Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH:2]1[CH2:3][CH2:4][C:5]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[O:8]2)[CH2:6][CH2:7]1)(=[O:27])=[O:26]
Reactant: O=C1OC2(CCC(O)CC2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OC(=O)c1ccccc12
Yield: 88 %

Procedure:
At r.t to the mixture of 4′-hydroxy-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (100 mg, 0.46 mmol), triethylamine (192 μL, 1.37 mmol) in methylene chloride (2 mL) was added methanesulfonyl chloride (42.6 μL, 0.55 mmol) with stirring. The mixture was stirred at r.t. overnight, then quenched with water and extracted with ethyl acetate. The extract was washed with water, then brine once; and dried over anhydrous sodium sulfate. After removal of solid, the solution was concentrated to yield 120 mg of 3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl methanesulfonate (yield: 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]([NH:17][NH2:18])=[N:11][CH:10]=1.[CH:19](O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]#[N:16])=[CH:13][C:12]2[N:11]([CH:19]=[N:18][N:17]=2)[CH:10]=1
Reactant: O=CO
Reactant: N#Cc1cc(NN)ncc1-c1ccc(Cl)cc1Cl
Product: N#Cc1cc2nncn2cc1-c1ccc(Cl)cc1Cl
Yield: 86 %

Procedure:
A solution of the crude 5-(2,4-dichloro-phenyl)-2-hydrazino-isonicotinonitrile (520 mg) in formic acid (15 mL) was stirred and refluxed for 1 h. The reaction mixture was concentrated under vacuum, then the remaining residue was diluted in AcOEt (50 mL) and washed with a 2.0 M aqueous NaHCO3 solution (2×25 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, DCM→DCM/MeOH 7:3) to yield the title compound (397 mg, 1.37 mmol, 86% over 2 steps). MS: 289 [M+1]+; HPLC: AtRet=1.79; TLC: RF 0.41 (DCM/MeOH 95:5).
Reaction SMILES: C([O:5][C:6](=[O:79])[C@H:7]([CH2:70][CH2:71][C:72]([O:74]C(C)(C)C)=[O:73])[NH:8][C:9](=[O:69])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:68])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:46][C:47](=[O:67])[NH:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:23][O:24][C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[CH:12][CH:11]=1)(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[CH2:49]([NH:48][C:47]([O:46][CH:22]([CH2:23][O:24][C:25](=[O:45])[NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][S:20][CH2:19][CH2:18][C:17]([NH:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:79])=[O:5])[CH2:70][CH2:71][C:72]([OH:74])=[O:73])=[O:69])=[CH:15][CH:14]=1)=[O:68])=[O:67])[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-[6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoylamino]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 31 (100 mg) in trifiuoroacetic acid (2 ml)-dichloromethane (0.5 ml) was stirred at room temperature for 1 hour. After solvent concentration under reduced pressure, the resulting residue was crystallized from chloroform-methanolwater to yield the title compound (99 mg, yield 100%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:30].CO.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[Cl:30][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH2:22][CH:23]([O:26][CH3:27])[O:24][CH3:25])=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=2)[CH:8]=1
Reactant: COC(COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COC(COc1ccc2c(Cl)cc(-c3nc(C(C)C)cs3)nc2c1Cl)OC
Temperature: 80 °C
Yield: 0.1 %

