Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:4][C:3]=1[O:17][CH3:18].[CH2:19]([O:21][C:22](=[O:30])[C:23]([C:25](OCC)=[O:26])=[O:24])[CH3:20]>C(O)(=O)C>[CH2:19]([O:21][C:22]([C:23]1([OH:24])[C:7]2[C:2](=[C:3]([O:17][CH3:18])[CH:4]=[C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH:6]=2)[NH:1][C:25]1=[O:26])=[O:30])[CH3:20]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: COc1cc(CCNC(=O)C(F)(F)F)ccc1N
Solvent: CC(=O)O
Product: CCOC(=O)C1(O)C(=O)Nc2c(OC)cc(CCNC(=O)C(F)(F)F)cc21

Procedure:
2.5 g of N-[2-(4-amino-3-methoxyphenyl)ethyl]trifluoroacetamide and 1.9 ml of mesoxalic acid diethyl ester are dissolved in 25 ml of acetic acid and refluxed for 4 hours. The mixture is concentrated, the residue dissolved in ethyl acetate and extracted twice by shaking with saturated sodium bicarbonate solution. The mixture is concentrated and chromatographed on silica gel with cyclohexane/ethyl acetate 1:1, thus obtaining 2.5 g of 2,3-dihydro-3-hydroxy-7-methoxy-2-oxo-5-(trifluoroacetamidoethyl)-3-indolecarboxylic acid ethyl ester, mp 115°-117° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[C:4]([N:9]2[CH2:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C1COCC1.O>[F:19][C:2]([F:1])([F:20])[C:3]1[C:4]([N:9]2[CH2:10][CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C1=CCN(c2ncccc2C(F)(F)F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=CCN(c2ncccc2C(F)(F)F)CC1
Reaction time: 2 h

Procedure:
Methyl 3′-(trifluoromethyl)-3,6-dihydro-2H-1,2′-bipyridine-4-carboxylate (15 mL) in THF (30 mL) was treated with 1N NaOH (27 mL) and stirred for 2 hours. The mixture was treated with additional 1N NaOH (16 mL), stirred for 1 hour, treated with 1N NaOH (14.5 mL), and stirred for 1 hour. The mixture was diluted with water and extracted with CH2Cl2. The aqueous layer was then acidified with concentrated HCl and extracted with CHCl3. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.C(N(CC)CC)C.[CH3:34][N:35]1[C:39]([C:40](Cl)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1>O1CCCC1>[CH3:34][N:35]1[C:39]([C:40]([NH:1][C:2]2[CH:26]=[CH:25][CH:24]=[C:4]([O:5][C:6]3[CH:7]=[CH:8][C:9]4[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[O:17])[N:14]=4)[N:11]=3)[CH:3]=2)=[O:41])=[CH:38][C:37]([CH3:43])=[N:36]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CCOCC4)cn3n2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CCOCC5)cn4n3)c2)n(C)n1
Yield: 26.9 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]tetrahydro-2H-pyran-4-carboxamide (200 mg, 0.57 mmol), triethylamine (237 mL, 1.70 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (180 mg, 1.13 mmol) and tetrahydrofuran (6.0 mL) as starting materials and in the same manner as in Example 96, the title compound (73 mg, 27%) was obtained as a white powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:3]=1.[CH:22]1(Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)c1cc(I)ccc1N=C1NCC2(CCCC2)S1
Reactant: BrC1CCCC1
