yl-(4-methoxy-phenyl)-methanone (2.40 g crude, HPLC purity 93%, 9.4 mmol) in THF (15 mL) and refluxed for 3 hours. The reaction mixture was poured into water (80 mL), extracted with CH2Cl2 (2×60 mL). The combined organic phases were washed with brine (60 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-benzo[1,3]dioxol-5-yl-3-(4-methoxy-phenyl)-acrylonitrile as an oil (1.98 g, 76% yield): 1H NMR (DMSO-d6) δ 3.79 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 6.10-6.13 (ms, 6H, 2CH2 and 2CH), 6.70-7.33 (m, 14H, Ar); 13C NMR (DMSO-d6) δ 55.3, 55.4, 93.0, 93.2, 101.6, 101.8, 107.8, 108.2, 108.3, 109.3, 113.9, 114.1, 118.6, 118.7, 123.6, 123.8, 129.3, 129.9, 130.4, 130.8, 130.9, 132.4, 147.3, 147.8, 148.4, 149.3, 160.3, 160.9, 161.0, 161.1. LC/MS showed desired peak at 280 for (M+1)+1 positive ion mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH3:22])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH3:22])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=CNc1ccc(Cl)cc1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Product: CCn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-ethyl-9H-purine.
Reaction SMILES: [CH3:1][CH:2]([NH:8][C:9]1[C:10]([O:17][CH3:18])=[N:11][CH:12]=[N:13][C:14]=1[O:15][CH3:16])[CH:3]=[N:4][O:5][CH2:6][CH3:7].[Cl:19][CH2:20][C:21](Cl)=[O:22].[OH-].[Na+]>C(Cl)Cl>[CH3:1][CH:2]([N:8]([C:9]1[C:14]([O:15][CH3:16])=[N:13][CH:12]=[N:11][C:10]=1[O:17][CH3:18])[C:21](=[O:22])[CH2:20][Cl:19])[CH:3]=[N:4][O:5][CH2:6][CH3:7]
Reactant: O=C(Cl)CCl
Reactant: CCON=CC(C)Nc1c(OC)ncnc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCON=CC(C)N(C(=O)CCl)c1c(OC)ncnc1OC

Procedure:
12.7 g N-[1-methyl-(ethoxyimino)ethyl]-4,6-dimethoxy-pyrimidine-5-amine and 150 ml dry CH2Cl2 are charged in a sulphonation flask. Thereto are added, dropwise, 6.2 g chloracetylchloride in 25 ml dry CH2Cl2. The reaction temperature rises from 22° to 28°. The reaction mixture is heated under reflux for 2 hours and cooled. Then 10% aqueous NaOH is added, the organic phase partitioned off, dried over Na2SO4 and evaporated.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:20][C:18]=4[N:19]=3)=[C:10]([F:31])[CH:9]=2)[CH2:2][CH2:3]1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CCNC2
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc2N2CCOC[C@@H]2C)C1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a stirred solution of (S)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (Example 163) (100 mg, 0.23 mmol) in DMF (2 ml) was added isopropyl isocyanate (35 μl, 0.35 mmol). Reaction mixture was stirred at 20° C. for 2 hours. The crude reaction mixture was then partitioned between water (10 ml) and DCM (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the title compound as a white solid (61 mg, 0.12 mmol, 52%)
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10]
Reactant: C[C@@H](O)C(=O)N1CCOCC1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 0 °C
Yield: 95 %

Procedure:
3,4-Dihydro-2H-pyran (90.5 ml, 1.2 eq) was added dropwise to a mixture of 4-[(R)-2-hydroxypropionyl]morpholine (132 g) and p-toluenesulfonic acid monohydrate (500 mg, 0.003 eq) in dry dichloromethane (500 ml) over a period of 15 min with stirring at 0° C. After being stirred for 30 min at 0° C., the mixture was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, using n-hexane: ethyl acetate (8:1)˜ethyl acetate as an eluent, gave 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (191.6 g, 95% yield) as a pale yellow oil.
Reaction SMILES: O=[C:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2.[NH3:15]>C(O)C.[Pt]=O>[NH2:15][CH:2]1[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][C:3]1([C:12]([OH:14])=[O:13])[CH2:4]3)[CH2:8]2
Reactant: N
Reactant: O=C(O)C12CC3CC(CC(C3)C1=O)C2
Agent: O=[Pt]
Solvent: CCO
Product: NC1C2CC3CC(C2)CC1(C(=O)O)C3