Procedure:
8-Chloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinolin-4-ol (512 mg, 1.25 mmol) was dissolved in pyridine (10 mL). POCl3 (2.30 mL, 25.0 mmol) was added slowly. The reaction was heated at 80° C. for 4 hours. The reaction was cooled to 0° C. and methanol (5 mL) was added. The reaction was neutralized with a sat NaHCO3(aq) solution. The product was extracted with EtOAc (3×20 mL). The combined organics were dried with Na2SO4, filtered and was concentrated. 4,8-dichloro-7-(2,2-dimethoxy-ethoxy)-2-(4-isopropyl-thiazol-2-yl)-quinoline (0.275 mg, 52%) was isolated by silica gel chromatography as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:21](OC(C)(C)C)(=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(OCC)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH2:9][C:21](=[O:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C(=O)CC(=O)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Under an atmosphere of nitrogen, a solution of 3′-chloroacetophenone (1.015 mL, 7.82 mmol) in anhydrous diethyl ether (50 mL) was allowed to cool to −78° C. for 15 minutes prior to the slow addition of a 1.0 M solution of LHMDS (8.60 mL, 8.60 mmol) in THF. The enolate formation was allowed to stir for 45 minutes at −78° C., after which di-tert-butyl oxalate (1.898 g, 9.38 mmol) was added as a single portion. The pale yellow reaction mixture was allowed to warm to RT and stir for 18 hours. The dark-green solution was then quenched with 50 mL of a 1.0 M aq. solution of HCl. The two layers were separated and the aq. layer was extracted twice more with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and the filtrate concentrated under reduced pressure to afford an orange oil. The crude reaction mixture was purified by silica gel chromatography (40 g REDISEP® column, eluting with a gradient from 100% hexanes to 80:20 hexanes:EtOAc solution). Fractions containing the product were combined and evaporated to afford Intermediate A129A (2.17 g, 98%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 7.94-7.99 (1H, m), 7.86 (1H, dt, J=7.78, 1.38 Hz), 7.58 (1H, ddd, J=7.97, 2.20, 1.13 Hz), 7.43-7.49 (1H, m), 6.94-6.99 (1H, m), 1.58-1.63 (9H, m).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)=[N:6][C:5]=1[NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[CH:26][CH:25]=1)(=[O:3])[NH2:2].[ClH:38]>O1CCOCC1>[N:32]1([C:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:5]3[N:6]=[C:7]([NH:10][C@@H:11]4[CH2:15][CH2:14][NH:13][CH2:12]4)[N:8]=[N:9][C:4]=3[C:1]([NH2:2])=[O:3])=[CH:25][CH:26]=2)=[O:31])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1.[ClH:38]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NC(=O)c1nnc(N[C@@H]2CCNC2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
(R)-tert-butyl 3-(6-carbamoyl-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazin-3-ylamino)pyrrolidine-1-carboxylate (82) (160 mg) was treated with 4N HCl in dioxane (30 mL) at RT for 3 h. The mixture was concentrated in vacuo to yield the title compound (83) as an HCl salt in quantitative yield. MS found C19H24N8O3 as (M+H)+ 413.1, (M−H)− 411.3. UV: λ=264, 283 nm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[NH:11][CH:10]([C:12]([OH:14])=O)[CH2:9][S:8]2)[CH:2]=1.[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.CO.C(OCC)(=O)C.CN(C)C=O>[N:15]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:12]([CH:10]3[CH2:9][S:8][CH:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[NH:11]3)=[O:14])[CH2:25][CH2:24]2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)C1CSC(c2cccnc2)N1
Reactant: c1cn(CCCN2CCNCC2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(C1CSC(c2cccnc2)N1)N1CCN(CCCn2ccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of 2-(3-pyridyl)thiazolidine-4-carboxylic acid 630 mg, 1-[3-(1-imidazolyl)propyl]piperazine 580 mg, 1-hydroxybenztriazole 410 mg and N,N-dimethylformamide 15 ml was added dicyclohexylcarbodiimide 620 mg under ice-cooling and then stirred overnight at room temperature. Ethyl acetate 100 ml was added to the solution, the resultant unsoluble matter filtered off and the solution washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride in succession. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, ethyl acetate added to the residue, the unsoluble matter filtered off and the solution concentrated to dryness under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (eluent: 20% methanol-ethyl acetate) to give an oily product. This was dissolved in ethyl acetate 30 ml, 2N hydrogen chloridedioxane 4 ml added and the precipitated powder filtered off to give 620 mg of 1-[3-(1-imidazolyl)propyl]-4-[2-(3-pyridyl)thiazolidine-4-ylcarbonyl]piperazine. 4 hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19](O)=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:19]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:20])=[CH:11][C:12]3[O:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:22])[CH:3]=1
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Product: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 1 h

Procedure:
To a solution of 5-((4-bromo-2-chlorophenyl)amino)-4-fluorobenzo[d]oxazole-6-carboxylic acid (463 mg, 1.20 mmol) in CH2Cl2 (10 mL) was added HOBt (254 mg, 1.63 mmol) and EDCI (314 mg, 1.63 mmol). The mixture was stirred for 1 h and O-(2-(vinyloxy)ethyl)hydroxylamine (172 mg, 1.62 mmol) was added. After stirring for 4 h at ambient temperature, the reaction was treated with saturated NH4Cl (aq.). The resultant mixture was extracted with CH2Cl2 (30 mL×3). The combined organic extracts were washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product (445 mg) was used directly in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:40])OC3C=CC=CC=3)[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2].[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.CCN(CC)CC>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[O:40])[CH2:26]2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:13][CH:12]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)Oc3ccccc3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: NC(=O)c1ccc(N2CCC[C@@H](NC(=O)N3CCOCC3)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 45.7 %

