Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][NH:20][CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26].[CH3:29][N:30]1[CH:34]=[C:33]([C:35](O)=[O:36])[CH:32]=[N:31]1.N1(O)C2C=CC=CC=2N=N1.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:24][CH2:23][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:35]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)=[O:36])[CH2:19]4)[C:11]=3[CH2:10]2)=[CH:5][C:4]=1[C:25]([F:28])([F:26])[F:27]
Reactant: Cn1cc(C(=O)O)cn1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(C(=O)c5cnn(C)c5)C4)c3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (prepared using step 1, example 91 from intermediate 13) (44 mg, 0.11 mmol), 1-methyl-1H-pyrazole-4-carboxylic acid (15 mg, 0.12 mmol), benztriazol-1-ol (19 mg, 0.12 mmol) in CH2Cl2 (1.0 mL) was added EDC (34 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 18 h. Partitioned between CH2Cl2 (10 mL) and sat. NaHCO3(aq) (2.0 mL) and the organic layer separated by filtering through a phase separation tube. Concentrated in vacuo and purified by flash chromatography through Biotage® amino silica gel eluting with cyclohexane/EtOAc, 100/0 to 0/100 to give {(S)-3-[6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(1-methyl-1H-pyrazol-4-yl)-methanone as a white lyophilized powder (44 mg, 75% yield). 1H NMR (400 MHz, CDCl3-d, 298K) δ ppm 2.26-2.45 (m, 2H) 3.04-3.10 (m, 2H) 3.49-3.57 (m, 2H) 3.89-4.00 (m, 7H) 4.01 (s, 3H) 4.10-4.18 (m, 2H) 5.78-5.83 (m, 1H) 7.60-7.62 (m, 1H) 7.76-7.89 (m, 2H) 8.04-8.07 (m, 1H) 8.61-8.66 (m, 1H) MS: [M+H]+=504.2, Rt(3)=1.59 min. Example 55 was prepared using procedures analogous to those used in example 54 using appropriate starting materials.
Reaction SMILES: [CH3:1][CH2:2][Mg+].[Br-].CON(C)[C:8]([C:10]1[CH:24]=[CH:23][C:13]2[N:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:15]=[N:16][C:12]=2[CH:11]=1)=[O:9].[NH4+].[Cl-].O>C1COCC1>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[N:14]1[C:13]2[CH:23]=[CH:24][C:10]([C:8](=[O:9])[CH2:2][CH3:1])=[CH:11][C:12]=2[N:16]=[CH:15]1
Reactant: CC[Mg+]
Reactant: CON(C)C(=O)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1ccc2c(c1)ncn2C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of EtMgBr (0.72 mL, 1 mol/L) was added to N-methoxy-N-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.24 mmol) in THF at 0° C. under argon. The mixture was stirred at 0° C. for 2 h. A solution of NH4Cl was added, carefully, to quench the reaction. The mixture was poured into water and extracted with EtOAc. The organics were washed sequentially with water and brine, then dried (Na2SO4). Removal of solvent followed by SiO2 chromatography afforded 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one as a colorless oil (45 mg, 72% yield).
