Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:16]([O:15][C:13]([NH:12][C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:14])[CH3:17]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCOC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)NC1=C(C(=O)OCC)CCC1
Yield: 64.3 %

Procedure:
A solution containing ethyl 2-oxocyclopentanecarboxylate (90 g, 0.63 moles), urethane (63.1 g, 0.70 mole) and p-toluenesulfonic acid (1 g) in benzene (100 mL) was refluxed for 15 hours in a Soxhlet extraction apparatus with sodium sulfate in the thimble. The reaction mixture was washed with water (3×100 mL), dried over magnesium sulfate then evaporated under vacuum. The resulting residue was recrystallized from methanol:water (9:1) to provide 92.1 g of ethyl 2-[(ethoxycarbonyl)amino]-1-cyclopentene-1-carboxylate as a white solid, m.p. 49°-51° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].C(N(CC)CC)C.[CH3:28][C:29]1([CH2:34][NH2:35])[CH2:33][CH2:32][NH:31][CH2:30]1>C(#N)C>[NH2:35][CH2:34][C:29]1([CH3:28])[CH2:33][CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1
Reactant: CC1(CN)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(CN)CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)C1
Yield: 95 %

Procedure:
To 1.05 g (3.50 mmol) of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added 15 ml of acetonitrile, 1.0 g (9.9 mmol) of triethylamine and 0.7 g (6 mmol) of the 3-methyl-3-pyrrolidinemethanamine. The mixture was refluxed 18 hours and cooled. Filtration gave 1.31 g of the title compound, mp 189°-191° C.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](I)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:24]#[CH:25]>C(#N)C.C(N(CC)CC)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:25]#[C:24][CH2:23][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)ncc1Cl
Reactant: C#CCNC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Reaction time: 0.75 h
Yield: 74.4 %

Procedure:
A suspension of N-(1-adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example2(i)) (0.43 g) and tert-butyl prop-2-ynylcarbamate, (0.31 g) in anhydrous acetonitrile (5 ml) and triethylamine (5 ml) was purged with nitrogen for 5 minutes and the copper (I) iodide (0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) were added. The mixture was stirred under nitrogen for 0.75 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel eluting with acetone:dichloromethane (1:19) to afford the sub-titled compound (0.34 g) as a yellow foam.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1[NH2:43].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH:34]1[NH:43][C:18]([C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)=[O:20]
Reactant: NC1CCc2ccccc2C1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCc5ccccc5C4)cc3)c(C#N)cc21
Reaction time: 0.5 h
Yield: 74 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (10 mg, 0.028 mmol) was diluted with DCM (500 uL) followed by the addition of oxalyl chloride in DCM (2M) (0.017 ml, 0.034 mmol) and 1 drop of DMF. After stirring for 30 minutes, 1,2,3,4-tetrahydro-naphthalen-2-ylamine (8.3 mg, 0.057 mmol) and DIEA (0.020 mL, 0.11 mmol) were added. After stirring for 2 hours, the reaction was loaded directly onto a biotage 12i cartridge and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-((1,2,3,4-tetrahydronaphthalen-2-yl)carbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (10 mg, 73% yield).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])=[O:22])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.[BH4-].[Na+].Cl>C(O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:14]3[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH2:30][CH3:31])[OH:22])[N:18]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccccc1C(O)CCc1coc(-c2ccc(OC)c(OCC3CC3)c2)n1
Reaction time: 2 h

