Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:22]I.[OH-].[K+]>O1CCCC1>[CH3:22][N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12](=[O:21])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Temperature: 36 °C
Reaction time: 5 h

Procedure:
A mixture of heptyl-carbamic acid-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.58 g., 2 mmol), methyl iodide (0.224 ml, 3.6 mmol) and pulverized potassium hydroxide (0.16 g., 2 mmol) in dry tetrahydrofuran (10 ml) was stirred for 5 hours at room temperature (36° C.). The reaction mixture was concentrated under vaccum, diluted with water (5 ml), extracted with ether (3×5 ml), dried over sodium sulphate and the combined ether fractions were concentrated under vaccum. The residue was then chromatographed on deactivated silica gel (water: silica gel=12.88, v/w) using dichloromethane: hexane (20:80) as eluant to give 2n; yield: 0.36 g. (59.2%).
Reaction SMILES: C([Mg]Br)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[O:12]=[C:13]1[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[OH:12][C:13]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14]1
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: COC(=O)C1CC(=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C1CC(O)(c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Anisylmagnesium bromide (15.6 mL of 0.5 M solution in THF, 7.80 mmol) was added dropwise over 1 h to a stirred solution of methyl 3-oxocyclobutanecarboxylate (1.00 g, 7.80 mmol) in dry Et2O (71.0 mL) at −78° C. under N2. The reaction mixture was allowed to warm to room temperature and was stirred for 1 h. Satd aq. Na2SO4 was added and the mixture was stirred until a clear solution resulted. This mixture was extracted with Et2O (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 20% EtOAc in hexanes over 2088 mL, gradient to 40% EtOAc in hexanes over 2448 mL) to afford methyl 3-hydroxy-3-(4-methoxyphenyl)cyclobutanecarboxylate. Rf=0.18 (20% EtOAc/hexanes). LCMS calc.=259.10. found=259.01 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 3.75 (s, 3H); 3.44-3.37 (m, 2H); 3.32-3.18 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH2:12])[CH2:10][CH3:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(OCC)=O>O.C(#N)C>[C:25]1(=[O:34])[N:12]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10][CH3:11])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCC(N)c1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 38.1 %

Procedure:
To a stirred solution of 1-(4′methoxyphenyl)propylamine (2.5 grams, 15.2 mmol) and sodium carbonate (1.74 grams, 16.4 mmol) in a mixture of water (50 milliliters) and acetonitrile (50 milliliters) was added N-carbethoxyphthalimide (3.34 grams, 15.2 mmol). The resulting suspension was stirred for 4.5 hours at room temperature, the acetonitrile was removed in vacuo and a solid formed. The slurry was filtered and the solid was washed with water and air dried to afford 1.73 grams (39%) of crude product as a white powder. The crude product was recrystallized from hexane/ethyl acetate and dried in vacuo (60° C., <1 mm) to afford 1.71 grams (38%) of the product as white crystals: mp 85-86° C.; 1H NMR (DMSO-d6) δ7.92-7.79(m, 4H), 7.46-7.28(m,2 H), 6.97-6.83(m, 2 H), 5.19-5.06(m, 1 H), 3.72(s, 3H), 2.56-2.13(m, 2 H), 0.87(t, J=7.3 Hz, 3 H);13C NMR (DMSO-d6) δ167.8, 1.5, 134.6, 131.7, 131.0, 128.6, 123.1, 113.7, 55.2, 54.9, 23.8, 11.3. Anal. Calculated for C18H17NO3. Theoretical: C,73.20; H,5.80; N, 4.74. Found: C,73.24; H, 5.74; N, 4.86. HPLC 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(CC(=O)O)cc(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)cc(OC)c1

