Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)(=O)C.[CH3:12][N:13]([CH3:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:30]=[CH:29][C:28]([N:31]([CH3:33])[CH3:32])=[CH:27][C:23]=2[C:24]([OH:26])=[O:25])=[O:21])=[CH:16][CH:15]=1.[OH-].[NH4+]>C1(C)C=CC=CC=1.CO>[CH3:1][O:21][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([N:13]([CH3:34])[CH3:12])=[CH:19][CH:18]=2)[C:22]2[C:23](=[CH:27][C:28]([N:31]([CH3:33])[CH3:32])=[CH:29][CH:30]=2)[C:24](=[O:26])[O:25]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21
Temperature: 47 °C

Procedure:
To a stirred mixture of 30.0 ml of acetic anhydride and 15.0 ml of glacial acetic acid there was added gradually 5.0 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid. The reaction mixture was heated slowly to approximately 47° C. and maintained at a temperature in the range of 45° to 50° C. for approximately thirty minutes. The resultant mixture was cooled to ambient temperature, stirred approximately forty-five minutes and then cooled to approximately 0° C. A solution of 15.0 ml of methyl alcohol and 19.4 ml of pryidine was added dropwise to the reaction mixture while maintaining a temperature of approximately 0° C. The resulting mixture was allowed to stir at ambient temperature for approximately two hours. After adding toluene to the reaction mixture, five percent aqueous ammonium hydroxide was added slowly until the resulting mixture was slightly alkaline. The toluene layer was separated from the alkaline water layer and toluene was removed under reduced pressure to obtain 4.67 g of 3-methoxy-3(4-dimethylaminophenyl)-6 -dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green-colored solid which melted at 140° to 147° C. A significant infrared maximum appeared at 1760 cm-1 (C=O; s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on an acid-clay coated paper developed a turquoise-colored image.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:1]([O:8][CH:9]1[CH2:12][C:11](=[O:13])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CC(=O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3-(tert-butyldimethylsilyloxy)cyclobutanol (2.59 g, 13 mmol), sodium bicarbonate (3 ml, 38 mmol), and Reactant 1 [?] (7 g, 15 mmol) in DCM (40 ml) was stirred at RT in 4 h, the solid was filtered; the filtrated was purified by ISCO (5% EtOAc/Hexanes) to give the title compound as a colorless oil.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1.[C:13](OCC)(=[O:16])[CH:14]=[CH2:15]>C(O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:11][C:10]2=[O:12])=[CH:7][CH:8]=1
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: C=CC(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(F)cc2)C(=O)C1
Yield: 10.4 %

Procedure:
Sodium (0.3 g, 0.013 moles) was dissolved in ethanol (50 ml) and 4-Fluorophenylacetone (2.0 g, 0.013 moles) was added in ethanol (10 ml). Ethyl acrylate (1.3 g, 0.013 moles) was and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool and evaporated under reduced pressure to give a brown gum. Dissolved in water and washed with diethyl ether. The aqueous layer was acidified to pH2 with conc. Hydrochloric acid and extracted with dichloromethane. The extracts were combined and washed with water. Dried over anhydrous magnesium sulphate and filtered. The filtrate was evaporated to give an orange oil. (1.7 g) This was purified using a silica column eluted with dichloromethane:ethyl acetate 8:2 and then dichloromethane:ethyl acetate 2:1 to give a colorless gum. (0.428 g) This was triturated with diethyl ether/isohexane to give 4-(4-Fluorophenyl)cyclohexane-1,3-dione (0.28 g) as a white solid.
Reaction SMILES: CC([O-:5])(C)C.[K+].[C:7]1([CH:13]([C:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=O)[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:23](Br)[CH:24]=[CH2:25]>C1COCC1>[C:7]1([C:13]2([CH3:14])[CH2:15][CH:17]([C:22](=[O:5])[CH:21]=[CH:20][CH2:19][CH3:18])[CH2:25][CH2:24][CH2:23]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C=CCBr
Reactant: CC(C(=O)C1CCCCC1)c1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC=CC(=O)C1CCCC(C)(c2ccccc2)C1
Yield: 91.6 %