Procedure:
A 0.21 g quantity of 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one obtained in Example 102 was added to 5 ml of ethanol, and the mixture was stirred with ice-cooling. A 37 mg quantity of sodium borohydride was gradually added thereto. After the temperature of the reaction mixture had reached room temperature, stirring was performed for 2 hours. An aqueous 5N hydrochloric acid solution was added to the reaction mixture, and solvent was then removed. Extraction was performed with dichloromethane, and the extract was washed with saturate brine. The extract was then dried over anhydrous magnesium sulfate, the solvent was removed, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give 0.18 g of colorless oily 3-[2-(3-cyclopropylmethoxy-4-methoxyphenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-ol.
Reaction SMILES: C(Cl)(=O)C.[O:5]=[C:6]1[O:12][C@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[C:9]([OH:10])=[C:7]1[OH:8].[CH3:17][C:18]([CH3:20])=O>>[CH3:17][C:18]1([CH3:20])[O:14][CH:13]([CH:11]2[O:12][C:6](=[O:5])[C:7]([OH:8])=[C:9]2[OH:10])[CH2:15][O:16]1
Reactant: CC(C)=O
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CC(=O)Cl
Product: CC1(C)OCC(C2OC(=O)C(O)=C2O)O1
Temperature: 32.5 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
5,6-O-isopropylidene-L-ascorbic acid was synthesized by the addition of acetyl chloride (124.9 mL) to a slurry of L-ascorbic acid USP (1000 g) in acetone (4.5 L). The mixture was stirred vigorously at 35-30° C. After two hours, the crystalline product separated. The crystals were collected by filtration, washed with cold acetone, and dried in a vacuum desciccator over potassium hydroxide pellets. The product, produced in 77% yield, consisted of needle-shaped crystals with a melting point of 217-223° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:23]=[C:24]([N+:28]([O-])=O)[C:25]=1[O:26][CH3:27])[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:12].[OH-].[Na+]>>[NH2:28][C:24]1[C:25]([O:26][CH3:27])=[C:8]([O:7][CH3:6])[CH:9]=[C:10]([CH:23]=1)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:12]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc([N+](=O)[O-])c1OC
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc(N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
49.5 g of tin dichloride dihydrate are added to 16.0 g of 3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 300 ml of ethanol), whereupon the mixture is stirred at 75° for 30 minutes. Thereupon, the reaction mixture is poured into 800 ml of ice-water. It is neutralized with 28 percent sodium hydroxide solution and extracted three times with 600 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulfate and evaporated. After recrystallization from methylene chloride/hexane there is obtained 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone of melting point 95°-96°.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7]Cl)(=[O:5])=[O:4])[CH3:2].[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>>[CH2:1]([S:3]([CH2:6][CH2:7][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)CCN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
Mix 2-chloroethyl ethyl sulfone (1.2 g, 7.66 mmol) and piperidine (2 mL, 20 mmol). Stir at room temperature for 2 hours. Treat with 5N sodium hydroxide, extract with ethyl acetate (3×50 mL) and dry (MgSO4). Concentrate in vacuo to yield 1.3 g yellow oil which crystallizes. Purify by silica gel chromatography (ethyl acetate) to yield 550 mg (35%) of the title compound as a clear oil which crystallizes; mp 45°-47° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][O:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[N:16][C:17]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[C:22]([Cl:35])[CH:21]=2)[NH:12][N:11]=1>C(O)C>[Cl:35][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][N:11]=[C:10]([O:9][CH2:8][CH2:7][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:18]=23)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)c1
Reactant: C1CCNC1
Solvent: CCO
Product: Fc1cccc(COc2ccc(Nc3ncnc4[nH]nc(OCCN5CCCC5)c34)cc2Cl)c1
Temperature: 120 °C
Yield: 31 %

Procedure:
Pyrrolidine (0.5 ml) was added to a suspension of 3-(2-chloroethoxy)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 12/0.2 g, 0.44 mmol) in ethanol (2 ml) and the reaction mixture was heated at 120° C. for 10 minutes in a microwave reactor. The resulting solution was concentrated in vacuo and the residue purified by chromatography using DCM to DCM-10% methanol/7N ammonia as eluant to give the title compound as a beige solid (67 mg, 31%); Mass Spectrum: 483.3 (MH+/retention time 1.56 minutes).
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][C:13]1[S:14][C:15]2[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=2[N+:17]=1[CH2:18][CH3:19].C(N(CC)CC)C.[Cl:31][C:32]([Cl:37])([Cl:36])[C:33](Cl)=[O:34]>C1(C)C=CC=CC=1>[Cl:31][C:32]([Cl:37])([Cl:36])[C:33]([CH:12]=[C:13]1[N:17]([CH2:18][CH3:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)=[O:34]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCN1C(=CC(=O)C(Cl)(Cl)Cl)Sc2ccccc21
Reaction time: 3 h

