Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Li]C1C=CN=CC=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26](=[O:35])[C:25]=2[CH:36]=1>CCOCC.CCCCCC>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[O:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH2:27][C:26]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)([OH:35])[C:25]=2[CH:36]=1
Reactant: Brc1ccncc1
Reactant: O=C1Cc2ccccc2Oc2ccc(Br)cc21
Agent: [Li]CCCC
Agent: [Li]c1ccncc1
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1(c2ccncc2)Cc2ccccc2Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 26.2 %

Procedure:
Under an argon atmosphere, a solution of 4-bromopyridine (16.6 g) in anhydrous ether (90 ml) previously cooled to -40°, was transferred slowly via a cannular to a stirred solution of n-butyl lithium in hexane (1.55M; 68 ml) cooled to -78°. The mixture was stirred at -78° for 20 minutes and the resulting 4-lithiopyridine was transferred to a chilled (-78°) stirred suspension of 8-bromodibenz[b,f]oxepin-10(11H)-one (15 g) in anhydrous ether (100 ml). The reaction was stirred at -78° for 30 minutes, then the cooling bath was removed and the mixture was treated with 100 ml of water and allowed to warm to room temperature. The solids were filtered off, washed with water and dried to give 5.0 g of 8-bromo-10,11-dihydro-10-(4-pyridinyl)dibenz[b,f]oxepin-10-ol. The mother liquor was worked up and a total of 9.4 grams of the starting ketone 8-bromodibenz[b,f]oxepin-10(11H)-one were recovered.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][O:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]1[C:14]([O:16][CH3:17])=[O:15].ClCC(=O)CC(OC)=O.C1(N=C=O)C=CC=CC=1.[NH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][N:43]=2)[C:38]([CH:45]=O)=[CH:37]1.N1CCCCC1>CC(O)C>[NH:36]1[C:44]2=[N:43][CH:42]=[CH:41][CH:40]=[C:39]2[C:38]([CH:45]=[C:6]2[O:5][C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([C:14]([O:16][CH3:17])=[O:15])[C:2]2=[O:1])=[CH:37]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: COC(=O)C1=C(Nc2ccccc2)OCC1=O
Agent: COC(=O)CC(=O)CCl
Solvent: CC(C)O
Solvent: O=C=Nc1ccccc1
Solvent: C1CCNCC1
Product: COC(=O)C1=C(Nc2ccccc2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 42.9 %

Procedure:
To a solution of methyl 4-oxo-2-(phenylamino)-4,5-dihydrofuran-3-carboxylate (0.047 g, 0.20 mmol) which similarly prepared according to the procedure described in the Example 2, First step using methyl 4-chloroacetoacetate and phenyl isocyanate, and 7-azaindole-3-carboxaldehyde (0.029 g, 0.20 mmol) in 2-propanol (1.0 mL), piperidine (0.022 mL, 0.22 mmol) was added at ambient temperature. The mixture was refluxed for 5 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound as solid (0.031 g, y. 43%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:6].[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+].O1CCCC1>C(OCC)(=O)C.O>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:3][CH2:4][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[O:6])=[O:19])=[CH:16][CH:15]=1
Reactant: NCC(=O)c1cccnc1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNC(=O)c1ccc(F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A mixture of 3-(2-aminoacetyl)pyridine dihydrochloride (50.00 g), 4-fluorobenzoylchloride (41.71 g) and sodium hydrogen carbonate (100.44 g) in ethyl acetate (1 liter) and water (0.6 liter) was stirred at room temperature for 2 hours. To the reaction mixture were added tetrahydrofuran (0.5 liter) and water (1 liter), and the organic layer was collected. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate to obtain 3-[2-(4-fluorobenzoyl)aminoacetyl]pyridine (40.87 g) as pale yellowish powder.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].Br[CH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:16]1[CH2:17][CH2:18][CH2:19][O:20][CH:15]1[CH2:14][CH2:13][C:5]1([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: COC(=O)C1CCCCC1=O
Reactant: BrCCC1OCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CCC2OCCCO2)CCCCC1=O