Procedure:
To a solution of 3,5-dimethoxyphenylacetic acid (1.99 g, 10.0 mmol) (Transworld) in methanol (20 mL) was added concentrated sulfuric acid (1.0 mL) and the reaction mixture was heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo. The residue was then diluted with ethyl acetate (100 mL) and successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude 3,5-dimethoxyphenylacetic acid methyl ester as a black oil which was used in the next step without further purification. (Yield 2.05 g, 97.6%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C)C=O>[CH3:30][C:29]([Si:26]([CH3:28])([CH3:27])[O:25][CH2:24][CH2:23][CH:7]([C:8](=[O:18])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([I:17])=[CH:15][CH:16]=1)[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:19])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)CC(=O)CCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(=O)CCc1ccc(I)cc1
Temperature: 70 °C
Yield: 70.3 %

Procedure:
A solution of 5-(4-iodo-phenyl)-3-oxo-pentanoic acid tert-butyl ester (10.0 g, 26.7 mmol) in dimethylformamide (25 mL) was added dropwise over 20 min to a stirred suspension of sodium hydride (60% mineral oil suspension; 1.12 g, 28.0 mmol) in dimethylformamide (25 mL) at 0° C. under nitrogen. After stirring for 20 min (2-bromoethoxy)-t-butyldimethylsilane (7.03 g, 6.31 mL, 29.4 mmol) was added dropwise over 20 min at 0° C. then the reaction heated to 70° C. for 3.5 h. On cooling to room temperature the reaction was quenched by careful addition of water (2 mL) then the volatiles evaporated. The residue was partitioned between saturated aqueous ammonium chloride solution (150 mL) and dichloromethane (150 mL) and the phases separated. The aqueous phase was washed with dichloromethane (3×150 mL) then the organic phases combined, washed with brine (150 mL), dried (sodium sulfate) and the solvent evaporated. The residue was chromatographed on silica gel (25% diethyl ether: cyclohexane) to give the title compound (10.0 g, 70%) as colourless oil which was a mixture of diastereomers. LC/MS: 4.55 min; z/e 533, calcd (M+1) 533. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 6.90 (2H), 3.55 (3H), 2.85 (4H), 2.15 (2H minor), 1.95 (2H major), 1.40 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([F:21])[CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[F:21][C:12]1[CH:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:22]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:23]3[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]3)=[N:4][CH:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(F)c1)c1cnc(N2CC[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 185 using (R)-5-bromo-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 198.1) and pyrimidin-5-ylboronic acid to afford a white powder. HPLC (Condition 4) tR=4.88 min, UPLC-MS (Condition 3) tR=0.96 min, m/z=464.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.77 (m, 1H) 1.79-1.92 (m, 1H) 2.78-2.94 (m, 1H) 3.15-3.25 (m, 2H) 3.32-3.48 (m, 1H) 4.13-4.26 (m, 1H) 4.87 (d, J=3.52 Hz, 1H) 7.46-7.65 (m, 2H) 7.91-8.00 (m, 1H) 8.07 (d, J=2.35 Hz, 1H) 8.78 (d, J=2.35 Hz, 1H) 8.87 (s, 2H) 9.18 (s, 1H) 10.30 (s, 1H).
Reaction SMILES: [CH:1]([O:3][C:4](=O)[CH3:5])=[O:2].C([O-])=O.[Na+].[CH2:11](O)/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17]CC>O>[CH:1]([O:3][CH2:4]/[CH:5]=[CH:11]/[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:2]
Reactant: CCCCCC/C=C/CO
Reactant: CC(=O)OC=O
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCC/C=C/COC=O
Temperature: 60 °C

Procedure:
Acetyl formate (39.6 g, 0.45 mole) is added dropwise to a cooled mixture of sodium formate (6.8 g, 0.10 mole) and trans-2-nonen-1-ol (47.3 g, 0.33 mole). When the addition is complete, the reaction mixture temperature is maintained at 60°C for 7 hours. The mixture is cooled and diluted with water. The organic layer is separated and washed with 5% sodium bicarbonate, water and then dried over sodium sulfate. Trans-2-nonenyl formate, 419 g is obtained on distillation, b.p. 60°-5°C/50-55 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:25])([F:24])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:43]([O-])=[O:44])C=1.[CH2:46]([NH2:51])[C:47]([CH3:50])([CH3:49])[CH3:48]>ClCCl>[CH2:46]([NH:51][C:43](=[O:44])[NH:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:28]=[CH:29][CH:30]=3)[C:18]([NH:20][C:21]([CH3:27])([CH3:26])[C:22]([F:24])([F:25])[F:23])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1)[C:47]([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)CN
Reactant: CC(C)(NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3)CC2)c1)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C(F)(F)F)c3)CC2)cc1
Yield: 69 %