Reaction SMILES: [C:1]1([CH:7]2[CH2:14][CH2:13][C:12](=O)[NH:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[S:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2CC(=O)NC3C=CC=CC=3S2)C=CC=CC=1.[ClH:38].[CH3:39][N:40]([CH3:64])[CH2:41][CH2:42][N:43]([CH3:63])[C:44](N1C2C=CC=CC=2SC(C2C=CC=CC=2)CC1)=[O:45]>>[ClH:38].[CH3:39][N:40]([CH3:64])[CH2:41][CH2:42][N:43]([CH3:63])[C:44]([N:11]1[C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[S:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13][CH2:12]1)=[O:45]
Reactant: O=C1CCC(c2ccccc2)Sc2ccccc2N1
Reactant: CN(C)CCN(C)C(=O)N1CCC(c2ccccc2)Sc2ccccc21
Agent: Cl
Agent: O=C1CC(c2ccccc2)Sc2ccccc2N1
Product: CN(C)CCN(C)C(=O)N1CCCC(c2ccccc2)Sc2ccccc21

Procedure:
By substituting an equivalent amount of 3,4-dihydro-2-phenyl-2H-1,6-benzothiazocin-5(6H)-one for the 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one in part (A) of Example 1 and carrying out the procedure of the Example, there is obtained N-(2-dimethylaminoethyl)-N-methyl-2phenyl-1,2,3,4,5,6-hexahydro-1,6-benzothiazocine-6-carboxamide hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH:18]=O)[N:5]([CH:16]=O)[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+:25].C(O)(=O)C>O>[CH3:1][O:2][C:3]([C:4]1[N:5]([CH:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][CH2:8][CH2:7]2)[CH:16]=[N:25][CH:18]=1)=[O:20]
Reactant: COC(=O)C(C=O)N(C=O)C1CCCc2ccccc21
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 4 h

Procedure:
A mixture of 16.5 g of N,α-bis-formyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester, 65.0 g of ammonium acetate and 100 ml of acetic acid are refluxed for 8 hours. Then additional 50 g ammonium acetate are added and the refluxing is continued for further 4 hours. The solution is diluted with 300 ml of water and extracted twice, with 100 ml of toluene each time. The organic phases are combined, concentrated and separated at silica gel by chromatography. Concentration of the eluate yields 1-(1,2,3,4-tetrahydronaphthalen-1-yl) -5-imidazolecarboxylic acid methyl ester, having a melting point of 63° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[H-].[Na+].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].O>O1CCCC1>[C:37]([O:36][C:34]([CH2:33][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
Under argon atmosphere a solution of 2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.94 g) that obtained from Referential Example 3 in anhydrous tetrahydrofuran (30 ml) was added to a suspension of 60% sodium hydride (400 mg) in anhydrous tetrahydrofuran (30 ml) at 0° C., the mixture was stirred at room temperature for one hour. Tert-butyl bromoacetate (1.46 g) in anhydrous tetrahydrofuran (15 ml) to this solution, the resultant mixture was stirred at room temperature for one hour. Water (300 ml) was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Isopropyl ether was added for trituration to the residue, filtered, to thereby obtain 1.74 g of the titled compound (Yield: 69.4%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:9])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Brc1ccc([C@@H]2CO2)cc1
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: O[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
(2R)-2-(4-Bromophenyl)oxirane (49.93 g, 250.8 mmol) was added to pyrrolidine (35 mL, 421.2 mmol) in a CH2Cl2 (150 mL) solution at 0° C. with magnetic stirring. Montmorillonite K10 clay (5.87 g) was added in one portion. The resulting mixture was stirred at room temperature for 16 h. The mixture was then filtered through a pad of Celite and the filtrate was concentrated to give a white solid. The crude material was recrystallized from Et2O to give (1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethanol as clear crystals (29.43 g, 109 mmol, 43% yield). MS (ES) m/e 272, 270 [M+H]+
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([CH2:13][C:14]#[N:15])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>[Pd].C1COCC1.C(O)(=O)C>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][C:14]#[N:15])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N#CCc1nc2c([N+](=O)[O-])cccc2o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: N#CCc1nc2c(N)cccc2o1