Procedure:
To a solution of 100 ml of 2-hydroxyadamantane dissolved in 250 ml pyridine is added 137.9 g of trifluoroacetic anhydride dropwise, and the reaction mixture is stirred overnight. The reaction mixture is poured over ice then diluted to 1.0 liter with water and extracted three times with 500 ml of diethyl ether. The combined diethyl ether extracts are washed with 5% hydrochloric acid until the wash is acidic then washed once with 5% sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed under reduced pressure to give 2-adamantyl trifluoroacetate as an oil. 50 Grams of 2-adamantyl trifluoroacetate are dissoled in 500 ml of hexane and photolyzed (254 nm) for 4 days. The solvent is removed under reduced pressure and the oily residue is placed in a low pressure column and eluted with dichloroethane. The starting material is the first major component eluted. The second major component is the product, 1-trifluoroacetyl-2-hydroxyadamantane which is crystallized from pentane. To 100 ml of 10% sodium hydroxide solution is added 13.0 g of 1-trifluoroacetyl-2-hydroxyadamantane. The reaction mixture is heated for 15 minutes on a steam bath then diluted to 200 ml with water and washed two times with 150 ml of diethyl ether. The aqueous solution is acidified with concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried in a steam cabinet to give 2-hydroxy-1-adamantanecarboxylic acid. 6.7 Grams of 2-hydroxy-1-adamantanecarboxylic acid are dissolved in 50 ml of acetone and enough 8 N Jones Reagent (chromic anhydride in dilute sulfuric acid) is added to retain a red color for 1 minute. Isopropyl alconhol is added to destroy any excess Jones reagent and the solvent is removed under reduced pressure. The residue is diluted with water, collected by filtration and washed with water then suction dried to give 2-keto-1-adamantanecarboxylic acid. 4.7 Grams of 2-keto-1-adamantanecarboxylic acid is dissolved in 75 ml of ethanol and hydrogenated over platinum oxide in the presence of ammonia gas under 60 psi of pressure at room temperature. The solvent is removed under reduced pressure. 15 ml of water is added to the residue and removed under reduced pressure. This step is repeated with another 15 ml of water then the residue is dried at 100° C. under reduced pressure for 1 hour to give 2-amino-1-adamantanecarboxylic acid which is represented by the following structure ##STR45##
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[O:28][B:29](OC)[O:30]C.Cl>O1CCCC1>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([B:29]([OH:30])[OH:28])=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1
Reactant: COc1ccc(Br)c(-c2ccccc2)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
An excess of 1.6M n-BuLi in hexane (50 mL, 80 mmol) was added to a solution of 2-bromo-5-methoxybiphenyl (19.1 g, 72.7 mmol) in 350 ml dry tetrahydrofuran at −78° C. under N2. The reaction mixture was then maintained at 0° C. for 1 h before cooling to −78° C., trimethylborate (10.4 g, 100 mmol) was added dropwise, the solution was then warmed slowly to room temperature and stirred for 24 h. 2N HCl (150 ml) was added and then the mixture was stirred for a further 1 h. The reaction mixture was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was evaporated in vacuum, and the residue was crystallized from n-hexane to give 9.5 g of the 5-methoxybiphenyl-2-ylboronic acid as a white solid (57%).
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:34]([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][OH:41])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: OCCCCCCO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COc1ccc(C(OCCCCCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
To a solution of 3.38 g (10 mmol) of DMTr-Cl and 3.45 mL (20 mmol) of diisopropylethylamine in 50 mL of dry pyridine was added 5.91 g (50 mmol) of 1,6-hexanediol. After stirring for 4 h, the mixture was quenched with 85 mL of 5% sodium bicarbonate and extracted with 2×100 mL of methylene chloride. The organic phase was washed with 2×100 mL of water and 100 mL of brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3.5×17 cm silica) using methylene chloride. The fractions containing pure product were combined and concentrated to give 1.40 g of 37 as a yellow syrup.