Procedure:
3((4-(4-Aminobenzoyl)piperazin-1-yl)methyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (0.129 mmol, 58 mg) and 4-nitrophenylchloroformate (0.142 mmol, 29 mg) were stirred together in dichloromethane (1 mL) for 16 hours. After this time neopentylamine (0.259 mmol, 32 μL) was added. The volatiles were removed under vacuum and this residue was purified by silica chromatography to yield the title compound (50 mg). MS (ESI) m/z 562.5 [M+H]+
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([NH2:19])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:23]1(=O)[O:28][C:26](=[O:27])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][CH:17]([N:19]4[C:26](=[O:27])[C:25]5[C:24](=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:23]4=[O:28])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)Oc1cccc(C23CC(N)CC(C2)N(C)CC3C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Oc1cccc(C23CC(CC(N4C(=O)c5ccccc5C4=O)C2)N(C)CC3C)c1
Yield: 61.9 %

Procedure:
5-(3-Isopropoxy-phenyl)-2,4-dimethyl-2-aza-bicyclo[3.3.1 ]non-7-ylamine (2.4) (1.69 g, 5.6 mmol) was dissolved in toluene followed by the addition of phthalic anhydride (2.5 g, 16.8 mmol) and the reaction mixture was refluxed with a Dean-Stark trap overnight. The solution was then cooled, diluted with ethyl acetate, and filtered into a separatory funnel. The organic layer was washed with 1 N NaOH (3×30 ml) and water. The organic layer was collected, dried (Na2SO4) and the solvent removed under reduced pressure yielding crude product. The crude product was purified by filtering through a short column of neutral alumina (Brockman activity II-III) eluting with ethyl acetate to afford the title compound (1.50 g, 62%) as an off white solid. 1H NMR (CDCl3) δ: 7.76 (m, 2H), 7.65 (m, 2H), 7.23 (t, 1H, J=7.8), 7.00-6.72 (m, 3H), 5.08 (m, 1H), 4.52 (sept., 1H, J=6.1 Hz), 3.15 (m, 1H), 2.96 (m, 1H), 2.62 (m, 1H), 2.45-2.32 (m, 4H), 2.23 (s, 1H), 2.11 (m, 1H), 1.67 (m, 2H), 1.31 (d, 6H, J=6.0 Hz), 1.15 (m, 1H), 0.94 (m, 1H), 0.73 (d, 3H, J=6.9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[N:30]1([C:36]2[S:37][C:38]3[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=3[N:40]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:33]3[CH2:34][CH2:35][N:30]([C:36]4[S:37][C:38]5[CH:44]=[CH:43][CH:42]=[CH:41][C:39]=5[N:40]=4)[CH2:31][CH2:32]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccc2sc(N3CCNCC3)nc2c1
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCc1ccc(F)cc1)C1(CCCCN2CCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 2-piperazin-1-yl-benzothiazole.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[SH:15].C(N(CC)CC)C.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][C:4](=[O:14])[C:3]=1[S:15][CH2:24][C:25](=[O:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=c1oc(-c2ccccc2)cc(O)c1S
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CSc1c(O)cc(-c2ccccc2)oc1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-3-mercapto-6-phenyl-2-pyrone (0.175, 0.840 mmol, prepared as in R. F. Harris, J. E. Dunbar, U.S. Pat. No. 3,818,046) in CH2Cl2 (3.0 mL) under an N2 atmosphere was treated with triethylamine (0.12 mL, 0.84 mmol) followed by bromoacetophenone (0.167 g, 0.840 mmol). The mixture was allowed to stir for 30 min. at ambient temperature then the solvent removed in vacuo. The residue was then diluted with diethyl ether and extracted with saturated Na2CO3 (3×50 mL). The aquous layers were then combined, acidifed with conc. HCl, and extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried with Na2SO4, and the solvent removed in vacuo to give the title compound (0.066 g, m.p. 164°-166° C.) which was dried in vacuo. 1H NMR (300 MHz, CDCl3) δ 9.900 (bs, 1 H), 7.970 (d, 2 H, J=7.1 Hz), 7.810 (d, 2 H, J=8 Hz), 7.615 (t, 1 H, J=4 Hz), 7.505-7.443 (m, 5 H), 6.619 (s, 1 H), 4.334 (s, 2 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[OH:25][C:21]1[CH:20]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cccc(O)c1
Product: COc1cc2ncc(C#N)c(Nc3cccc(O)c3)c2cc1OC
Yield: 91.8 %