Procedure:
A solution of (R)-phenyl 1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino)pyridin-2-yl)piperidin-3-ylcarbamate (30 mg, 0.055 mmol), morpholine (7.20 mg, 0.083 mmol), and Et3N (0.012 mL, 0.083 mmol) in CH2Cl2 (2 mL) was heated at 50° C. overnight. The reaction mixture was diluted with CH2Cl2, washed with satd. NaHCO3 and water, and concentrated. The residue was purified by prep-HPLC and the product containing fractions were collected, neutralized with saturated NaHCO3, extracted with CH2Cl2, separated, and concentrated to obtain 13.5 mg of (R)—N-(1-(5-carbamoyl-6-(4-(morpholine-4-carbonyl)phenylamino) pyridin-2-yl)piperidin-3-yl)morpholine-4-carboxamide as a light yellow solid as free base.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:5][S:6][N:7]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[N:5][S:6][N:7]=1)=[O:1]
Reactant: N#Cc1ccc(-c2nsnc2CO)cc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: N#Cc1ccc(-c2nsnc2C=O)cc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 49.5 %

Procedure:
A mixture of 4-[4-(hydroxymethyl)-1,2,5-thiadiazol-3-yl]benzonitrile (230 mg, 1.06 mmol, 1.00 equiv) and MnO2 (922 mg, 10.61 mmol, 10.02 equiv) in dichloromethane (20 mL) was stirred at 40° C. for 1.5 h. The reaction was cooled to room temperature and the solids were removed by filtration. The filtrate was concentrated under vacuum and the residue was purified on a silica gel column eluted with 2.5-5% of ethyl acetate in petroleum ether to give 113 mg (50%) of 4-(4-formyl-1,2,5-thiadiazol-3-yl)benzonitrile as a white solid. 1H-NMR (300 MHz, CDCl3): δ 10.34 (s, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H) ppm.
Reaction SMILES: [CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=O)=[CH:13][CH:12]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:32][CH2:33][C:34]2[CH:35]=[C:36]([NH2:39])[NH:37][N:38]=2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1.C[Al](C)C.C(Cl)Cl.CCOCC>C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:10][CH2:9][CH2:8][N:7]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:39][C:36]4[NH:37][N:38]=[C:34]([CH2:33][CH2:32][C:26]5[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=5)[CH:35]=4)=[O:17])=[CH:20][CH:21]=3)[CH2:6][CH2:5]2)[CH2:2][CH2:3]1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: CCOC(=O)c1ccc(N2CCCN(C3CC3)CC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCCN(C5CC5)CC4)cc3)[nH]n2)cc(OC)c1
Yield: 33.7 %

Procedure:
4-(4-cyclopropyl-1,4-diazepan-1-yl)-N-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide was prepared using the same procedure as for Example 159, but starting from ethyl 4-(4-cyclopropyl-1,4-diazepan-1-yl)benzoate (0.288 g, 1 mmol, 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1 mmol) and a 2M solution of trimethylaluminium (1.250 mL, 2.50 mmol) in toluene. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford a gum which solidified on trituration with DCM/Ether to afford the title compound (0.165 g, 33.7%).
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(CC)CC>C1COCC1>[CH:19]1([NH:24][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C(#Cc1cnc(NC2CCCC2)nc1)c1ccccc1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
2-Methanesulfonyl-5-phenylethynyl-pyrimidine (100 mg, 3.11 mmol), cyclopentylamine (80 μl, 6.22 mmol) and Et3N (110 μl, 6.22 mmol) were suspended in 1 ml THF and stirred for 1 hour at 65° C. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography by directly loading the crude material onto a silica gel column and eluting with (heptane:ethyl acetate 100:0→0:100). The desired compound was obtained as a white solid (85 mg, 83%), MS: m/e=264.2 (M+H+).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:22](=[O:23])[N:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.N1C=CC=NC=1>C(O)C.[Pd]>[CH:24]1([N:21]2[C:22](=[O:23])[C:17]3[CH:16]=[N:15][C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:19][C:18]=3[CH2:20]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C1c2cnc(N3CCN(Cc4ccccc4)CC3)nc2CN1C1CCCCC1
Agent: [Pd]
Solvent: c1cncnc1
Solvent: CCO
Product: O=C1c2cnc(N3CCNCC3)nc2CN1C1CCCCC1
Yield: 99.4 %