Procedure:
A solution of 31.39 g (0.2797 mol) of t-BuOK in 100 mL of THF was added dropwise to a solution of 55.00 g (0.2543 mol) of cyclohexyl 1-phenylethyl ketone and 26.4 mL (0.3052 mol) of allyl bromide in 136 mL of THF (cooled in a wet ice acetone bath). THF washings (16 mL) were added to the reaction mixture. The cooling bath was removed after addition. After reaction completion (2 h), the reaction mixture was quenched with 300 mL of 1 N HCl (pH=0) and extracted with 300 mL of heptane. The heptane extract was washed with 10% NaHCO3 (aq) (pH=9), dried over MgSO4, gravity filtered and concentrated under vacuum to afford 59.70 g (91.58%) of title compound as an amber oil: 1H NMR (d6-DMSO): δ 7.32-7.42 (m, 2H, phenyl CH), 7.24-7.31 (m, 3H, phenyl CH), 5.34-5.47 (m, 1H, —CH═CH2), 5.02 (dd, J=17.1 Hz, J=2.1 Hz, 1H, —CH═CH—H (trans)), 4.97 (ddd, J=10.2 Hz, J=2.2 Hz, J=1.0 Hz, 1H, —CH═CH—H (cis, W-coupling)), 2.66 (ddd, J=14.2 Hz, J=6.9 Hz, J=1.0 Hz, 1H, CH2CH═CH2), 2.59 (ddd, J=14.2 Hz, J=7.3 Hz, J=1.0 Hz, 1H, —CH2CH═CH2), 2.38-2.49 (m, 1H, cyclohexyl CH), 1.48-1.69 (m, 4H, cyclohexyl —CH2), 1.46 (s, 3H, —CH(CH3)Ph), 1.36-1.44 (m, 1H, cyclohexyl —CH2), 0.82-1.36 (m, 5H, cyclohexyl —CH2).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([CH:10]=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1(S(CP(OCC)(=O)OCC)(=O)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C[O-].[Na+].[CH:40]([S:42]([CH:45]=[CH2:46])(=[O:44])=[O:43])=C.[ClH:47]>CCOC(C)=O>[ClH:47].[C:19]1([CH:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[C@@H:2]([NH2:1])[CH:10]=[CH:40][S:42]([CH:45]=[CH:46][C@H:2]([NH2:1])[CH:3]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:44])=[O:43])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CS(=O)(=O)C=C
Reactant: CCOP(=O)(CS(=O)(=O)c1ccccc1)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: N[C@@H](C=CS(=O)(=O)C=C[C@H](N)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Yield: 88 %

Procedure:
Boc-D-Phe-VS-Ph was prepared by reaction of Boc-D-Phe-H with diethyl phenylsulfonylmethanephosphonate in the presence of 2 N sodium methoxide, yield 85%. 1H-NMR (CDCl3) δ 1.3-1.4 (s, 9H, Boc), 2.9 (d, 2H, CH2-Phe), 4.4-4.5 (b, 1H, α-H), 4.6-4.7 (b, 1H, NH), 6.3 (d, 1H, CH═), 6.9-7.0 (dd, 1H, CH═), 7.1-7.3 (m, 5H, Ph), 7.5-7.8 (m, 5H, SO2-Ph). MS (FAB+) m/z 388 (M+1, 15%), 288 (M−Boc+1, 100%). Boc-D-Phe-VS-Ph was deblocked with 6.7 N HCl in EtOAc to give D-Phe-VS-Ph.HCl, yield 88%. 1H-NMR (DMSO-d6) δ 2.9-3.0 (m, 1H, CH2-Phe), 3.1-3.2 (m, 1H), 4.2 (b, 1H, α-H), 6.7-6.8 (m, 2H, CH═), 7.1-7.3 (m, 6H, CH═ and Ph), 7.6-7.8 (m, 5H, SO2-Ph), 8.6-8.8 (b, 2H, NH2). MS (FAB+) m/z 288 (M−Cl, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C=O)C>[CH2:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:4]=1[C:5]([Cl:16])=[O:6])[CH3:2]
Reactant: CCc1cccc(C)c1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cccc(C)c1C(=O)Cl
Reaction time: 15 h