Product: CC(C)(C)c1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-tert-Butylaniline was converted to 4-iodo-2-tert-butylaniline according to Method A5a. The aniline was converted to 4-iodo-2-tert-butylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-tert-butylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-tert-butylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[C:28]([C:32]([NH:34][CH3:35])=[O:33])=[CH:27][CH:26]=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:36][CH3:37])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:42](C)=O.[Na+]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH3:42])[C:6]2([CH2:9][O:10][C:11]3[CH:20]=[C:19]4[C:14]([C:15]([O:21][C:22]5[CH:23]=[C:24]6[C:29](=[CH:30][CH:31]=5)[C:28]([C:32]([NH:34][CH3:35])=[O:33])=[CH:27][CH:26]=[CH:25]6)=[CH:16][CH:17]=[N:18]4)=[CH:13][C:12]=3[O:36][CH3:37])[CH2:7][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(NCC6CC6)CC5)c(OC)cc34)ccc12
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC(=O)c1cccc2cc(Oc3ccnc4cc(OCC5(N(C)CC6CC6)CC5)c(OC)cc34)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound of Example 13 (40 mg) was mixed with HCHO (2 eq, 37% in H2O), NaBH(OAc)3 (2 eq) in DCM (5 ml) and stirred at RT for 3 hours. The reaction was evaporated and purified with silica gel column to give the titled product (20 mg). Mass: (M+1), 512
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[F:13][C:14]1[C:15]2[CH2:16][CH:17]3[CH:26]([NH2:27])[CH:20]([CH2:21][C:22]=2[CH:23]=[CH:24][CH:25]=1)[CH2:19][CH2:18]3>C1COCC1.C(OCC)(=O)C>[OH:8][C:7]1[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=1[O:5][S:1](=[O:3])(=[O:4])[NH:27][CH:26]1[CH:20]2[CH2:19][CH2:18][CH:17]1[CH2:16][C:15]1[C:14]([F:13])=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:21]2
Reactant: O=S(=O)(O)Oc1ccccc1O
Reactant: NC1C2CCC1Cc1c(F)cccc1C2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(NC1C2CCC1Cc1c(F)cccc1C2)Oc1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
Catechol sulphate (332 mg, 1.93 mmol) was added to an ice-cooled solution of the amine from Step 4 (360 mg, 1.76 mmol) in THF (5 ml). The mixture was allowed to warm to room temperature, stirred for 18 hours, diluted with ethyl acetate and washed with ammonium chloride (aq) followed by brine. The organic phase was dried and evaporated to give a crude oil which was purified by column chromatography on silica gel eluting with 4:1 isohexane-ethyl acetate to give an orange oil 335 mg (51%). 1H NMR (CDCl3, 360 MHz) δ 7.27 (1H, m), 7.21 (1H, m), 7.05 (2H, m), 6.85–7.95 (3H, m), 6.32 (1H, br s), 5.40 (1H, br d, J=7.5 Hz), 4.02 (1H, q, J=6.4 Hz), 3.19–3.25 (1H, dd, J=16.7, 7.6 Hz), 3.04 (1H, d, J=16.3 Hz), 2.70 (1H, m), 2.50–2.61 (3H, m), 1.74 (2H, m), 1.21 (2H, m). m/z 376 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1[CH:23]=O)([CH3:15])([CH3:14])[CH3:13].C[O-].[Na+]>CO>[C:12]([Si:16]([CH3:31])([CH3:30])[O:17][CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:22]=1/[CH:23]=[C:8](/[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[F:11])\[C:9]#[N:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1C=O
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Yield: 96.5 %

