Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[O:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 76 %

Procedure:
The title compound (0.21 g, 76%) was prepared from the compound from step 1 (0.30 g, 0.81 mmol) and 4 N HCl in dioxane by the procedure described in step 2 of Example 4: MS (ESI) m/z 269 (M+H); 1H NMR (500 MHz, DMSO-d6) δ 1.86 (br, 2H), 2.08 (m, 2H), 3.10 (br, 1H), 3.30 (br, 2H) 3.66 (m, 2H), 5.25 (br, 2H), 6.96-7.03 (m, 4H), 7.12 (m, 2H). 7.38 (m, 3H), 8.22 (br, 2H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:13][CH3:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:13]([O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([F:10])[C:4]=1[F:3])[CH3:14]
Reactant: CCBr
Reactant: Oc1cccc(F)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCOc1cccc(F)c1F
Temperature: 80 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
Sodium hydroxide (75.9 g) was added to a water (400 ml) solution of 2,3-difluorophenol (T-1) (195.0 g), bromoethane (196.2 g) and tetrabutylammonium bromide (TBAB) (24.2 g), and the mixture was heated with stirring at 80° C. for 6 hours under an atmosphere of nitrogen. After the completion of the reaction, the reaction mixture was extracted with heptane, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a black oil. The oil was purified by distillation to give 1-ethoxy-2,3-difluorobenzene (T-1) as a colorless oil (230.0 g) in 97% yield.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8]C)=[O:7])[CH2:2][CH2:3][CH3:4].C1(C(CCC)(CCC)C(OC)=O)C=CC=CC=1>>[CH2:1]([C:5]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CCCC)(C(=O)OC)c1ccc(F)cc1
Agent: CCCC(CCC)(C(=O)OC)c1ccccc1
Product: CCCCC(CCCC)(C(=O)O)c1ccc(F)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1C, substituting the compound of Example 18B for the compound of Example 1B. 1H NMR (300 MHz, CDCl3): δ 0.87 (t, J=7.17 Hz, 6 H) 1.08 (m, 4 H) 1.31 (m, 4 H) 1.98 (m, 4 H) 7.02 (m, 2 H) 7.29 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:15].S(Cl)([Cl:18])=O>>[Cl:15][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:2]=1[NH2:1])[C:6]([Cl:18])=[O:7]
Reactant: Nc1c(Cl)cc(C(=O)O)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Product: Nc1c(Cl)cc(C(=O)Cl)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
13 g (0.0543 mol) of 4-amino-3-chloro-5-trifluoromethyl-benzoic acid was added to 32.5 ml of thionyl chloride. The suspension was heated until the crystals have dissolved, then refluxing was continued for another 2 h. After cooling to room temperature, the remaining thionyl chloride was evaporated under reduced pressure, thus obtained crude 3-chloro-4-amino-5-trifluoromethyl-benzoyl chloride, which was dissolved in chloroform at heating. Filtered with heating and evaporated under reduced pressure to remove chloroform, obtained the subject product. Yield: 80–90%, melting point: 110–115° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=2)[CH:8]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>ClCCCl>[F:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([C:8]2[C:7]([O:6][CH3:5])=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][C:12]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13]3)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: COc1ccc2cc(S(C)(=O)=O)ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1ccc2cc(S(C)(=O)=O)ccc2c1S(=O)(=O)c1ccc(F)cc1
Yield: 6 %