Procedure:
A solution of 2-ethyl-6-methylbenzoic acid (49 mg, 0.30 mmol) in dichloromethane (3 mL) containing DMF (1 drop) was treated with oxalyl chloride (0.14 mL, 1.6 mmol) and the mixture was stirred for 15 h. The mixture was concentrated, azeotroping with toluene to remove traces of oxalyl chloride and the residue was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.[Cl:17][C:18]1[N:19]=[N:20][C:21](Cl)=[C:22]([CH3:25])[C:23]=1[CH3:24].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:17][C:18]1[N:19]=[N:20][C:21]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][N:7]=3)[CH2:14][CH2:13]2)=[C:22]([CH3:25])[C:23]=1[CH3:24]
Reactant: Cc1c(Cl)nnc(Cl)c1C
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)nnc(N2CCN(c3ccc(C(F)(F)F)cn3)CC2)c1C
Yield: 82 %

Procedure:
1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (10 g, 43.3 mmol) is combined with 3,6-dichloro-4,5-dimethyl-pyridazine (14.4 g, 84.3 mmol), triethylamine (8.25 mL), and NMP (40 mL). The reaction mixture is irradiated to a temperature of 180° C. for 25 min, and then concentrated in vacuo. The residue is purified by flash chromatography on silica gel (0-8% MeOH/CH2Cl2) to afford the title compound (13.2 g, 82%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[N:11]1([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.[Si](C#N)(C)(C)C.[N:30]1([C:35](N2C=CN=C2)=[O:36])C=CN=[CH:31]1>[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:19]([C:18]4[CH:21]=[CH:22][CH:23]=[C:16]([N:11]5[CH2:15][CH2:14][CH2:13][CH2:12]5)[CH:17]=4)[CH2:31][NH:30][C:35]3=[O:36])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1cccc(N2CCCC2)c1
Agent: [Pd]
Agent: C[Si](C)(C)C#N
Product: O=C1NCC(c2cccc(N3CCCC3)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (0.400 g, 3 mmol), 3-(pyrrolidin-1-yl)benzaldehyde (0.526 g, 3 mmol), TMSCN (0.375 mL, 3 mmol), Pd/C (10%, 0.02 g), TEA 1.05 mL, 7.5 mmol), di-(imidazol-1-yl)methanone (0.730 g, 4.5 mmol) as described in method 2.
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: Nc1cc(Cl)c(Cl)cn1
Reactant: C1COCCN1
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: [Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][OH:10])=[CH:4][C:3]=1[CH3:15].[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[C:13]([CH3:14])=[CH:12][C:5]([O:6][CH2:7][C@@H:8]([CH3:11])[CH2:9][O:10][S:17]([CH3:16])(=[O:19])=[O:18])=[CH:4][C:3]=1[CH3:15]
Reactant: Cc1cc(OC[C@@H](C)CO)cc(C)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(OC[C@@H](C)COS(C)(=O)=O)cc(C)c1Br