Procedure:
Step B In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (1.7 g, 10 mmol) was reacted with 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-benzaldehyde (3.8 g, 12.5 mmol), methanolic solution (25 wt %) of sodium methoxide (2.5 mL, 11 mmol) in methanol (60 mL) at 50° C. for 3 h to give (Z)-3-{2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-chloro-phenyl}-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile as a yellow oil (4.5 g, 80%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[CH:19]1([CH2:25][C:26]#[CH:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]#[C:27][C:2]2[N:3]=[C:4]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]3=[N:6][CH:7]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C#CCC1CCCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(Br)cnc21
Product: C[Si](C)(C)CCOCn1ccc2nc(C#CCC3CCCCC3)cnc21
Yield: 87.6 %

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (402 mg, 1.22 mmol) and 3-cyclohexyl-1-propyne (745 mg, 6.1 mmol) were reacted under the same conditions as described in example 4 above. The crude product was adsorbed onto silica (1.5 g) and purified by silica gel chromatography, eluting with 5% to 20% ethyl acetate in hexanes to afford 395 mg of 2-(3-cyclohexyl-prop-1-ynyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin as a light brown semi-mobile oil. MS (M+H)+=370.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:45])([CH3:44])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>CCOCC>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:30])[CH:26]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([CH3:44])([CH3:45])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:33][C:32]=2[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2=O)c(OCc2ccccc2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
To a 0° C. solution of 7.0 mmols. of 3-phenylpropylmagnesium bromide in 7 ml. of tetrahydrofuran is slowly added a solution of 2.48 g. (5.0 mmols) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-piperidone in 10 ml. of tetrahydrofuran. The resultant mixture is stirred for one hour and is then added to 250 ml. of saturated ammonium chloride-250 ml. ether. The ether phase is dried over magnesium sulfate and evaporated. The residue is purified via column chromatography on 200 g. of silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2.[Mg].CO>O>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]2[C:3]=1[CH2:4][CH:5]([C:12]([O:14][CH3:15])=[O:13])[NH:6]2
Reactant: COC(=O)c1cc2c(C)ccc(C)c2[nH]1
Agent: [Mg]
Solvent: CO
Solvent: O
Product: COC(=O)C1Cc2c(C)ccc(C)c2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
A flask dried with heating was charged with 1.6 g (7.9 mmol) of methyl 4,7-dimethylindole-2-carboxylate and 3.8 g (158 mmol) of chipped magnesium. After addition of 400 ml of anhydrous methanol, the reaction mixture was stirred vigorously for 30 minutes. The flask was placed in an ice bath to cool the reaction mixture to 0° C., and the reaction mixture was stirred overnight. The reaction mixture was diluted with 300 ml of water, filtered and extracted with 100 ml of methylene chloride three times. The methylene chloride layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solids thus obtained were purified by silica gel column chromatography to provide 1.28 g of light red crystals. Yield: 79%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14].C(O)(=O)C>C1(C)C=CC=CC=1>[C:13]([O:16][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[N:10]=1)(=[O:15])[CH3:14]
Reactant: [O-][n+]1cccc2cccc(O)c21
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc2cccc(O)c2n1
Temperature: 135 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
64 g (397 mmol) of 8-hydroxyquinoline N-oxide, 550 ml of acetic anhydride and 40 ml of acetic acid are placed in a 1 l round-bottomed flask. The reaction mixture is heated at reflux (135° C.) for 24 h, 40 ml of acetic acid are then again added and heating is continued for 1 h 30. The reaction mixture is allowed to return to ambient temperature and 400 ml of toluene are added. A precipitate appears and is filtered off. A further 400 ml of toluene are added and filtration is carried out. The precipitate is washed with 200 ml of ethyl ether and is dried in a desiccator under vacuum over phosphorus pentoxide to provide to provide 70.5 g of 2-acetoxy-8-hydroxyquinoline in the form of a brown solid. (Yield: 88%)
Reaction SMILES: [OH:1][C@@H:2]([CH3:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.CN(C=O)C>C(Cl)Cl>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][C@@H:2]([OH:1])[CH3:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cc1nc(C(=O)O)cn1C[C@H](C)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1C[C@H](C)O
Yield: 13.7 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from (S)-1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.608 mmol, 112 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.507 mmol, 141 mg) using DMF (2 ml) as the solvent. After the reaction had stopped, DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography. The purified product was dissolved in a mixture of MeOH/DCM and washed twice with 1M NaHCO3. The organic phase was dried, filtered and evaporated. The product was further purified by trituration from diethyl ether, filtered and dried with vacuum. 31 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.01-1.08 (m, 6H), 2.33 (s, 3H), 3.68-3.91 (m, 3H), 4.22-4.48 (m, 3H), 4.91 (d, 1H), 7.02 (d, 1H), 7.47 (s, 1H), 7.86 (d, 1H), 7.94 (d, 1H), 8.01 (s, 1H), 8.06 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[CH3:10][C:11]1([CH2:15]O)[CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]2([CH3:15])[CH2:14][O:13][CH2:12]2)=[CH:4][C:3]=1[F:9]
Reactant: CC1(CO)COC1
Reactant: Oc1ccc(Br)c(F)c1
Product: CC1(COc2ccc(Br)c(F)c2)COC1

Procedure:
The title compound was prepared from 4-bromo-3-fluorophenol and (3-methyl-oxetan-3-yl)-methanol in analogy to Example 9c): MS (EI): 274 and 276 M+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+].[Br:22][CH2:23][CH2:24]Br>CN(C)C=O>[Br:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCBr)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of the product of step (i) (5 g) and potassium carbonate (13.14 g) in dimethylformamide (100 ml) was treated with 1,2-dibromoethane (8.2 ml) and stirred overnight at room temperature. The mixture was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% ethyl acetate in isohexane. Yield 4.6 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15]O.Cl>>[OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)nc2ccccc12
Agent: Cl
Product: COC(=O)c1cc(O)nc2ccccc12