Procedure:
Dissolved in 30 ml of ethanol was 1.2 g (3.07 mmol, Referential Example 79) of 2-(4-benzylpiperazino)-6-cyclohexyl-5-oxo-5,6-dihydro(7H)pyrrolo-[3,4-d]pyrimidine, followed by an addition of 0.16 g of 10% Pd-C. The pyrimidine derivative was hydrogenated at 60° C. After completion of the reaction, Pd-C was filtered off and ethanol was distilled off to obtain 0.92 g of the above-identified compound as crystals (yield: about 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10]C)[C:3]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[N:14]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([OH:10])[C:3]=1[N:12]([CH2:21][CH3:22])[C:13]1[N:14]=[C:15]([CH3:20])[CH:16]=[C:17]([CH3:19])[N:18]=1
Reactant: CCN(c1nc(C)cc(C)n1)c1c(Br)cc(OC)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(c1nc(C)cc(C)n1)c1c(O)cc(OC)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
N-(2-Bromo-4,6-dimethoxyphenyl)-N-ethyl-4,6-dimethyl-2-pyrimidinamine (214 mg, 0.58 mmol) in 15 mL dichloromethane under nitrogen was cooled in a dry ice/acetone bath, and boron tribromide (1.0 M in dichloromethane, 0.58 mL) was slowly added. The reaction was allowed gradually to warm to room temperature whereupon it was stirred overnight. After quenching with water, the aqueous portion was basified with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried with magnesium sulfate and concentrated in vacuo to give a tan solid. The solid was recrystallized form ethyl acetate/hexanes to yield 58 mg product; mp 157-160° C. Anal. Calcd. %C: 51.15: %H: 5.15: %N: 11.93: %Br: 22.69. Found %C: 51.02: %H: 5.10: %N: 11.83: %Br: 22.52.
Reaction SMILES: C[CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH2:4][N:3]1[C:9]#[N:10].[CH3:11][O-:12].[Na+]>CO>[CH3:8][CH:6]1[CH2:5][CH2:4][N:3]([C:9](=[NH:10])[O:12][CH3:11])[CH2:2][CH2:7]1
Reactant: C[O-]
Reactant: CC1CCN(C#N)C(C)C1
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCC(C)CC1

Procedure:
In the manner given in Example 2, methyl 4-methyl-1-piperidinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-methyl-1-piperidinecarboximidate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])=[CH:8][CH:7]=1
Reactant: COc1ccccc1B(O)O
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (1.88 g, 4.39 mmol, prepared as described in Preparation 23, was dissolved in glyme (58 ml) and water (4 ml). To this solution 2-methoxyphenylboronic acid (2.0 g, 13.16 mmol), tetrakistriphenylphosphine palladium (0) (2.79 g, 2.41 mmol) and potassium carbonate (2.12 g, 15.37 mmol) were added. The reaction mixture was degassed and then heated at 80° C. for 6 h. The mixture was diluted with EtOAc (100 ml), washed with saturated aqueous NaHCO3 (100 ml) and brine (100 ml) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (9:1 to 4:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-(2′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (1.1 g, 65%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH3:23])=[C:17]([CH:21]=1)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CO>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:14]=[C:13]([Cl:12])[CH:21]=[CH:17][C:16]=2[O:22][CH3:23])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc(Cl)cc1-c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
4-bromo-2-chlorobenzoic acid (0.4 g), 5-chloro-2-methoxybenzoic acid (0.4 g), Pd(dppf)Cl2 (0.12 g), sodium carbonate (0.9 g), dioxan (15 ml) and methanol (5 ml) were charged to a flask and heated at reflux for 16 h. Cooled to room temp and filtered (hyflo). The filtrate was concentrated in vacuo, then dissolved in ethyl acetate. The suspension was made basic by addition of dilute NaOH. The aqueous layer was separated and acidified using 2M HCl, extracted with EtOAc, dried (MgSO4) and evaporated in vacuo to give the sub-title compound Yield 0.4 g
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17]Br)[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K]>CN(C=O)C>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[C:13]2[C:8]([C:9]([CH3:19])=[C:10]([CH2:17][N:24]3[C:23](=[O:25])[C:22]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]4[C:20]3=[O:30])[C:11](=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(=O)Oc1ccc2c(C)c(CBr)c(=O)oc2c1C
Agent: [K]
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(C)c(CN3C(=O)c4ccccc4C3=O)c(=O)oc2c1C
Temperature: 0 °C

Procedure:
A mixture of 7-acetoxy-3-bromomethyl-4,8-dimethylcoumarin (200 mg, 0.617 mmol) and potassium phthalimide (126 mg, 0.680 mmol) was stirred overnight at room temperature in DMF (3 mL). The slurry was poured into ice water, filtered and washed with a copious amount of water to remove traces of DMF to give 7-acetoxy-4,8-dimethyl-3-phthalimidomethylcoumarin, a creamy white solid after drying (221 mg, 91.7%). 1H NMR (CDCl3): δ7.84-7.67 (m, 4H), 7.55 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.8 Hz, 1H), 4.92 (s, 2H), 2.62 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H).