Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[Na+].O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1>CS(C)=O>[OH:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:1]#[N:2])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(CCO)cc2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCCc1ccc(CCO)cc1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
Sodium cyanide (1.8 g, 37 mmol) was added to a stirred solution of the intermediate from Step B (10 g, 31 mmol) in DMSO (100 mL). The mixture was heated to 60° C. overnight (˜16 hours) and then the DMSO was removed under reduced pressure. DCM (100 mL) was added to the residue and the resulting mixture was washed with water (1×100 mL), saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 5.4 g of the title intermediate (99% yield), which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cn1
Temperature: 15 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-bromo-3-pyridinol (10 g, Commercial eg Apollo Scientific Ltd.) in DMF (100 ml) was added potassium carbonate (17.8 g). The reaction mixture was stirred for 15 min at 25-30 C. before cooling to 15° C. To this was added slowly benzyl bromide (7.5 ml) and this was stirred at 25-30° C. for 48 h. The reaction mixture was poured into cold water and the solid was collected by filtration to give the title compound, 14.5 g
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1)=O.[NH3:14]>>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([C:3](=[O:2])[NH2:14])[CH:10]=1)(=[O:13])[CH3:12]
Reactant: COC(=O)c1cncc(C(C)=O)c1
Reactant: N
Product: CC(=O)c1cncc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-acetyl-3-pyridinecarboxylic acid methyl ester (5.0 g) in 28% ammonia solution (30 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration to afford 3-acetyl-5-carbamoylpyridine (3.38 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:35]1([CH2:38][OH:39])[CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:39][CH2:38][CH:35]2[CH2:37][CH2:36]2)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1Cl
Reactant: OCC1CC1
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1OCC1CC1

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 399 instead of the compound prepared in Example 215 and cyclopropylmethanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [OH-:1].[K+].Cl[C:4](Cl)(Cl)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH3:13].Cl.[CH2:17]([OH:21])[CH2:18][CH2:19][CH3:20]>>[Cl:12][C:8]1[C:7]([CH3:13])=[C:6]([CH2:5][C:4]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[O:1])[CH:11]=[CH:10][CH:9]=1
Reactant: CCCCO
Reactant: [OH-]
Reactant: Cc1c(Cl)cccc1CC(Cl)(Cl)Cl
Agent: Cl
Agent: [K+]
Product: CCCCOC(=O)Cc1cccc(Cl)c1C

Procedure:
To 10.9 g. of potassium hydroxide of the same grade used in the examples above was added 50 ml. of butanol, and the mixture was stirred for 1 hour. To it was added 5.0 g. of 1,1,1-trichloro-2-(3-chloro-2-methylphenyl)ethane, and the mixture was stirred under reflux at 115° for 6 hours and allowed to cool overnight to ambient temperature. The mixture was then worked up as described in Example 4 above to obtain 4.5 g. of crude product as the major product. It was then taken up in 15 ml. of butanol and stirred with 40 ml. of 1 N hydrochloric acid at ambient temperature for 30 minutes. The layers were then separated, extracted and dried as described in Example 5 above to obtain 3.41 g. of product, found to be 92% pure by vapor phase chromatography.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:13])[F:24])=[N:16][CH:17]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 ml scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1.1, 237 mg, 1.30 mmol), 6-(trifluoromethyl)nicotinoyl chloride (328 mg, 1.57 mmol), and NMP (5 mL) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was then diluted with water, filtered, and the filter cake rinsed thoroughly with water. Drying with suction under a stream of dry nitrogen resulted in the desired product N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A) as a pink solid. 1H NMR (DMSO-d6) δ: 11.87 (s, 1H), 9.29 (d, J=2.3 Hz, 1H), 8.62 (dd, J=8.0, 1.9 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 6.51 (s, 1H), 2.46 (s, 3H); ESI-MS: m/z 356.1 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:33]([O-])([O-])=O.[K+].[K+].[C:39]1([CH:45](Cl)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][CH:42]=[CH:41]C=1>CN(C=O)C>[C:46]1([C:45]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:39]=2)[CH:47]=[CH:48][C:49]([CH2:33][N:12]2[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15](=[O:16])/[C:11]/2=[CH:10]/[C:7]2[N:6]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=2)=[CH:50][CH:51]=1
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2ccc(-c3ccccc3)cc2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 16 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]benzoate (0.438 g, 1.00 mmol) in DMF (10 mL) is added K2CO3 (0.42 g, 3.00 mmol). After stirring for 5 minutes diphenylmethyl chloride (0.210 g, 1.00 mmol) is added. The mixture is stirred for 16 hours, filtered, and evaporated in vacuo. The gum is dissolved in ethyl acetate and washed with water, brine and dried over MgSO4. Chromatography eluting with (50-100)% ethyl acetate in hexane, evaporation in vacuo affords a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([CH2:17][CH3:18])[CH2:15][C:14](=[O:19])[CH2:13][CH:12]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH2:30](O)[CH2:31][OH:32]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]([CH2:17][CH3:18])[CH2:15][C:14]3([O:32][CH2:31][CH2:30][O:19]3)[CH2:13][CH:12]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCOC(=O)C1CC(=O)CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CC(CC)N1S(=O)(=O)c1ccc(Cl)cc1)OCCO2
Yield: 95.5 %