Procedure:
10 g (28.6 mmol) of 2-methyl-3-ethyl-benzothiazolium p-toluenesulfonate are suspended in 150 ml of toluene, 6.8 g (67.2 mmol) of triethylamine are added and, at 5°-10° C. 6 g (33 mmol) of trichloroacetyl chloride, dissolved in a minor amount of toluene, are added dropwise. After three hours at room temperature, the ammonium salts are filtered off with suction, and the reaction solution is washed with water, dried over sodium sulfate and concentrated in vacuo. The product is caused to crystallize from the diisopropyl ether.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:5])=[O:4].[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1.C1N2CCN(CC2)C1>C(#N)C>[CH3:1][N:2]([CH3:19])[S:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH:16][C:17]([NH:20][C:21]1[N:22]=[C:23]([O:29][CH3:30])[CH:24]=[C:25]([O:27][CH3:28])[N:26]=1)=[O:18])(=[O:14])=[O:15])(=[O:4])=[O:5]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CN(C)S(=O)(=O)Cc1ccccc1S(=O)(=O)N=C=O
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2CS(=O)(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
A mixture of 2.6 g of the product of Example 5, 0.9 g of 2-amino-4,6-dimethoxypyrimidine and a few crystals of DABCO in 15 ml of dry acetonitrile was heated at 50°-55° for 1 hour under a nitrogen atmosphere, then stirred overnight at room temperature. The precipitate was filtered off, washed with acetonitrile and dried to give 2.1 g of 2-[(dimethylamino)sulfonylmethyl]-N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]benzenesulfonamide, m.p. 172°-176°.
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:5]=1[C:6](OC)=[O:7])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([C:4]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:5]=1[CH2:6][OH:7])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(F)c(F)cc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCc1cc(F)c(F)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a mixture of methyl 2-allyl-4,5-difluorobenzoate (360 mg, 1.697 mmol) in THF (4 mL) was added LAH (3.39 mL, 3.39 mmol) and the reaction was stirred at rt for 1 h. It was then quenched with NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to isolate (2-allyl-4,5-difluorophenyl)methanol (150 mg, 0.814 mmol, 48.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.34-7.24 (m, 1H), 7.08-6.97 (m, 1H), 5.96 (ddt, J=16.8, 10.4, 6.2 Hz, 1H), 5.14 (d, J=10.0 Hz, 1H), 5.03 (d, J=17.1 Hz, 1H), 4.67 (d, J=5.1 Hz, 2H), 3.40 (d, J=6.1 Hz, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:17][C:14]3([CH2:16][CH2:15]3)[N:13]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:12][CH2:11]2)=[N:3][CH:2]=1.S(N[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)(=O)N>>[CH2:27]([NH:21][S:18]([N:13]1[CH2:12][CH2:11][N:10]([C:4]2[C:5]3[CH:9]=[CH:8][NH:7][C:6]=3[N:1]=[CH:2][N:3]=2)[CH2:17][C:14]21[CH2:16][CH2:15]2)(=[O:20])=[O:19])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NS(=O)(=O)NCCc1ccccc1
Reactant: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Product: O=S(=O)(NCCc1ccccc1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
Prepared in a way similar to intermediate 1, using 2-(sulfamoylamino)-ethylbenzene instead of sulfamide.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)C.[BH4-].[Na+]>CO>[F:27][C:23]1[CH:22]=[C:21]([C@H:7]([O:6][CH2:5][CH2:4][OH:3])[C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CO[C@@H](c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCO)c2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(2-ethoxy-2-oxoethoxy)(3-fluorophenyl)methyl)piperidine-1-carboxylate (29.88 g, 75.9 mmol) in MeOH (300 mL) was added NaBH4 (23 g, 605.2 mmol) in portions while the temperature was lower than 40° C. After addition, the mixture was stirred at rt for 2-3 hr. The solvent was removed in vacuo to give a residue which was partitioned between water and EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica gel chromatography to afford (R)-tert-butyl 3-((R)-(3-fluorophenyl)(2-hydroxyethoxy)methyl)piperidine-1-carboxylate (11 g, 41%).
Reaction SMILES: [CH2:1]([C@H:3]1[O:5][CH2:4]1)Cl.C(OC)(C)(C)C.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([O:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:3]1[O:5][CH2:4]1
Reactant: ClC[C@@H]1CO1
Reactant: Oc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: c1ccc(OC[C@H]2CO2)cc1
Reaction time: 37 h
Yield: 74.6 %