Procedure:
Aluminum chloride (1.13 g, 8.46 mmol) was added to a solution of 2-methoxy-6-methylsulfonylnaphthalene (1.0 g, 4.2 mmol) [prepared as described in example 2 above], and 4-fluorobenzenesulfonyl chloride (1.65 g, 8.46 mmol) in 1,2 dichloroethane (40 ml). The reaction mixture was heated at reflux for 16 h, and then poured into 2N HCl and extracted into methylene chloride. The organic layer was separated, washed with water and brine, and dried over sodium sulfate. Purification by flash chromatography gave 0.1 g of 5-(4-fluoro-phenylsulfonyl)-6-methoxy-2-methylsulfonylnaphthalene as a solid (16% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCCc1ccc(Cl)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CCCBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a solution of 3-(4-chlorophenyl)propan-1-ol (0.25 g, 1.46 mmol) in dichloromethane (5.5 mL) cooled at 0° C. was added triphenylphosphine (0.42 g, 1.6 mmol) and carbon tetrabromide (0.51 g, 1.5 mmol) and the reaction was stirred at rt overnight. The reaction was quenched with water and extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (0% to 70% EtOAc/hexanes) to afford 1-(3-bromopropyl)-4-chlorobenzene (0.34 g, quant.). LC-MS: (FA) ES+ 234.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24]Br)[CH3:19]>>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][CH2:23][CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:19]
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the method described in Example 5, the use of p-(1-adamantyl)-phenol and 4-bromobutyric acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]-butyric acid ethyl ester of boiling point 150° C (0.03 mm).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.CN(C=O)C>[CH3:11][O:10][C:8]([C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)=[CH:7][N:6]=1)=[O:9]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
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: CN(C)C=O
Product: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 80 °C
Yield: 27.2 %

Procedure:
A solution of 5.18 g (30 mmol) methyl 5-chloropyrazine-2-carboxylate in 150 ml degassed DMF was treated with 3.47 g (0.1 mmol) tetrakis(triphenylphosphine)palladium and heated at 80° C. 6.27 g (33 mmol) of 4-(trifluoromethyl)benzeneboronic acid and 14 66 g (45 mmol) of cesium carbonate were added and heated for 3.5 h. The reaction was cooled to RT and extracted with H2O (0° C.)/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (NaSO4) and evaporated. Purification by flash-chromatography on silica gel (heptane/AcOEt 95:5 to 2:1) gave 2.3 g (27%) of 5-(4-trifluoromethyl-phenyl)-pyrazine-2-carboxylic acid methyl ester.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:52][N:53]([CH3:59])[CH2:54][CH2:55][CH2:56][CH2:57][NH2:58]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:58][CH2:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:59])[CH3:52])=[O:21])[CH:17]=2)[NH:12][N:11]=1
Reactant: CN(C)CCCCN
Reactant: O=C(O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)CCCCNC(=O)c1ccc2[nH]nc(-c3cc4ccccc4o3)c2c1
Yield: 30 %

Procedure:
The title compound was prepared as described in Example 277 using of 3-benzo[d]furan-2-yl-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylic acid (210 mg, 0.58 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (242 mg, 0.63 mmol) and 4-dimethylaminobutyl amine (139 mg, 1.2 mmol); (67 mg, 30% yield). 1H NMR (DMSO-d6) δ 13.8 (s, 1H), 8.7 (m, 2H), 8.0 (d, 1H), 7.6-7.8 (m, 4H), 7.4 (m, 2H), 3.3-3.6 (m, 4H), 2.3 (s, 6H), ES-MS (m/z) 377 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([Cl:14])[N:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:2]2[C:11]3[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[N:7][C:6]=3[CH:5]=[C:4]([Cl:14])[N:3]=2)=[CH:17][CH:16]=1
Reactant: NCc1ccncc1
Reactant: Cn1cnc2cc(Cl)nc(Cl)c2c1=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cnc2cc(Cl)nc(NCc3ccncc3)c2c1=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
5,7-dichloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (200 mg, 0.87 mmol) and (pyridin-4-yl)methanamine (188 mg, 1.74 mmol), DIEA (302 μL, 1.74 mmol) were dissolved in dioxane (5 mL). The reaction mixture was stirred at 90° C. overnight and then cooled to room temperature. The solvent was removed under vacuum and the crude product was purified by silica column chromatography using hexane/ethyl acetate/7N NH3 in methanol (60:33:7) to obtain the yellow 5-((pyridin-4-yl)methylamino)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one. 1H NMR (DMSO-d6) δ 9.45 (t, J=6 Hz, 1H), 8.49 (m, 3H), 7.32 (d, J=6H, 2H), 6.68 (s, 1H), 4.73 (d, J=6 Hz, 2H), 3.46 (s, 3H); ESI-MS m/z 302.1 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][CH2:23][C:24](=[O:28])[N:25]([CH3:27])[CH3:26])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][CH2:22][CH2:23][C:24](=[O:28])[N:25]([CH3:26])[CH3:27]
Reactant: CN(C)C(=O)CCCSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CN(C)C(=O)CCCSc1c(Cl)ccc2c1CCNCC2
Yield: 57 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-(3-dimethylcarbamoyl-propylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine in DCM (1 mL) at ambient temperature and add 4M hydrogen chloride in dioxane (200 μL, 0.8 mmol). Continue stirring until TLC shows consumption of starting material. Concentrate in vacuo, triturate the obtained solid with dry diethyl ether and dry at 50° C. under high vacuum overnight to give the title compound as a hygroscopic white solid (45.0 mg, 57%). MS (ES+) m/z: 327 (M+H)+.
Reaction SMILES: Br[C:2]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[N:12][C:5]2[O:6][CH2:7][C:8](=[O:11])[N:9]([CH3:10])[C:4]=2[CH:3]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F-].[Cs+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][N:9]1[C:8](=[O:11])[CH2:7][O:6][C:5]2[N:12]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:2]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)=[CH:3][C:4]1=2
Reactant: OB(O)c1cccnc1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(Br)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3cccnc3)cc21
Temperature: 80 °C
Yield: 21.1 %