Procedure:
(S)-3-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propan-1-ol (130 mg), methanesulfonyl chloride (0.073 mL) and triethylamine (0.264 mL) are stirred in 5 mL of dichloromethane at room temperature overnight. The reaction mixture is washed with citric acid saturated aqueous solution and with brine. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound, used in the next step without further purification. Yield: 148 mg.
Reaction SMILES: C(OC(=O)C[C:6]([CH2:8][C:9](=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])=[O:7])C.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:6](=[O:7])[CH2:8][C:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: CCO
Product: CCOC(=O)CC(=O)Cc1ccccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
30 gm (0.103M) ethyl-o-nitrophenylacetylacetoacetate was added over a period of 15-20 minutes to a saturated ammoniacal ethanol solution (prepared by bubbling NH3 gas into 400 cc. absolute alcohol for 15-20 minutes while cooling the solution to 0°-5° C.). The orangy mixture was stirred for 1 hour at 5°-10° C. and then left in the refrigerator overnight. The ethyl-γ-2-nitrophenylacetoacetate crystals formed were filtered and dried in vacuum. Additional solid was obtained after evaporation of the filtrate and washing with water to remove any amide formed.
Reaction SMILES: C1COCC1.C[Si](Cl)(C)C.Br[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].I[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>[Zn].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.O.CN(P(N(C)C)(N(C)C)=O)C>[C:16]([O:15][C:13]([CH2:12][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
11.4 g (0.170 mol) of powdered zinc and 50 ml of THF are-introduced into a three-necked flask, 2.2 ml of trimethylsilyl chloride are added and the mixture is stirred for 15 minutes, 28 ml (0.174 mol) of tert-butyl 2-bromoacetate are then introduced dropwise and the mixture is stirred for 30 minutes. It is cooled to 0° C. (icebath), 5 g (4.3 mmol) of tetrakis(triphenylphosphine)palladium(0), 10.8 g (43.5 mmol) of 4-iodobenzoic acid and 50 ml of HMPA are introduced and the mixture is heated to 40° C. for one hour. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (95:5). After evaporation of the solvents, 8.1 g (80% ) of the expected product, melting point 132°-133° C., are collected.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C.C1(C)C=CC=CC=1>[CH2:15]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][C:3]([C:2]([F:13])([F:14])[F:1])=[CH:11][CH:10]=1)[NH2:12])[CH3:16]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
19.8 grams of 4-trifluoromethylanthranilic acid are dissolved in 350 ml of anhydrous ethanol and 300 ml of dry toluene. To this solution is added 21.8 grams of anhydrous p-toluenesulfonic acid. The solution is refluxed under an extractor containing a thimble of anhydrous magnesium sulfate for 2 weeks with periodic replacement of the drying agent. The solvent is then removed on a rotary evaporator. The residue is treated with 200 ml of 2N sodium hydroxide. The resultant mixture is extracted thrice with combined 75 ml portions of diethylether. The combined extracts are washed with 2N sodium hydroxide, then distilled water and finally brine. The organic solution is dried over anhydrous potassium carbonate. The drying agent is filtered off, and the solvent is removed on a rotary evaporator. The resultant oil is chromatographed on a filter column of silica gel with chloroform as the eluant. The first fractions contain 4-trifluoromethylanthranilic acid ethyl ester, which is recovered by crystallization. Melting Point: 42°-43° C.
Reaction SMILES: C([O:5][CH:6]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])N(C)C)(C)(C)C.[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22](C(O)=O)[CH:21]=[CH:20][C:19]=12>CN(C)C=O.C1(C)C=CC=CC=1>[CH:15]1[N:16]=[CH:17][N:18]2[CH:23]=[C:22]([C:6]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:5])[CH:21]=[CH:20][C:19]=12
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc2cncn2c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc2cncn2c1
Temperature: 90 °C