Procedure:
A solution of 2-carbomethoxycyclohexanone in DMF is reacted with 2-(2-bromoethyl)-1,3-dioxane and potassium carbonate by the method of Example 102 to generate the title compound.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[C:16](=[O:20])[N:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[O:28][C:29]4[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[CH:32][C:30]=4[N:31]=3)[CH:22]=1)[C:14]2=[O:39])=[O:10])C1C=CC=CC=1.[CH2:40]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[C:41]1[CH:49]=[CH:48][C:47]2[O:46][CH2:45][O:44][C:43]=2[CH:42]=1>>[CH2:40]([N:50]1[CH2:55][CH2:54][N:53]([C:36]([C:34]2[CH:33]=[CH:32][C:30]3[N:31]=[C:27]([C:23]4[CH:22]=[C:21]([N:15]5[C:14](=[O:39])[C:13]6[C:17](=[CH:18][CH:19]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=6)[C:16]5=[O:20])[CH:26]=[CH:25][CH:24]=4)[O:28][C:29]=3[CH:35]=2)=[O:37])[CH2:52][CH2:51]1)[C:41]1[CH:49]=[CH:48][C:47]2[O:46][CH2:45][O:44][C:43]=2[CH:42]=1
Reactant: O=C(Cl)c1ccc2nc(-c3cccc(N4C(=O)c5ccc(C(=O)OCc6ccccc6)cc5C4=O)c3)oc2c1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4ccc(C(=O)N5CCN(Cc6ccc7c(c6)OCO7)CC5)cc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 76 g), from 2-[3-(6-chlorocarbonylbenzoxazol-2-yl)phenyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol) and 1-piperonylpiperazine (31 mg, 0.14 mmol) the title compound was obtained (32 mg, 54%). 1H NMR (DMSO) δ 8.33(dd, 1H), 8.25(m, 2H), 8.17(dt, 1H), 8.01(d, 1H), 7.79–7.65(m, 4H), 7.37(d, 1H), 6.77–6.72(m, 2H), 6.64(dd, 1H), 5.88(s, 2H) 3.45(s, 2H), 3.40–3.2(bm, 4H) 2.48–2.22(bm, 4H). MS 629.2 m/z (M−H)−.
Reaction SMILES: CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[CH3:14][C:15]1([C:23](=[O:25])[CH3:24])[CH:20]([CH3:21])[CH2:19][C:18]([CH3:22])=[CH:17][CH2:16]1.C(O)(C)C.CC(C)=O>C(O)(C)C>[CH3:14][C:15]1([CH:23]([OH:25])[CH3:24])[CH:20]([CH3:21])[CH2:19][C:18]([CH3:22])=[CH:17][CH2:16]1
Reactant: CC(=O)C1(C)CC=C(C)CC1C
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CC1=CCC(C)(C(C)O)C(C)C1
Reaction time: 10 h

Procedure:
A solution of 0.33 moles (68 g) aluminum isopropylate in 600 ml isopropanol was heated to boiling in a 1-liter 3-necked flask with a magnetic stirrer, packed column, dropping funnel and thermometer. Within two hours 1 mole (166 g) 1-(1,4,6-trimethylcyclohex-3-en-1-yl)ethan-1-one (as per Example 1) was added dropwise to the boiling solution, and at the same time the isopropanol/acetone mixture formed was distilled off. After 10 hours the reaction was ended (after no more acetone could be detected in the distillate). Thereupon isopropanol still remaining was drawn off, and 175 ml 20% by weight hydrochloric acid was added to the residue after cooling. Extraction was carried out and the organic phase was washed free of acid. After fractional distillation 151 g of the desired end product was obtained, corresponding to 90% of the theoretical amount.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][C:19]=3[N:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:39]([CH3:43])[CH2:40][CH2:41][N:42]=4)=[CH:34][CH:33]=3)[C:17](=[O:44])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.[C:47](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[Cl:8][C:9]1[CH:46]=[CH:45][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:25][C:19]=3[N:18]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:42]([CH3:47])[CH2:41][CH2:40][N+:39]=4[CH3:43])=[CH:34][CH:33]=3)[C:17](=[O:44])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C3=NCCN3C)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1ccc2c(c1)N(Cc1ccc(C3=[N+](C)CCN3C)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
11 mg (0.017 mmol) of ethyl 4-(4-chlorobenzoyl)-2-oxo-1-[4-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylate trifluoroacetate obtained in Example 204 was dissolved in 3 ml of acetonitrile. 10 mg (0.08 mmol) of potassium carbonate and 0.05 ml (0.32 1) of methyl iodide were added to the obtained solution, and they were stirred at room temperature for 5 hours. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([OH:19])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>C(C(C)=O)C>[C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:19][CH2:29][CH2:28][CH2:27][Br:26])=[C:15]([CH2:16][CH2:17][CH3:18])[C:10]=3[O:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCBr
Reactant: CCCc1c(O)ccc2c(-c3ccccc3)coc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(-c3ccccc3)coc12

