Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][CH2:2][C:3]([N:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCl)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
Chloroacetyl chloride (0.32 ml, 4.02 mmol) was dissolved in a mixed solvent of toluene (6 ml) and tetrahydrofuran (2 ml). The solution was added with diphenylamine (690 mg, 4.08 mmol) at room temperature, and the heated at 100° C. for 80 minutes. The solvent was evaporated under reduced pressure, and the solid precipitated was suspended and washed in ethyl ether. The solid was collected by filtration and dried under reduced pressure to obtain the title compound as colorless solid (746 mg, yield: 75%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:29])[C:13]([CH:23]([OH:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].C(=O)([O-])O.[Na+]>C1COCC1>[CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:29])[C:13]([CH:23]([O:28][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:24]([O:26][CH3:27])=[O:25])=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC(C(=O)OC)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
146 mg of methyl [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](hydroxy)acetate was dissolved in 10 ml of THF, and 46 mg of 60% sodium hydride was added under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 58 μl of ethyl bromoacetate was added to the reaction mixture, followed by stirring at room temperature for 5 hours. 46 mg of 60% sodium hydride and 10 ml of THF were further added under ice-cooling, followed by stirring at room temperature for 2 hours. Then, 58 μl of ethyl bromoacetate was added thereto, followed by stirring at room temperature for 17 hours. Aqueous saturated sodium hydrogen carbonate was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate, concentration was carried out under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 66 mg of methyl [7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl](2-ethoxy-2-oxoethoxy)acetate.
Reaction SMILES: [ClH:1].O1CCOCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[C:37]4[C@H:44]([CH3:45])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:32][CH2:31]2)=[O:29])[CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>O1CCOCC1>[ClH:8].[ClH:1].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])[C:28]([N:30]2[CH2:35][CH2:34][N:33]([C:36]3[C:37]4[C@H:44]([CH3:45])[CH2:43][CH2:42][C:38]=4[N:39]=[CH:40][N:41]=3)[CH2:32][CH2:31]2)=[O:29])=[CH:11][CH:10]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 189.5 %

Procedure:
4M HCl/dioxane (7.83 ml, 31.3 mmol) was added to a slightly cloudy solution of tert-butyl(S)-2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.679 g, 1.25 mmol) in dioxane (8 mL). The reaction mixture was stirred overnight under nitrogen (16 hours). The reaction mixture was concentrated to dryness and dried on a high vacuum line. The resulting residue was dissolved in minimal MeOH, and the solution was added dropwise to a stirring solution of ether, which caused a white precipitate to form. The resulting precipitate was isolated by filtration through a medium frit funnel with nitrogen pressure, rinsed with ether, dried with nitrogen pressure, dried in vacuo and then further in a 55° C. high vacuum oven for 2 days to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.610 g, 94.6% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>CN(C=O)C>[Cl:8][C:6]1[C:5]([I:16])=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: Nc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: Nc1cc(Cl)c(I)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
To a solution of 2-amino-4-chloropyridine (150 g, 0.78 mol) in DMF (1.5 L) was added NIS (341 g, 1.52 mol) and the reaction mixture stirred at RT for 18 h before being concentrated in vacuo to 300 mL volume. The resultant residue was poured into 10% aqueous sodium thiosulfate solution (1.2 L), stirred for 15 min and the precipitate formed collected by filtration, washed with water then dried at 35° C. in vacuo to give the title compound as a pale brown solid (185 g, 62%). 1H NMR 400 MHz (CDCl3) δ: 8.33 (1H, s), 6.68 (1H, s), 4.52 (2H, s).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH2:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC(N(C)C)=O>[Cl:8][C:7]1[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:3][C:4]([NH2:9])=[N:5][CH:6]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Cl)c(Cl)cn1