Procedure:
Using the method described in Example 105, 0.7 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile and 0.38 g of 3-aminophenol was converted to 0.83 g of the title compound: mass spectrum (electrospray, m/e,): 321.9, 322.8 (M+H)+
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][Zr:4]([CH3:26])(=[SiH2:25])([CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:24])[CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:14].[H][H]>ClCCl.[Pt]=O>[Cl-:1].[Cl-:1].[CH3:26][Zr:4]([CH3:3])(=[SiH2:25])([CH:15]1[C:23]2[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=2[CH:17]=[C:16]1[CH3:24])[CH:5]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]1[CH3:14]
Reactant: [H][H]
Reactant: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Agent: O=[Pt]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1=CC2=C(CCCC2)C1[Zr](C)(C)(=[SiH2])C1C(C)=CC2=C1CCCC2

Procedure:
Dimethylsilylenebis(2-methyl-4,5,6,7-tetrahydroindenyl)zirconium dichloride was prepared by first synthesizing dimethylsilylenebis(2-methylindenyl)zirconium dichloride as in Example-A13, and the latter in an amount of 1.0 g was dissolved in 150 ml of dichloromethane and was introduced in an autoclave of 500 ml capacity in which it was reacted in the presence of 0.1 g of platinum oxide added with hydrogen under a pressure of 50 kg/cm2G at room temperature for 5 hours. The platinum oxide catalyst was then removed and the solvent used was removed in vacuo whereby a solid was obtained, which solid was extracted with toluene and recrystallization was conducted to give 0.32 g of dimethylsilylenebis(2-methyl-4,5,6,7-tetrahydroindenyl)zirconium dichloride desired.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>ClCCCl>[Cl:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Into the solution of 1,3-difluorobenzene in 1,2-dicholoroethane (DCE) was added anhydrous aluminium chloride (1.2 molar equivalent of 1,3-difluorobenzene) at 25-30° C. and stirred for 30 minutes. The reaction mixture was then cooled to 0° C. and chloroacetyl chloride (1.1 molar equivalent of 1,3-difluorobenzene), in DCE, was then added into it over a period of 30-60 min keeping the reaction temperature below 20° C. After the addition was over, the reaction mixture was stirred at 25-30° C. for 5-7 hours. The reaction mixture was then diluted with DCE and poured into dil. hydrochloric acid (5%) at 0-5° C. The mixture was then extracted with DCE. The combined organic layer was washed successively with 5% aq. sodium bicarbonate solution and water. Evaporating DCE from the organic layer under reduced pressure gave an oil which on triturating with n-Hexane gave the title compound as white crystalline material (Yield 75% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]2.Cl.[CH:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.O>[CH:17]1([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:5]3)=[O:21])[CH2:19][CH2:18]1
Reactant: COC(=O)c1cnc2ccc(N)cc2c1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cnc2ccc(NC(=O)C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 6-aminoquinoline-3-carboxylate.2 HCl (Int-3, 0.125 g, 0.524 mmol) and cyclopropanecarboxylic acid (45.7 μL, 0.576 mmol) in pyridine (1.98 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.301 g, 1.57 mmol). The reaction mixture was stirred for 5 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (hexanes to 40/60 hexanes/ethyl acetate gradient) to afford Int-4 (0.071 g, 50%). LC-MS: (FA) ES+ 271; 1H NMR (400 MHz, d6-DMSO) δ ppm 10.65 (s, 1H), 9.17 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H), 8.05 (d, J=9.1 Hz, 1H), 7.98 (dd, J=9.1, 2.3 Hz, 1H), 3.93 (s, 3H), 1.86 (tt, J=7.1, 7.1, 5.3, 5.3 Hz, 1H), 0.90-0.80 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N+:16]([O-])=O)[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:16])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Br)cc(OCc2ccccc2)c1
Temperature: 65 °C