Procedure:
To a solution of 3-phenyl-6-hydroxy-7-propylbenzofuran (3.54 g, 13.99 mmol) and potassium carbonate (2.08 g, 15.05 mmol) in dry methyl ethyl ketone (50 ml) was added 1,3-dibromopropane (2.84 ml, 27.98 mmol). The reaction mixture refluxed for 5 hours under nitrogen. The mixture was partitioned between isopropyl acetate and pH4 buffer. The organic was dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography (silica gel, 50% methylene chloride in hexane) to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.C(N(C(C)C)CC)(C)C.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29]>C1COCC1.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:27](=[O:30])[CH:28]=[CH2:29])[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cccc(-c2cnc3ccccc3n2)c1
Reaction time: 24 h
Yield: 87.6 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (100 mg, 0.452 mmol) and diisopropylethylamine (DIEA, 90 μL, 0.542 mmol) in THF (5 mL), acryloyl chloride (41 μL, 0.497 mmol) was added at room temperature and the reaction mixture was stirred for 24 hrs. Upon diluted with ethyl acetate (25 mL), the organic phase was washed with water (25 mL), dried over MgSO4, filtered and the solvent evaporated in vacuo to afford N-(3-(quinoxalin-2-yl)phenyl)acrylamide (109 mg, 87% yield). LCMS calculated for C17H13N3O (M+H): 276.31. found 276.17. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.49 (1H, br.), 9.52 (1H, s), 8.60 (1H, m), 8.13-8.16 (2H, m), 8.05-8.08 (1H, m), 7.80-7.95 (3H, m), 7.55-7.60 (1H, m), 6.48-6.58 (1H, dd, J=10 Hz and 16.5 Hz), 6.32 (1H, d, J=16.5 Hz), 5.80 (1H, d, J=10 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:32][CH2:33][CH3:34])[CH2:29][CH2:30][CH3:31])=[CH:18][CH:17]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O>ClCCl>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH2:30][CH3:31])[CH2:32][CH2:33][CH3:34])[S:44]([CH3:43])(=[O:46])=[O:45])=[CH:20][CH:21]=1)[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCNCc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCCN(CCC)CCCCN(Cc1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (182.6 mg) obtained in Example 21-4 was dissolved in dichloromethane (5.3 ml) and added with triethylamine (0.105 ml) and methanesulfonyl chloride (43.6 μl), and the whole was stirred at room temperature for 0.5 hours. The reaction solution was added with water, subjected to extraction with chloroform, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate), thereby obtaining the subject compound (148.0 mg) as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]([CH3:14])[NH:11][CH:10]([CH3:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH:12]([CH3:14])[N:11]([S:24]([C:19]3[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=3)(=[O:26])=[O:25])[CH:10]([CH3:15])[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CN(c2ncccc2Cl)CC(C)N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(c2ncccc2Cl)CC(C)N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
1-(3-chloropyridin-2-yl)-3,5-dimethylpiperazine (370 mg, 1.644 mmol) was dissolved in anhydrous dichloromethane (6 mL) added with 3,4-dichlorobenzene sulfonyl chloride (509 mg, 1.97 mmol) and diisopropylethylamine (0.72 mL, 4.11 mmol). The reaction mixture thus prepared was stirred overnight at room temperature. The reaction was complete as determined by TLC. It was purified via flush column chromatography to afford 4-(3-chloropyridin-2-yl)-1-[(3,4-dichlorophenyl)sulfonyl]-2,6-dimethylpiperazin in 13% yield (110 mg) as a sticky solid.
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:10]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[C:9]1[C:40]([O:42][CH2:43][CH3:44])=[O:41])C1C=CC=CC=1.[H][H]>[C].[Pd].C(O)(=O)C>[CH2:30]([O:29][C:10]1[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:8][C:9]=1[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCOc1c(OCCCCCCCCCC)c(C(=O)OCC)n(Cc2ccccc2)c1C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCOc1c(C(=O)OCC)[nH]c(C(=O)OCC)c1OCCCCCCCCCC
Reaction time: 84 h
Yield: 75.9 %