Reaction time: 15 h
Yield: 62.9 %

Procedure:
The mixture of 4-nitro-2-benzoxazoleacetonitrile (27.22 g, 0.13 mole) and Palladium on carbon (3 g) in THF (320 ml) and acetic acid (5 ml) in a Parr bottle was hydrogenated at 50 psi for 15 h. It was filtered over a patch of celite (1.5 cm) covered with activated carbon (0.5 cm) and washed with isopropyl ether. The filtrate was evaporated and the residue was triturated with isopropyl ether and propyl acetate and filtered to give 4-amino-2-benzoxazoleacetonitrile (14.16 g, 61%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24](=[O:40])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][Si](C)(C)C)=[C:28]([N+:37]([O-:39])=[O:38])[CH:27]=1)([CH3:22])([CH3:21])[CH3:20].[I:41][C:42]1[C:47]([CH:48]=[O:49])=[C:46]([O:50][CH3:51])[N:45]=[CH:44][CH:43]=1>C1COCC1>[C:19]([O:23][C:24](=[O:40])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:48]([OH:49])[C:47]2[C:46]([O:50][CH3:51])=[N:45][CH:44]=[CH:43][C:42]=2[I:41])=[C:28]([N+:37]([O-:39])=[O:38])[CH:27]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1nccc(I)c1C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(C[Si](C)(C)C)c([N+](=O)[O-])c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1nccc(I)c1C(O)Cc1ccc(NC(=O)OC(C)(C)C)cc1[N+](=O)[O-]

Procedure:
The resultant (3-nitro-phenyl)-carbamic acid tert-butyl ester 2 can then be placed into solution with THF and reacted with ((trimethylsilyl)methyl)magnesiumchloride. A solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF can then be added and allowed to react under conditions known to a skilled artisan to afford (3-nitro-4-trimethylsilanylmethyl-phenyl)-carbamic acid tert-butyl ester 3. Tetra-butylammonium fluoride can then be added to a solution of ester 3 and 4-iodo-2-methoxynicotinaldehyde in THF to afford {4-[2-hydroxy-2-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl]-3-nitro-phenyl}-carbamic acid tert-butyl ester 4. A solution of compound 4, in turn, can be added to 2,2,2-trifluoroacetic anhydride and allowed to react to afford trifluoro-acetic acid 2-(4-tert-butoxycarbonyl-amino-2-nitro-phenyl)-1-(4-iodo-2-methoxy-pyridin-3-yl)-ethyl ester 5.
Reaction SMILES: [F-].[K+].[NH2:3][CH2:4][C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][S:20]([N:23]([CH3:31])C(=O)OC(C)(C)C)(=[O:22])=[O:21])=[CH:15][CH:14]=2)[CH:6]=1.Cl[C:33]1[N:38]=[CH:37][C:36]([Cl:39])=[CH:35][N:34]=1>CS(C)=O>[Cl:39][C:36]1[CH:35]=[N:34][C:33]([NH:3][CH2:4][C:5]2[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH2:19][S:20]([NH:23][CH3:31])(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:6]=2)=[N:38][CH:37]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Cc1nc(CN)cc(Oc2ccc(CS(=O)(=O)N(C)C(=O)OC(C)(C)C)cc2)n1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNS(=O)(=O)Cc1ccc(Oc2cc(CNc3ncc(Cl)cn3)nc(C)n2)cc1
Temperature: 120 °C
Reaction time: 17 h
Yield: 45 %

Procedure:
Add potassium fluoride (53.9 mg, 0.93 mmol) to a solution of tert-butyl N-[[4-[6-(aminomethyl)-2-methyl-pyrimidin-4-yl]oxyphenyl]methylsulfonyl]-N-methyl-carbamate (280 mg, 0.46 mmol) and 2,5-dichloropyrimidine (69.1 mg, 0.46 mmol) in DMSO (10 mL). Heat the mixture to 120° C. and stir it at that temperature for 17 hours. Cool the mixture to ambient temperature and quench the reaction with water. Extract the resulting mixture with EtOAc; combine the extract(s); dry the extracts with magnesium sulfate; filter; and concentrate the filtrate under reduce pressure to provide a residue. Purify the title compound using silica gel chromatography eluting with a gradient of EtOAc in hexanes (0-100%). Further purify the title compound using a second silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. Concentrate the appropriate fractions under reduced pressure to provide the title compound as a glassy yellow solid (90 mg, 44.6%). MS (m/z): 435 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:5]1[CH:4]=[CH:3][C:2]([CH:9]2[CH2:11][CH2:10]2)=[CH:7][N:6]=1
Reactant: Clc1ccc(Br)cn1