Procedure:
Ethyl 1-(4-chlorophenylsulfonyl)-6-ethyl-4-oxopiperidine-2-carboxylate (109; 5.31 g, 14.2 mmol), TMSCl (5.41 ml, 42.6 mmol), and ethylene glycol (3.96 ml, 71.0 mmol) were added to CH2Cl2 (50 ml) and refluxed under nitrogen for 3 hours. The reaction mixture was concentrated tinder reduced pressure, and taken up in equal portions of EtOAc and water. The aqueous layer was washed with several more portions of EtOAc, dried over Na2SO4, and concentrated to give 5.67 g (96%) of a mixture of cis/trans (4:96) isomers as a clear oil which solidified upon standing. The material was used without further purification.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.ClC(OCC(C)C)=O.CN1CCOCC1.[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH2:42])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1>O1CCCC1.N1C=CC=CC=1>[Br:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([NH:42][C:6]([CH:1]4[CH2:5][CH2:4][CH:3]=[CH:2]4)=[O:8])[CH:40]=3)[N:35]=[CH:34][N:33]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)C1C=CCC1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1)C1C=CCC1
Reaction time: 8 h
Yield: 23.1 %

Procedure:
A solution of 0.43 g of 2-cyclopentenoic acid in 5 ml of tetrahydrofuran was cooled in an ice bath. A 0.49 ml portion of isobutyl chloroformate followed by a 0.41 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.0 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. Another 0.5 equivalents of mixed anhydride was added. The mixture was stirred for 5 hours. The solvents were removed at reduced pressure and the solid was purified by chromatography on silica gel to give 0.30 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-cyclopenteneamide: mass spectrum (m/e): 409 (M+H, EI).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.Cl.Cl[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]Cl>ClC1C=CC=CC=1>[C:15]1([N:13]2[C:12](=[O:21])[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][C:2]([N:1]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)=[CH:3][C:4]=4[C:5]3=[N:14]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCCNCCCl
Reactant: Nc1ccc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Agent: Cl
Solvent: Clc1ccccc1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)cc3c-2nn1-c1ccccc1
Temperature: 175 °C
Reaction time: 60 h
Yield: 75 %

Procedure:
Equimolar quantities of 6a and bis(chloroethyl)amine hydrochloride were suspended in chlorobenzene and stirred at 175° C. for 60 hours. The solid was collected by filtration and washed with methanol, acetonitrile and diethylether in 75% yield. 1H-NMR (DMSO-d6) δ (ppm): 3.25 (4H, br), 3.52 (4H, br), 7.12 (1H, t, J=7.47 Hz), 7.39 (3H, m), 7.45 (1H, m), 7.68 (1H, m), 8.22 (2H, dd, J=8.55, 0.98 Hz), 8.60 (1H, d, J=5.86 Hz), 9.12 (1H, br). m/z 346.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Cl:1])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: Nc1ccc(Oc2ccc(C=O)cc2Cl)cc1[N+](=O)[O-]