Procedure:
Tert-butyl (1-(4-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (57 mg, 0.117 mmol), pyridin-3-yl boronic acid (21.52 mg, 0.175 momol), triphenylphosphine (9.18 mg, 0.035 mmol), cesium fluoride (89 mg, 0.584 mmol) were dissolved in 1,2-dimethoxyethane (2 ml) to give an orange solution. The reaction mixture was degassed by bubbling nitrogen for 10 minutes. Palladium(II)acetate (3.93 mg, 0.018 mmol) was added at room temperature. The resulting reaction was degassed and heated to 80° C. for 18 hours. The reaction mixture was concentrated to dryness under reduced pressure. The crude was purified by preparatory HPLC to give the title compound (12 mg, 21%). LCMS (Method D) RT 1.158 min, M+1=487. 1H NMR (500 MHz, CDCl3): 7.64-7.52 (1H, m), 7.37-7.21 (8H, m), 4.94 (2H, s), 3.43 (3H, s), 2.59-2.36 (4H, m), 2.15-2.01 (1H, m), 1.91-1.77 (1H, m), 1.47-1.20 (9H, br s).
Reaction SMILES: CC(C)([O-])C.[K+].[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH2:37][C@@H:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39]1>COCCOC.CCOC(C)=O>[Si:7]([O:14][C@@H:15]1[C@H:19]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:18][C@@H:17]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:37][C@@H:38]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39]3)[CH:31]=2)[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(Cl)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N[C@H]1CCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N[C@H]3CCc4ccccc43)c2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.08 h
Yield: 94.8 %

Procedure:
To a mixture of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-yl](chloro)[(2,3-η)-(1Z)-1-phenylprop-1-ene-2,3-diyl]palladium(2+) (7.8 mg, 0.000012 mol) and potassium tert-butoxide (73.7 mg, 0.000656 mol) under an atmosphere of argon was added 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-cyclopentyl]oxy}-2-chloropyridine (281.8 mg, 0.0005968 mol) in 1 ml DME. The solution was stirred for 5 mins, then (S)-(+)-1-aminoindane (0.10 mL, 0.000776 mol) in 1.0 ml DME was added dropwise over 15 min. The solution was stirred overnight, then dissolved in 50 mL EtOAc, washed with water, and concentrated. The residue was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound (0.3219 g, 95%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]([C:14]1([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:23][CH2:22][C:17]2(OCC[O:18]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]([C:14]1([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:15][CH2:16][C:17](=[O:18])[CH2:22][CH2:23]1)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC(NC(=O)OCc1ccccc1)C1(c2ccc(OC)cc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
534 mg of {1-[8-(4-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-propyl}-carbamic acid benzyl ester (96) were dissolved in 1 mL of a 2:1 mixture of acetone and 6N aqueous hydrochloric acid. The reaction mixture was stirred for 16 h at room temperature, then dropped into 150 mL of saturated aqueous sodium bicarbonate solution. The phases were separated and the aqueous phase was extracted three times with dichloromethane (100 mL each). The combined organic phases were dried over magnesium sulphate, filtered and concentrated to give the ketone 97. Rt=1.58 min (Method 19). Detected mass: 396.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([S:15](Cl)(=O)=O)=[CH:10][CH:9]=2)=[O:4].COC(C1COC2C(C=1)=CC(SCC1SC(C3C=CC(C(F)(F)F)=CC=3)=NC=1C)=CC=2)=O>>[CH3:1][O:2][C:3]([C:5]1[CH2:6][O:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([SH:15])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)C1=Cc2cc(S(=O)(=O)Cl)ccc2OC1
Agent: COC(=O)C1=Cc2cc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc2OC1
Product: COC(=O)C1=Cc2cc(S)ccc2OC1