Procedure:
To a reaction vessel were added (S)-epichlorohydrin (99% ee, 2.64 g, 29 mmol), benzyltrimethylammonium chloride (72 mg), tert-butylmethyl ether (6 ml) and water (6 ml), and the mixture was cooled with ice. After addition of phenol (1.78 g, 19 mmol), thereto 24% aqueous NaOH solution (4.75 g, 29 mmol) was dropped in a ten minute period under stirring. The mixture was stirred for 30 minutes under ice-cooling and then for 37 hours at room temperature. After the aqueous layer was removed, the organic layer was neutralized with 5% HCl and washed with water twice. The solvent was removed to give objective crude (R)-glycidylphenyl ether (2.13 g, yield 75%, optical purity 98% ee) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=O)=[N:4][CH:3]=1.[O:16]1[C:25]2[CH:24]=[C:23]([CH2:26][N:27]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:22]=[CH:21][C:20]=2[O:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH2:13][N:38]2[CH2:37][CH2:36][CH:35]([N:27]([CH2:26][C:23]3[N:22]=[CH:21][C:20]4[O:19][CH2:18][CH2:17][O:16][C:25]=4[CH:24]=3)[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:40][CH2:39]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2ncc(Br)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.5 %

Procedure:
To 7.00 g of (7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde, a solution of 10.07 g of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbamate in 140 mL of chloroform and 1.57 g of acetic acid were added, and the mixture was stirred at room temperature for 19 hours, then, 8.77 g of sodium triacetoxyborohydride was added thereto and the mixture was stirred for 2 hours. To the reaction mixture, 140 mL of a saturated aqueous sodium hydrogen carbonate solution was added, the organic layer was separated, then washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Chromatorex-NH made by Fuji Silysia Chemical Ltd., and gradient elution with hexane:ethyl acetate=50:50 to 5:95, and then recrystallized in 24 mL of ethanol to obtain 11.26 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a white solid.
Reaction SMILES: IC.[Br:3][C:4]1[CH:10]=[CH:9]C(N)=[C:6]([Cl:11])[CH:5]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]([CH:21]=O)[CH3:20]>>[Br:3][C:4]1[CH:10]=[CH:9][C:21]([N:19]([CH3:20])[CH3:18])=[C:6]([Cl:11])[CH:5]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(C)c1ccc(Br)cc1Cl
Yield: 78 %

Procedure:
Under nitrogen, 11.6 mL (186 mmol) of iodomethane was added to a stirred solution of 12.8 g (62 mmol) of 4-bromo-2-chloroaniline and 42.8 g (310 mmol) of powdered K2CO3 in 200 mL of DMF. Purification by silica gel chromatography (Waters Prep-500A)with ethyl acetate/hexane (5:95) gave 11.3 g (78%) of 4-bromo-2-chloro-N,N-dimethylaniline as a colorless liquid: NMR (CDCl3) δ 2.79 (s, 6H), 6.92(d, J=9 Hz, 1H), 7.25-7.34 (m, 1H), 7.49 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([O:22]C)=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([NH:8][C:9]2[O:10][C:11]3[C:17]([F:18])=[C:16]([CH2:19][C:20]([OH:22])=[O:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cc(Cl)ccc3C)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(Cl)cc1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.7 %

Procedure:
In THF/methanol (4:1, v/v, 100 ml) was dissolved methyl (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.67 g, 4.79 mmol). To the resulting solution was added 1N NaOH (40 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(5-chloro-2-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.39 g, 87%) as a colorless crystalline powder.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[CH3:27]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[CH3:27]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cc1cc(N)ccc1F
Agent: [Na+]
Product: Cc1cc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)ccc1F
Yield: 61.5 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 240 mg of 4-fluoro-3-methylaniline in place of the 2,4-difluoroaniline. 204 mg of N-(4-fluoro-3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:9]([C:26]2[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=2)[NH:10][C:11](=[O:25])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:13]=1[CH3:14])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43]>CN(C)C=O.CO>[C:30]([C:29]1[CH:28]=[CH:27][C:26]([CH:9]2[N:10]([CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)[C:13]([CH3:14])=[C:8]2[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])=[CH:33][CH:32]=1)#[N:31]
Reactant: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=C(C(=O)c2ccco2)C(c2ccc(C#N)cc2)N(CC(=O)OC(C)(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred suspension of 4-{5-(2-furoyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetr-a-hydropyrimidin-4-yl}benzonitrile (Example 20A) (150 mg, 0.33 mmol) and potassium carbonate (83 mg, 0.60 mmol) in dimethylformamide (5 ml) is treated with tert.-butyl bromoacetate (71 mg, 0.36 mmol), then stirred at room temperature overnight (16 h). The reaction solution is then diluted with methanol (7 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/water 10:90→90:10).