Procedure:
4-[(4-Amino-3-nitrophenyl)oxy]-3-chlorobenzaldehyde was prepared from 3-chloro-4-fluorobenzaldehyde (and 4-amino-3-nitrophenol using the procedure of method 5 step 1. (M-1) 291.1, 2.59 min (LC/MS method A)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.O.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>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccc(C(F)(F)F)cc2)ccc1C#N
Temperature: 110 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
To a solution of 4-bromo-2-methoxybenzonitrile (2.08 g, 9.81 mmol) and 4-(trifluoromethyl)phenylboronic acid (2.80 g, 14.7 mmol), potassium fluoride (1.71 g, 29.4 mmol) and Pd(PPh3)4 (1.13 g, 0.98 mmol) in toluene (40 mL) added water (10 mL). The mixture was stirred at 110° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography gave 3-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (2.66 g) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=8.4 Hz, 2H), 7.63-7.56 (m, 3H), 7.15 (dd, J=8.0, 1.2 Hz, 1H), 7.06 (s, 1H), 3.95 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2ccc(F)c(Cl)c2)CC1
Yield: 85.3 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.12 mL, 1 mmol), triethylamine (0.14 mL, 1 mmol) and 1-(3-chloro-4-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-1, 0.14 g, 0.32 mmol) provided 0.14 g of the title compound as a solid.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.1 of product m.p. 191-93° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 3.83-3.85 (m, 9H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 6.72 (s, 2H); 6.92 (d, 1H, J=16 Hz); 7.12 (d, 1H, J=8.9 Hz); 7.15 (d, 1H, J=16 Hz); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=1)#[N:3].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19](CO)[C:20]([OH:22])=O.[OH2:25]>CO>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]1[C:20](=[O:22])[C:4]([C:5]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][N:6]=2)=[C:2]([NH2:3])[O:25]1
Reactant: O
Reactant: Cc1ccnc(CC#N)c1
Reactant: O=C(O)C(CO)c1ccccc1Cl
Agent: [Na]
Solvent: CO
Product: Cc1ccnc(C2=C(N)OC(c3ccccc3Cl)C2=O)c1
Yield: 28 %

Procedure:
Sodium (0.35 g, 15.2 mmol) was added in methanol (8 ml) and stirred at room temperature under nitrogen atomsphere till complete dissolution of sodium, and then 2-cyanomethyl-4-methylpyridine (1.10 g, 8.51 mmol) and 2-(o-chlorophenyl)2-hydroxymethylacetic acid (1.78 g, 1.35 mmol) were slowly added. After refluxing for 2 hours with stirring the solution was cooled with a small amount of water and concentrated under the reduced pressure. The residue was extracted with methylene chloride and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to get crude product. The residue was separated and purified by column-chromatography over silica gel to obtain the desired product (0.54 g, yield=28%).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)#[N:2].[C:9](=[S:11])=[S:10].[OH-].[K+].Br[CH2:15][CH:16](Br)[CH2:17][CH:18]([CH3:20])[CH3:19]>O.CS(C)=O>[N:4]1([C:3](=[C:9]2[S:11][CH:16]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:15][S:10]2)[C:1]#[N:2])[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CC(C)CC(Br)CBr
Reactant: S=C=S
Reactant: N#CCn1ccnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CC1CSC(=C(C#N)n2ccnc2)S1
Reaction time: 1 h