Reactant: OB(O)C1CC1
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: C1COCCO1
Product: Clc1ccc(C2CC2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
To a suspension of 5-bromo-2-chloropyridine (990 mg, 5.15 mmol), cyclopropylboronic acid (893 mg, 10.39 mmol) and Cs2CO3 (5.082 g, 15.45 mmol) in 1,4-dioxane (25 mL) was added Pd(PPh3)4 (601 mg, 0.52 mmol) at r.t. under N2. The reaction was stirred at 100° C. for 1 h. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (PE:EtOAc=50:1) to give 452 mg (57%) of the title compound as a colorless oil. [M+H] Calc'd for C8H8NCl, 154. Found, 154.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][C:7]=1[O:14][CH3:15].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][C:17](=[O:19])[CH3:18])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)COc1ccc(CO)cc1OC
Solvent: c1ccncc1
Product: COC(=O)COc1ccc(COC(C)=O)cc1OC
Temperature: 0 °C
Yield: 64 %

Procedure:
A solution of (4-Hydroxymethyl-2-methoxy-phenoxy)-acetic acid methyl ester 72 (40 grams, 177 mmol), Acetic anhydride (80 mL) and pyridine (4 mL) was refluxed for 4 hours. Reaction mixture was poured in to ice water (200 mL) and crude 73 was extracted into chloroform, dried over Na2SO4, and distilled. The crude was vacuum distilled to give pure 73 (30 grams, 64%) as a color less liquid, Bp15 210° C. The structure was confirmed with IR and NMR. IHNMR (CDCl3) δ 2.08 (s, 3H,O═C—CH3), 3.78(s, 3H,ester), 3.90(s, 3H, OCH3), 4.65(s, 2H,OCH2), 5.00 (s, 2H, CH2), 6.76(d,1H,Ar), 6.80 (d, 2H,Ar), 6.85 (dd,1H,Ar).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:12][CH2:13][C:14]([CH3:16])=O.Cl.O1CCOCC1>CC(O)=O>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:14]([CH3:16])=[C:13]2[CH2:12][C:11]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NNc1ccc(Br)cc1
Reactant: CCOC(=O)CCC(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)[nH]c2ccc(Br)cc12
Yield: 70.9 %

Procedure:
A mixture of 4-bromophenylhydrazine hydrochloride (2.23 g, 10 mmol) and ethyl levulinate (1.58 g, 11 mmol) in 10 mL HOAc was heated to reflux for 20 h. The HOAc was removed under vaccum. The residue was dissolved in 10 mL EtOH. A solution of HCl in dioxane (12 mmol, 4M solution) was added. The mixture was heated to reflux for 4 h. The mixture was concentrated under vacuum and the residue was purified by flash chromatography on silica gel, eluting with 20% EtOAc in hexane to afford 2.1 g (78%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8](Cl)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][C:12]1([CH3:20])[O:17][C:16](=[O:18])[CH2:15][C:14](=[O:19])[O:13]1.N1C=CC=CC=1.Cl>C(Cl)Cl>[CH:1]1([CH2:6][CH2:7][C:8]([CH:15]2[C:16](=[O:18])[O:17][C:12]([CH3:20])([CH3:11])[O:13][C:14]2=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)CCC1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(C(=O)CCC2CCCC2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
3-Cyclopentylpropionyl chloride (0.64 ml, 4.16 mmol) was added to a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (500 mg, 3.47 mmol) in anhydrous methylene chloride (10 ml). After cooling to 0° C., pyridine (0.56 ml, 6.94 mmol) was added in portions. After stirring for 1 hour at 0° C. and 2 hours at ambient temperature the mixture was poured onto water (20 ml) containing concentrated hydrochloric acid (0.5 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 5-(3-cyclopentylpropionyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (900 mg, 96%).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([F:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:51])[CH3:50])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([F:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:47])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:50])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](F)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 3.1 mg (0.02 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 3 ml of abs. tetrahydrofuran, 0.15 ml (0.84 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 105 mg (0.21 mmol) of 5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 