Procedure:
Into a 1-L autoclave, 121.1 g (0.197 mole) of the diethyl N-benzyl-3,4-didecyloxypyrrole-2, 5-dicarboxylate, 600 ml of acetic acid and 12.0 g of 10% palladium-carbon were put, and the reaction was carried out for 84 hours at 30° C. and a hydrogen pressure of 1.8×106 Pa. After the reaction was completed, the 10% palladium-carbon was removed by filtration, and the filtrate formed was evaporated to dryness. The residue formed was purified by silica gel column chromatography (eluent: toluene/acetic acid=5/1) to obtain 78.3 g of diethyl 3,4-didecyloxypyrrole-2,5-dicarboxylate (yield: 75.8%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1)=[O:5]
Reactant: O=C1CCNCC1
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCN(C(=O)c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
2-Fluorobenzoyl chloride (10.5 g, 66.5 mmol) was added to a stirred solution of 4-piperidone hydrochloride (6.0 g, 60.5 mmol) and DIPEA (3.0 mL, 17.1 mmol) in DCM (150 mL). The mixture was stirred at room temperature for 2 hours and extracted with a 10% solution of citric acid, a saturated solution of Na2CO3 and H2O. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 1-(2-fluorobenzoyl)-4-piperidinone (5.5 g, 41% yield) that was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6].[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][CH:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.CN(C)C=O>[Cl:9][C:10]1[C:18]([Cl:19])=[C:17]2[C:13]([CH2:14][C:15]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:2][C:3]#[C:4][Si:5]([CH3:8])([CH3:7])[CH3:6])[C:16]2=[O:20])=[CH:12][C:11]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: C[Si](C)(C)C#CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of 1-bromo-3-(trimethylsilyl)-2-propyne (2.87 g., 15.0 mmol) prepared according to methods of Corey, Tet. Lett., 3963 (1973) and Miller, Syn. Comun., 2, 267 (1972) in 50 ml. of dimethylformamide is added to a mixture of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate (2.9 g., 7.65 mmol) and powdered potassium carbonate (2.65 g., 19.2 mmol) under an argon atmosphere. After stirring at 60° for a period of 2 hr. and cooling to room temperature, ether is added to the reaction mixture followed by dilute hydrochloric acid. The acidified solution is extracted with ether and the ethereal extract sequentially washed with water and brine, and then dried over magnesium sulfate. Removal of solvent under reduced pressure affords 4.72 g. of tan solid. Crystallization of this material from cyclohexane provides 3.26 g., (87% yield) of ethyl [6,7-dichloro-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate, m.p. 111.5°- 113° (corr.).
Reaction SMILES: Cl.[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:4])[NH2:3].[CH2:24]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:36][CH2:37][CH3:38])[C:34]=1[F:35])[CH:30]=O)[CH3:25].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:30][C:29]2[CH:32]=[C:33]([O:36][CH2:37][CH3:38])[C:34]([F:35])=[C:27]([O:26][CH2:24][CH3:25])[CH:28]=2)[CH2:17][CH2:18]1)=[O:11])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C=O)cc(OCC)c1F
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(N)=O)c3)CC2)cc(OCC)c1F

Procedure:
In analogy to the procedure described in example 50k), 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 504.3 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C#N)c1ccc(O)c(N)c1
Reaction time: 3.8 h
Yield: 52.4 %

Procedure:
2-(3-Nitro-4-hydroxyphenyl) propionitrile (38.4 g., 0.2 mole.) was suspended in absolute ethanol (250 ml.) and hydrogenated at 4 atmospheres pressure and room temperature over 10% palladium on charcoal. Hydrogenation was complete in 3.8 hours. The catalyst was removed by filtration. Evaporation of the filtrate yielded 2-(3-amino-4-hydroxyphenyl) propionitrile (17 g.), m.p. 110° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].[CH2:14](N(CC)CC)C.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]([CH2:14][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CCNC(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.1 %

Procedure:
Crude intermediate (c) (418 mmol) was dissolved in CH2Cl2 (275 mL) and triethylamine (58.3 mL, 418 mmol) was added followed by ethyl chloroformate (d) (39.8 mL, 418 mmol). The reaction was stirred at ambient temperature for about 24 h. After the reaction was complete, the volatile components were removed under vacuum. The crude product was then distilled under vacuum (about 5 mm Hg) and dissolved in EtOAc which was washed with aqueous saturated KHSO4×3, with brine×1 and dried over Na2SO4. Following filtration, the volatile components were removed under vacuum to afford intermediate (e) as a clear oil (74.8 g, 272 mmol) in 65% yield over two steps.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:5]([N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1)=[O:6].[CH2:35](B(O)O)[CH2:36][CH3:37]>>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:7]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[C:5](=[O:6])[C:4]2[CH:3]=[C:2]([CH2:35][CH2:36][CH3:37])[CH:33]=[C:32]([Cl:34])[CH:31]=2)=[CH:22][CH:23]=1)([CH3:29])([CH3:28])[CH3:30]
Reactant: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc(Br)c2)cc1
Reactant: CCCB(O)O
Product: CCCc1cc(Cl)cc(C(=O)N(CCc2cccc(C(F)(F)F)c2)Cc2ccc(C(C)(C)C)cc2)c1

Procedure:
The title compound was prepared in analogy to example 3, using 3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (Example B176) and n-propylboronic acid. 516.2 [ISP (M+H)+]
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[Cl:23])(=[O:15])=[O:14])[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[S:13]([CH:10]1[CH2:11][CH2:12][CH:8]([C:6]([OH:7])=[O:5])[CH2:9]1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1CCC(S(=O)(=O)c2ccc(F)cc2Cl)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120 %

Procedure:
To a mixture of Rac-(1S,3S)-3-(2-Chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid tert-butyl ester (278 mg) in dichloromethane (4 mL) was added trifluoroacetic acid (1.34 g). The reaction mixture was stirred overnight at room temperature and the volatiles were removed in vacuo to afford the title compound (282 mg, quant.) as light brown oil, used in the next step without further purification. MS (EI): 305.1 (M−H)−.