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCOCC2)c(Cl)cn1
Temperature: 200 °C
Yield: 88.3 %

Procedure:
A mixture of 4,5-dichloropyridin-2-amine (300 mg, 1.84 mmol) and morpholine (480 mg, 5.52 mmol) in DMA (3.6 mL) was heated at 200° C. for 60 minutes by microwave irradiation. The mixture was purified by ion exchange chromatography on SCX-II acidic resin (2 g) eluting with methanol, then 2M ammonia-methanol. The basic fractions were combined and solvent was evaporated. Flash chromatography on silica, eluting with ethyl acetate-hexane (1:1) gave 5-chloro-4-morpholinopyridin-2-amine as a colourless solid (347 mg, 88%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]([CH3:31])[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]1)[N:11]=[CH:10][N:9]=2)=[O:5].[CH3:33][Mg]Cl>C1COCC1>[C:4]([C:6]1[N:7]([CH3:31])[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]3[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[NH:23][C:22]3=[O:30])[CH2:17][CH2:16]1)[N:11]=[CH:10][N:9]=2)(=[O:5])[CH3:33]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Solvent: C1CCOC1
Product: CC(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
N-Methoxy-N,9-dimethyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide (30 mg, 0.07 mmol) was dissolved into THF (2 mL) under nitrogen and cooled to −78° C. Methylmagnesium chloride (3 M in THF; 0.046 mL, 0.14 mmol) was added to the reaction mixture. The reaction was stirred at −78° C. for 30 minutes and slowly warmed to room temperature. After 1 hour, the crude reaction mixture was concentrated, diluted with ethyl acetate, washed with water and saturated potassium carbonate. The organic layer was collected, was concentrated, was dissolved into methanol and was purified by preparative HPLC to afford 1-[1-(8-acetyl-9-methyl-9H-purin-6-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (9.3 mg, 0.023 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.85 (s, 1H), 8.35 (s, 1H), 7.20-7.14 (m, 1H), 6.96-6.88 (m, 3H), 6.27-4.92 (m, 2H), 4.66-4.45 (m, 1H), 3.93 (s, 3H), 3.42-3.20 (m, 2H), 2.63 (s, 3H), 2.42-2.26 (m, 2H), 1.87 (br d, 2H). MS (EI) for C20H21N7O2: 392 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16](=[O:33])[C@@H:17]([NH:25]C(=O)OC(C)(C)C)[CH2:18][S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[NH2:25][C@@H:17]([CH2:18][S:19][S:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]([NH:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSSC(C)(C)C)C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSC[C@H](N)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of (R)-tert-butyl (1-(benzylamino)-3-(tert-butyldisulfanyl)-1-oxopropan-2-yl)carbamate (Compound tk92) (1.049 g, 2.63 mmol) in dichloromethane (9 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then extracted with ethyl acetate/saturated sodium bicarbonate, and the organic layer was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford (R)-2-amino-N-benzyl-3-(tert-butyldisulfanyl)propanamide (Compound tk93) (810 mg, 100%).
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([C:3]3[O:2][CH:6]=[CH:5][CH:4]=3)[CH:8]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: Nc1cccc(-c2ccco2)c1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Agent: Cl
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2ccco2)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(furan-2-yl)aniline.hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-2-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 77%). Note that 3-(furan-2-yl)aniline.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 25 g of 4-bromo-2-fluorophenol, 19 g of potassium carbonate and 100 ml of acetone was refluxed under stirring for 30 minutes. The reaction mixture was cooled, to which 17.40 g of benzyl chloride were dropwise added taking 15 minutes. The resultant was refluxed under stirring for 7 hours and filtered. The filtrate was distilled to remove acetone. The residue to which water was added was extracted with chloroform. The extract was washed, dried and purified by a silica gel column chromatography using chloroform. The eluate was evaporated under reduced pressure to obtain 22.24 g of the intended benzyl 4-bromo-2-fluorophenyl ether.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(c1O)CCC2