Procedure:
To a mixed solution of 0.55 g (0.005 mole) of 1-cyanomethylimidazole, 0.4 g (0.005 mole) of carbon disulfide and 10 ml of dimethyl sulfoxide was added 0.8 g (0.014 mole) of potassium hydroxide powder with stirring, and the reaction was carried out at room temperature for 1 hour. Then, 1.5 g (0.006 mole) of 1,2-dibromo-4-methylpentane was added dropwise with stirring, and the resulting solution was subjected to reaction for 2 hours. After completion of the reaction, 20 ml of water was added to the reaction solution, after which the resulting mixture was subjected to extraction with ethyl acetate, and the organic layer was washed with water and dried. The solvent was distilled off and the residue was purified by silica gel chromatography to obtain 0.45 g of the Z isomer and 0.3 g of the E isomer individually in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[K+].[Br-].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1>C(#N)C>[Br-:10].[CH2:11]([C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH3:25])[C:35]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCCCCCCCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromoundecane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, resulting in a yellow/white precipitate.
Reaction SMILES: O1CCCC1.C[Si](C)(C)[C:8]([F:11])([F:10])[F:9].[O:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH2:15]1.Cl>O.CCOC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[F:9][C:8]([F:11])([F:10])[C:16]1([OH:20])[CH2:17][CH2:18][CH2:19][O:14][CH2:15]1
Reactant: O=C1CCCOC1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)CCCOC1
Temperature: 0 °C
Yield: 47.1 %

Procedure:
Tetrahydrofuran (50 mL) was added to a round bottom flask and placed under N2. trimethyl(trifluoromethyl)silane (1.033 mL, 6.99 mmol) was then added and stirred under N2 and then cooled to 0° C. Dihydro-2H-pyran-3(4H)-one (500 mg, 4.99 mmol) was then added via syringe and stirred for 5 minutes at 0° C. to ensure complete mixing. TBAF (0.050 mL, 0.050 mmol) was added dropwise slowly via syringe. The reaction was then allowed to warm up to RT for 30 min. The reaction was then cooled back down to 0° C. and added 1M HCl (50 mL) and then stirred at RT for overnight. The reaction was diluted with water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and evaporated to give the crude product 3-(trifluoromethyl)tetrahydro-2H-pyran-3-ol (400 mg, 47.1% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 4.01-3.93 (m, 1H), 3.82 (dd, J=11.8, 2.5 Hz, 1H), 3.60 (d, J=12.0 Hz, 1H), 3.41 (td, J=11.8, 2.5 Hz, 1H), 2.10-2.08 (m, 2H), 1.97-1.90 (m, 1H), 1.82 (dd, J=12.9, 4.4 Hz, 1H), 1.65-1.55 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: NCc1ncccc1OCc1ccccc1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ncccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Add dropwise with stirring a solution of 3.5 ml acetyl chloride in 50 ml THF (tetrahydrofuran) to a cooled solution of 10 gm of 2-aminomethyl-3-phenylmethoxypyridine and 7.1 ml triethylamine in 125 ml THF. Warm to room temperature and stir an additional hour. Remove triethylamine hydrochloride by filtration and evaporate the filtrate under reduced pressure. Recrystallize the residue from toluene to obtain 2-acetamidomethyl-3-(phenylmethoxy)pyridine, mp 94°-96°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:38][O:39][C:40]1[CH:41]=[CH:42][C:43]2[O:48][CH2:47][CH:46]([CH2:49][NH2:50])[O:45][C:44]=2[CH:51]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:50][CH2:49][CH:46]1[O:45][C:44]2[CH:51]=[C:40]([O:39][CH3:38])[CH:41]=[CH:42][C:43]=2[O:48][CH2:47]1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Reactant: COc1ccc2c(c1)OC(CN)CO2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCCc1c[nH]c3ccc(F)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.8 %

Procedure:
5-Fluoroindole-3-butyric acid (1.2 g, 5.4 mmole), 1-hydroxybenzotriazole hydrate (0.88 g, 6.5 mmole) and 1,3-diisopropylcarbodiimide (2.0 ml, 13.0 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.3 g, 5.4 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions containing product were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (56%) of the desired product, (7-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3-yl)-butanamide, as an oil.