Procedure:
To 2-hydroxyquinoline-4-carboxylic acid (V. 5.52 g) is added a saturated methanol/hydrochloric acid mixture in 50 ml aliquots over 5 days. The methanol/hydrochloric acid is then removed under reduced pressure and the residue is carefully treated with aqueous sodium bicarbonate. When the aqueous layer tests basic, the solid is collected, washed with water, and dried under reduced pressure to give methyl 2-hydroxyquinoline-4-carboxylate (VI), mp 240°-241°.
Reaction SMILES: [CH:1]([NH:8][C:9](=[N:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:10][CH2:11][CH:12]=[CH2:13])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2].[CH2:23]([N:41]=[C:42]=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>O1CCCC1>[CH:1]([N:8]([C:42](=[O:43])[NH:41][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:9](=[N:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[S:10][CH2:11][CH:12]=[CH2:13])([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: C=CCSC(=NCCCCCCCC)NC(C)CCCCC
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: C1CCOC1
Product: C=CCSC(=NCCCCCCCC)N(C(=O)NCCCCCCCCCCCCCCCCCC)C(C)CCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The procedure and equipment were the same as in Example 26. 1.9 g (0.006 mole) 1-sec-heptyl-3-n-octyl-2-S-allyl isothiourea was mixed with 25 ml of tetrahydrofuran to which 1.77 g (0.006 mole) n-octadecylisocyanate was added to the mixture. The reaction mixture was then stirred at ambient temperature overnight and then vacuum evaporated to produce 3.79 g (100 weight percent of theory yield) of a clear liquid having a nD30 of 1.4769. The product was identified as the title product by IR and NMR spectra analyses. Compound No. 144 in Table I.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH3:10][C:11]1([CH3:32])[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]([OH:31])=[CH:16][CH:17]=2)[O:12]1>>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:31][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:20][C:11]([CH3:32])([CH3:10])[O:12]2)=[CH:17][CH:16]=1)[CH3:3]
Reactant: CCN(CC)CCCl
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Agent: Cl
Product: CCN(CC)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1
Yield: 49 %

Procedure:
Reaction of 2-diethylaminoethylchloride hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound as a colourless oil in 49% yield.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][C:6]12[O:10][CH2:9]1.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:11][C:2]([C@@H:3]1[CH2:4][CH:5]=[C:6]([CH2:9][OH:10])[CH2:7][CH2:8]1)=[CH2:1]
Reactant: CC1(C)C2CCC3(CO3)C1C2
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: C=C(C)[C@@H]1CC=C(CO)CC1

Procedure:
Among other routes that have been developed to prepare perillyl alcohol from beta pinene oxide is that reported by T. K. Keenan in 1966 who produced perillyl acetate from beta-pinene oxide by refluxing beta-pinene oxide with acetic anhydride and acetic acid for seven hours followed by removal of the acetate to afford a nine percent (9%) yield of perillyl alcohol based on the starting beta-pinene oxide (B.S. Thesis Mass. Institute of Tech.). The applicants found the process to be reproducible albeit in low yield. F. C. Delay in Swiss Patent 5671/84 reported the production of perillyl alcohol in which he treated beta-pinene oxide with nitromethane and ammonium nitrite at a temperature between 20° C. and 90° C. in an overall yield of thirty percent (30%). Two years later Wang and co-workers published in Tetrahedron 1986, 620-638 complete details of this procedure and reported an overall yield of sixty-eight percent (68%) perillyl alcohol.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[C:8](OC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1(C(C2C=CC=CC=2)(C2C=CC=C(C(F)(F)F)C=2)N2C=NC=N2)C=CC=CC=1>>[C:1]1([C:7]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]#[CH:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)(c1ccccc1)n1ccnc1
Reactant: FC(F)(F)c1cccc(C(c2ccccc2)(c2ccccc2)n2cncn2)c1
Product: C#CC(c1ccccc1)(c1ccccc1)n1ccnc1

Procedure:
methyl α,α-diphenyl-1H- imidazole-1-acetate; and 1-[diphenyl[3-(trifluoromethyl)phenyl]methyl]-1H-1,2, 4-triazole, generically designated as fluotrimazole.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1>>[NH2:7][C:8]1[C:17]2[N:18]=[C:19]([CH2:26][CH2:27][CH2:28][CH3:29])[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:2](=[O:3])[O:4][CH2:5][CH3:6])[C:16]=2[C:15]2[N:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOC(=O)Cl
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)OCC
Yield: 81.3 %

Procedure:
Using the general method of Example 55, ethyl chloroformate (46 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmol) to provide 0.15 g of ethyl N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate as a white powder. Analysis Calculated for C20H28N6O2: %C, 62.48; %H, 7.34; %N, 21.86; Found: %C, 61.73; %H, 7.28; %N, 21.62.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 25 %

Procedure:
To a mixture of 3-chloro-4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide from Step 1 (2.35 g, 7.3 mmol) and sodium bicarbonate (1.23 g, 14.6 mmol) in isopropanol (100 mL), 3-bromo-1,1,1-trifluoroacetone (5.4 mL, 52 mmol) was added. After heating to reflux the reaction mixture for 24 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture (7.3 g) was chromatographed (silica gel, toluene/ethyl acetate, 1/1) to give 2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.79 g, 25%) as a white solid: mp 201° C. Anal. Calc'd. for C18H16N2SO3F3Cl.0.5 PhCH3 : C, 53.92, H, 4.21, N, 5.81. Found: C, 54.20, H, 4.19, N, 5.67.