Product: CCOC(=O)c1cnc2c(c1Cl)CCC2

Procedure:
A mixture of 2.6 g of ethyl 6,7-dihydro-4-hydroxy-5H-cyclopenta[b]pyridine-3-carboxylate [J. Heterocyclic Chem. 12, 1245 (1975)] and 100 mL of phosphorous oxychloride is refluxed for 2.5 hours. The excess phosphorous oxychloride is then removed by evaporating under reduced pressure. The residue is dissolved in chloroform and washed with ice-cold saturated sodium bicarbonate aqueous solution. The chloroform layer is separated, dried over magnesium sulfate, passed through a short silica gel column and evaporated to dryness to yield ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][N:11]=1.C>C1CCCCC1.C(O)(=O)C>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[CH3:6])=[N:11][CH:12]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1ccc(Br)cn1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(C)n1-c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
Hexane-2,5-dione (97 mL, 831 mmol) was added to a solution of 2-amino-5-bromo-pyridine (125 g, 722 mmol) in cyclohexane (625 mL) and acetic acid (20 mL). The solution was heated to reflux under argon atmosphere with a Dean-Stark trap. A total of 30 mL of water was collected from the Dean-Stark trap. The mixture was allowed to cool to room temperature, diluted with water, and extracted with diethyl ether. The organic phase was washed with 1N hydrochloric acid (4×), saturated aqueous sodium bicarbonate solution (2×) and saturated aqueous sodium chloride solution (2×). The organic phase was dried (MgSO4) and concentrated in vacuo to yield a yellow solid. The product was dissolved in hot hexanes (200 mL). Charcoal was added and the mixture filtered. Crystallization proceeded over three hours at 0° C. The solid was collected by filtration to yield yellow crystals (145 g, 80%). Mp=69° C.; 1H NMR (CDCl3, 300 MHz) δ 8.66 (d, 9 Hz, 1 H), 7.96 (dd, 9 Hz, 8 Hz, 1 H), 7.15 (d, 8 Hz, 1 H), 5.91 (s, 2 H), 2.14 (s, 6 H); MS (CI) m/z 251 (MH+); Anal. Calcd. for C11H11BrN2 : C, 52.61; H, 4.42; N, 11.16; Br, 31.82. Found: C, 52.62; H, 4.56; N, 11.18; Rf =0.4 (60:40 dichloromethane/hexanes).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[NH:15][C:14](=O)[C:13]3=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[C:14]([NH:27][C:26]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:13]3=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]3[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: COc1ccc(-c2nn3c(C)nc(C)c3c(=O)[nH]2)cc1Cl
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(Nc3cc(OC)c(OC)c(OC)c3)c3c(C)nc(C)n3n2)cc1Cl
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 30 mg (0.08 mmol) of the compound of Example 33A with 100 mg (0.55 mmol) of 3,4,5-trimethoxyaniline is stirred in the form of a melt for 16 hours at a bath temperature of 120° C. It is taken up in ethyl acetate, washed with water, dried and concentrated. After purification on a silica gel column using dichloromethane/ethyl acetate [lacuna] to 2:1 and filtering off with suction using ether/heptane, 28.6 mg (43.31% of theory) of almost colourless crystals are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1([C:10]([F:13])([F:12])[F:11])[O:7][CH:6]([CH2:8][OH:9])[CH2:5][O:4]1.[H-].[Na+].[Na].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1.CO>[F:13][C:10]([F:11])([F:12])[C:3]1([C:2]([F:1])([F:14])[F:15])[O:7][CH:6]([CH2:8][O:9][CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5][O:4]1
Reactant: OCC1COC(C(F)(F)F)(C(F)(F)F)O1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(C(F)(F)F)OCC(COC(c2ccccc2)c2ccccc2)O1

Procedure:
A sample of 12 grams (0.05 mols) of 2,2-bis(trifluoromethyl)-4-hydroxymethyl-1,3-dioxolane in 50 ml toluene is treated with 1.93 grams sodium hydride - mineral oil (53.4%, 0.043 mols) at 25°-33° C. The sodium salt is stirred for 2 hours at 35° C. Benzhydryl bromide, 10.6 grams, (0.043 mols) is added at 37° C. and then the temperature is raised to 75°-95° C. for 3 hours. The mixture is filtered and the filtrate washed with water. Vacuum-stripping gives an oil which is dissolved in methanol and clarified by filtration through Super Cel. Yield of product is 17.0 grams at this point. A forerun is distilled in a 4 inch column filled with stainless steel packing, the remainder without packed column. The product obtained is distilled at 137° C. under 0.45 mm of mercury pressure to yield 2,2-bis(trifluoromethyl)-4-diphenylmethoxymethyl-1,3-dioxolane.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[N:12]1[C:21]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]=2[CH:15]=[CH:14][C:13]=1[C:22]([O:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([NH:8][C:9]([N:18]1[CH2:19][CH2:20][C:21]2[N:12]=[C:13]([C:22]([O:24][CH3:25])=[O:23])[CH:14]=[CH:15][C:16]=2[CH2:17]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(n1)CCNC2
Reactant: O=C=NCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(n1)CCN(C(=O)NCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a vial containing benzyl isocyanate (0.0166 g, 0.125 mmol), was added methyl 5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate hydrochloride (0.0220 g, 0.0962 mmol), DIPEA (0.0586 mL, 0.337 mmol) and DMF (2 mL). The resulting solution was then shaken at rt for 13 h and then concentrated to give methyl 6-(benzylcarbamoyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
7-Oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.7 g, 48.6 mmol) was dissolved in methylene chloride (100 mL). Et3N (13.5 mL, 97.3 mmol) and 4-chlorobenzenesulfonyl chloride (12.3 g, 58.4 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 20/1 to 1/1) to give 16.6 g (82%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.164, method [1], MS (ESI) 437.0 (M+Na); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 4.40 (d, J=4.4 Hz, 2H), 4.18-3.95 (m, 2H), 2.95-2.81 (m, 2H), 2.59 (dd, J=15.9, 6.0 Hz, 2H), 2.38 (d, J=15.9 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH2:21][CH2:22][F:23])[N:12]=[N:11][N:10]=1
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCn1nnnc1-c1cccc(Cl)c1Cl
Reaction time: 0.25 h
Yield: 65.9 %

Procedure:
To 100 mL of acetonitrile was added 5 g of 5-(2,3-dichlorophenyl)-1H-tetrazole (Lancester Synthesis Inc., Windham, N.H.) followed by 2.5 g of potassium carbonate. After stirring for 15 min, 5 g of 1-bromo-2-fluoroethane was added dropwise. After the addition, the resulting mixture was then heated to reflux for 3 hours and then filtered. The solvent was then evaporated under reduced pressure leaving 4 g of 5-(2,3-dichlorophenyl)-1-(2-fluoroethyl)-1H-tetrazole as an oil.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][CH:20]=1>>[CH:21]([C:18]1[N:19]=[CH:20][C:15]([NH:14][C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: CC(C)c1ccc(N)cn1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cn1
Yield: 86.4 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.51 g) and 5-amino-2-isopropylpyridine (1.17 g) as starting materials, N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.18 g) was obtained. melting point: 155.7° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([OH:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][O:24][CH2:25]Cl>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([NH2:21])=[O:20])=[C:13]([O:22][CH2:23][O:24][CH3:25])[CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(=O)CCc1ccc(OCc2ccccc2)cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(OCc2ccccc2)ccc1CCC(N)=O
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 5.64 g of 60% sodium hydride in oil in 628 mL of N,N-dimethylformamide was added 34.8 g of 3-(4-benzyloxy-2-hydroxyphenyl)propionamide under ice-cooling, and the mixture was stirred at 50° C. for 40 minutes. To the reaction mixture was added 12.39 g of chloromethyl methyl ether under ice-cooling, and the mixture was stirred at room temperature for 15 hours. After the reaction mixture was concentrated under reduced pressure to remove the solvent, the residue was poured into a mixture of 500 mL of ethyl acetate, 100 mL of toluene, and 200 mL of water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a colorless solid. The solid was triturated in ethyl acetate-diisopropyl ether to collect by filtration of 35.3 g of 3-(4-benzyloxy-2-methoxymethoxy-phenyl)propionamide as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.16 min; [M+H]+=475.07.