Procedure:
To a solution of 3-benzyloxy-5-bromo-nitrobenzene (27.0 g, 87.60 mmol) in THF (800.0 mL) was added SnCl2.2H2O (99.0 g, 438.30 mmol) and the resulting reaction mixture was heated to reflux at 65° C. for 2 h. The reaction mass was then cooled to 0-5° C. and basified with a saturated solution of NaHCO3 till pH 8 and then extracted with EtOAc (3×1.0 L). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue thus obtained (23.60 g, 95%) was carried forward to the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12](=[CH2:15])[CH2:13][OH:14].[OH-].[K+].O>CS(C)=O>[CH3:15][C:12]([CH2:13][O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[CH2:11]
Reactant: N#Cc1c(Cl)cccc1Cl
Reactant: C=C(C)CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=C(C)COc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
A solution of 30.0 grams (0.174 mole) of 2,6-dichlorobenzonitrile and 14.7 mL (0.174 mole) of 2-methyl-2-propen-1-ol in 200 mL of dimethyl sulfoxide is stirred, and 12.7 grams (0.191 mole) of 85% potassium hydroxide is added portionwise during a 5 minute period. During the addition, the reaction mixture temperature rises from 20° C. to about 35° C. Upon completion of the addition, the reaction mixture is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is poured into 600 mL of water. The mixture is filtered to collect a solid. The solid is washed with water and dried under vacuum, yielding 33.9 grams of 2-methyl-3-(3-chloro-2-cyanophenoxy)-1-propene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C@:10]([CH2:16][CH3:17])([C:12]([O:14][CH3:15])=[O:13])[CH2:9][C:8]=2[CH:18]=1)(=O)C.ClC1C=CC=C(C(OO)=[O:27])C=1.C([O-])(O)=O.[Na+]>ClCCl>[CH3:15][O:14][C:12]([C:10]1([CH2:16][CH3:17])[CH2:9][C:8]2[CH:18]=[C:4]([OH:27])[CH:5]=[CH:6][C:7]=2[O:11]1)=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC[C@@]1(C(=O)OC)Cc2cc(C(C)=O)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCC1(C(=O)OC)Cc2cc(O)ccc2O1

Procedure:
Methyl (2S)-5-acetyl-2-ethyl-2,3-dihydro-benzofuran-2-carboxylate (3.8 g, ca. 15 mmol), m-chloroperbenzoic acid (70%, 7.7 g, 30 mmol) and NaHCO3 (3.8 g, 45 mmol) in dichloromethane (150 mL) was stirred under reflux for 2 hrs. The reaction mixture was washed successively with saturated aqueous sodium sulfite (100 mL) and aqueous NaHCO3 (2×100 mL). After removal of solvent, the residue was dissolved in methanol (100 mL) and treated with aqueous KOH (5 N, 3 mL) at 0° C. for 5 min. The reaction was neutralized with excess solid sodium bicarbonate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with 8:2 hexane:ethyl acetate to give the title compound.