Procedure:
3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are added to 570 mg (3.52 mmol) of imidazo[1,5-a]pyridine-6-carboxylic acid [described in Bioorg. Med. Chem. Lett., (2002), 12(3), 465-470] in a mixture of 5 ml of dimethylformamide and 5 ml of toluene and the mixture is heated at 90° C. for 6 hours. 3.37 ml (14.06 mmol) of N,N-dimethylformamide di(tert-butyl)acetal are again added to the reaction medium and the mixture is heated at 90° C. for a further 4 hours. The reaction medium is poured onto water and extracted with ethyl acetate. The organic phase is separated by settling, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The product is purified by filtration through a bed of silica, elution being carried out with a mixture of dichloromethane and methanol (98/2). After evaporation, 580 mg of a beige powder are obtained. Melting point: 77° C.; 1H NMR (d6-DMSO): 1.59 (9H, s), 7.71 (1H, d), 7.36 (1H, s), 7.58 (1H, d), 8.56 (1H, s), 9.03 (1H, s).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>C(O)(C)C>[Cl:26][C:27]1[N:32]=[C:31]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:13]=[CH:14][C:4]([O:3][C:2]([F:15])([F:16])[F:1])=[CH:5][CH:6]=2)[CH:30]=[CH:29][N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCCCOc1ccc(OC(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: FC(F)(F)Oc1ccc(OCCCNc2ccnc(Cl)n2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
To a solution of 3-(4-(trifluoromethoxy)phenoxy)propan-1-amine (450 mg, 1.91 mmol) in isopropanol (8 mL, 3 mL/mmol) was added DIPEA (0.5 mL, 2.86 mmol) and 2,4-dichloropyrimidine (340 mg, 2.29 mmol) and the mixture was stirred at 80° C. for 24 h. Then reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 mL) and water (2×30 mL). The EtOAc layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography provided 2-chloro-N-(3-(4-(trifluoromethoxy)phenoxy)propyl)pyrimidin-4-amine (400 mg, 60%) as a solid. Observed mass (M+1): 348.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]O.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6][Cl:16]
Reactant: O=S(Cl)Cl
Reactant: OCCOc1c(Cl)cc(Cl)cc1Cl
Product: ClCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
Reacting the 2-(2,4,6-trichlorophenoxy)-ethanol with thionyl chloride in the presence of a catalytic amount of a tetra-alkyl ammonium halide at a temp. of from 30° C. to 100° C., optionally in the presence of a solvent to form 2-(2,4,6-trichlorophenoxy)-ethyl chloride;
Reaction SMILES: O[CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][CH2:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(OCCCN2CCCCC2)cc1
Solvent: ClCCl
Product: ClCc1ccc(OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[3-(4-hydroxymethylphenoxy)propyl]piperidine (5.617 g) in dichloromethane (50 mL), cooled at a temperature close to 0° C., is added dropwise thionyl chloride (3 mL). The mixture is stirred for 18 hours at room temperature and concentrated under reduced pressure. The residue is crystallized in diethyl ether to give 1-[3-(4-chloromethylphenoxy)propyl]piperidine as an off white solid used without further purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH:33]2[CH2:36][CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Reactant: NC1CCC1
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CCC4)ncnc32)[C@]1(C)F
Yield: 46.5 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.4 g, 0.86 mmol) in ethanol (about 5 ml) was added cyclobutylamine (about 0.88 ml, 10.38 mmol) and refluxed for about 2 hours. Completion of the reaction monitored by thin-layer chromatography and water added to the reaction mixture. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.20 g) as a colorless gummy mass. Yield: 46.5%.
Reaction SMILES: [CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O>>[CH2:1]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=S(Cl)Cl
Reactant: CCCCCc1ccc(C(=O)O)cc1
Product: CCCCCc1ccc(C(=O)Cl)cc1

Procedure:
15 g. of p-n-pentylbenzoic acid are dissolved in 100 ml. of thionyl chloride and boiled at reflux for 1 hour. The excess thionyl chloride is then removed by distillation and the acid chloride is distilled under high vacuum. The p-n-pentylbenzoic acid chloride which is obtained has a boiling point of 104° C/2 mm.
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[Cl:7][C:8]1[CH:22]=[C:21]([F:23])[C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=2)=[C:10]([F:24])[CH:9]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:7][C:8]1[CH:22]=[C:21]([F:23])[C:11]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[CH2:1])=[CH:15][CH:14]=2)=[C:10]([F:24])[CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: O=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (8.7 g, 24.35 mmol) and KOt-Bu (3.4 g, 30.3 mmol) in dry THF (20 mL), which was stirred at room temperature for 1 h under nitrogen, was added a solution of 4-(4-chloro-2,6-difluorophenoxy)benzaldehyde (5.4 g, 20.10 mmol) in THF (8 mL). The mixture was stirred at room temperature overnight, and quenched with water. The aqueous phase was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.6 g, 9.75 mmol, 48.5% yield). LCMS: rt=4.06 min, [M+H+]=267