Procedure:
Compound 16E was prepared according to the method of example 1C utilizing compound 16D. Compound 16E was prepared in 20% yield. MS: 221 (M−1)+. Preparation of 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-2H-chromene-3-carboxylic acid methyl ester (Compound 16F)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[C:24]1([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccccc4)CC3)c2cc1OC
Yield: 26.4 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with isocyanato-benzene (19.6 mg, 0.165 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (11.4 mg, 27%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.37 (m, 6H), 7.06 (m, 1H), 6.42 (br s, NH), 4.31-4.27 (m, 2H), 4.08 (s, 6H), 3.62 (m, 1H), 3.19 (m, 2H), 2.17 (m, 2H), 2.04-1.98 (m, 2H); LC/MS (ESI): calcd mass 392.2, found 393.3 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C@H:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:7]=1.[CH3:29][NH2:30]>CO>[CH3:29][NH:30][C:3](=[O:2])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C@H:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:12]=2)[CH:7]=1
Reactant: CN
Reactant: COC(=O)COc1ccc2cc(OC[C@H](O)CCc3cccnc3)ccc2c1
Solvent: CO
Product: CNC(=O)COc1ccc2cc(OC[C@H](O)CCc3cccnc3)ccc2c1

Procedure:
A solution of 6-((2R)-2-hydroxy-4-(3-pyridyl)-1-butoxy)naphthalen-2-yloxyacetic acid methyl ester (0.215 g) in methanol (10 ml) was saturated with methylamine gas. After 16 hours the crystalline product was collected by filtration and dried under vacuum to give the title compound as a solid (0.10 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH:24][C:26]3[N:27]=[CH:28][C:29]4[CH:34]=[C:33]([C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[N:32]([CH:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[C:30]=4[N:31]=3)=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 95 %

Procedure:
Following general Scheme 5 on a 1.023 mmole scale, 3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide which yielded after SiO2 gel Chromatograped (5-8% CH3OH-ethyl acetate), 0.57 grams (95% yield) of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester, TLC RF 0.4 in 5% CH3OH-ethyl acetate, MS m/z 589 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:14]=[CH:13][C:12]=1[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].C=O.C(N(CCOCCOC)CCOCCOC)COCCOC>C1(C)C=CC=CC=1.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:14]=[CH:13][C:12]=1[C:25](=[CH2:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:9])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=C(C(=O)OCC)c1ccc(NC(=O)OC(C)(C)C)cc1CN(C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 10 h
Yield: 31.7 %

Procedure:
15D (0.573 g, 1.356 mmol) was dissolved in toluene (5 mL), and to the resulting solution were sequentially added potassium carbonate (0.375 g, 2.71 mmol), paraformaldehyde (0.407 g, 13.56 mmol) and tris(3,6-dioxaheptyl)amine (tda-1) (0.043 mL, 0.136 mmol). The reaction mixture was stirred at 85° C. for 10 h. The reaction mixture was diluted with EtOAc (20 mL) and water (10 mL) and stirred for 15 min. The organic phase was separated, washed with water (3×10 mL), brine (1×10 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified flash chromatography (0-35% EtOAc/hexanes). Fractions were combined and concentrated under reduced pressure to give 15E (0.187 g, 31.7% yield) as a colorless syrup. MS (ESI) m/z: 435.1 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 7.40 (1H, d, J=5.77 Hz), 7.06 (2H, d, J=8.28 Hz), 6.50 (1H, s), 5.67 (1H, d, J=1.76 Hz), 4.27-4.39 (2H, m), 4.21 (2H, q, J=7.03 Hz), 2.61-2.77 (3H, m), 1.38-1.55 (18H, m), 1.26 (3H, t, J=7.03 Hz).