53A), dissolved in 4 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 6 h. 3 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product is purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 10:1). This gives 110 mg of a mixture of the two target compounds. Subsequent chromatographic separation on a chiral phase [column: chiral silica gel selector based on poly(N-methacryloyl-L-leucine-tert-butylamide), 670 mm×40 mm; mobile phase: MTBE/isohexane 15:85; flow rate: 80 ml/min; 24° C.; detection: 280 nm] gives 36 mg (36% of theory, 98% ee) of Example 30 and 45 mg (43% of theory, >99% ee) of Example 31.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[C:14](F)[CH:13]=[C:12]([N:17]([CH3:19])[CH3:18])[N:11]=2)[CH2:6][CH2:5]1)(=O)C.[CH3:20][O-:21].[Na+].O>CO>[CH3:19][N:17]([CH3:18])[C:12]1[CH:13]=[C:14]([O:21][CH3:20])[N:15]=[C:10]([N:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)[N:11]=1
Reactant: CC(=O)N1CCN(c2nc(F)cc(N(C)C)n2)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N(C)C)nc(N2CCNCC2)n1
Yield: 123.9 %

Procedure:
1-Acetyl-4-(6-(dimethylamino)-4-fluoropyrimidin-2-yl)piperazine (1.0 g) obtained in Example 109(1) and sodium methoxide (1.1 g) were refluxed under heating in methanol (10 ml) for 28 hr. The reaction mixture was poured into water (100 ml) and extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated to give the title compound (1.1 g) as a pale-yellow oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[C:11]([CH2:21][CH2:22][CH3:23])[C:10]([O:24][CH2:25][O:26][CH3:27])=[CH:9][CH:8]=1.[F:28][C:29]([F:37])([F:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[O:31].O>O1CCCC1>[F:28][C:29]([F:37])([F:36])[C:30]([C:7]1[CH:8]=[CH:9][C:10]([O:24][CH2:25][O:26][CH3:27])=[C:11]([CH2:21][CH2:22][CH3:23])[C:12]=1[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)([OH:31])[C:32]([F:35])([F:34])[F:33]
Reactant: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c(OCOC)ccc(C(O)(C(F)(F)F)C(F)(F)F)c1COC1CCCCO1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Under an argon atmosphere, n-butyl lithium (1.58 mol/L hexane solution 1.55 mL, 2.45 mmol) was dropped at −78° C. into a solution of 2-(6-bromo-3-(methoxymethoxy)-2-propylbenzyloxy)tetrahydro-2H-pyrane (725 mg, 1.75 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at the same temperature for 15 minutes and then stirred at the elevated temperature of −45° C. for 1.5 hours. A tetrahydrofuran (4 mL) solution of hexafluoroacetone was dropped at −78° C., and the mixture was stirred at 0° C. for 5 hours and then stirred at room temperature for 12 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (728 mg, 90%) was obtained as colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](F)[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18].[OH-:19].[Na+].O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:18]
Reactant: [OH-]
Reactant: O=c1ccc2ncc(F)cc2n1CC1OCCO1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1ccc2ncc(O)cc2n1CC1OCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.50 g of 1-(1,3-dioxolan-2-ylmethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 3 mL of tetrahydrofuran, 3 mL of a 20% aqueous sodium hydroxide solution was added, and the mixture was heated under reflux while stirring for 1 hour. Thereto was added 3 mL of water, and the mixture was heated under reflux while stirring for 3 hours 30 minutes. Thereto was added 3 mL of a 20% aqueous sodium hydroxide solution, and the mixture was heated under reflux while stirring for 4 hours. Tetrahydrofuran was distilled off under reduced pressure, and the mixture was then heated under reflux while stirring for 1 hour 30 minutes. After cooling to room temperature, the reaction mixture was added with 2 mol/L hydrochloric acid and adjusted to pH 5. Thereto was added ethyl acetate, the organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diethyl ether was added to the resultant residue, and the solid was filtered off to obtain 0.32 g of 1-(1,3-dioxolan-2-ylmethyl)-7-hydroxy-1,5-naphthyridin-2(1H)-one as a yellow solid.