Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:33]2([CH3:34])[C:12](=[CH:13][CH:14]=[C:15]3[C@@H:32]2[CH2:31][CH2:30][C@@:29]2([CH3:35])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:28])[CH:21]([OH:27])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)[CH2:9]1.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>N1C=CC=CC=1.O>[CH3:43][S:44]([O:27][CH:21]([C@H:20]([C@@H:19]1[C@:29]2([CH3:35])[C@H:16]([C:15]3[C@H:32]([CH2:31][CH2:30]2)[C@:33]2([CH3:34])[C:12]([CH2:11][C@@H:10]([O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)[CH2:9][C@@H:8]2[O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:13][CH:14]=3)[CH2:17][CH2:18]1)[CH3:28])[CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CCC(O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)CCC(OS(C)(=O)=O)[C@@H](C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
In 20 ml of pyridine was dissolved 0.58 g of the 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-ol obtained as above. To this solution was added 0.12 g of methanesulfonyl chloride and the mixture was stirred at 0° C. for 2 hours. Then, at room temperature, the reaction mixture was diluted with water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. The low-boiling fraction was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography. The procedure yielded 0.57 g of 1α,3β-bis(tetrahydropyran-2-yloxy)cholesta-5,7-dien-22-yl methanesulfonate (yield: 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([CH:9]2[C:17](=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=O)=O)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[C:9]3[CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10]=3[NH:23][N:24]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C2C(=O)c3ccccc3C2=O)cc1
Reactant: NN
Solvent: O
Product: COc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 0 °C

Procedure:
A mixture of 2-(4-methoxybenzoyl)indan-1,3-dione (1.4 g, prepared by a modification of the method disclosed in J. Het. Chem. 8, 855-859 (1971)), and hydrazine hydrate (15 ml) was boiled under reflux for 24 hours. The mixture was cooled, poured into ice-water and the solid which precipitated was collected by filtration, washed with absolute ethanol and dried to give 3-(4-methoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 247° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Cl.Br[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[N:20]1[CH:21]=[CH:22][C:17]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: Brc1ccncc1
Agent: Cl
Product: COC(=O)CCc1ccc(C#Cc2ccncc2)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (94 mg, 0.50 mmol) and 4-bromopyridine hydrochloride (108 mg, 0.55 mmol) according to the general procedure IC to give 72 mg (54%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:5). Rf=0.26 (EtOAc:PE, 1:1); 1H NMR (CDCl3) δ 8.52 (dd, J=4.5, 1.5 Hz, 2H), 7.45-7.39 (m, 2H), 7.29 (dd, J=4.5, 1.6 Hz, 2H), 7.14 (d, J=8.3 Hz, 2H), 3.60 (s, 3H), 2.90 (t, J=7.7 Hz, 2H), 2.57 (t, J=7.7 Hz, 2H); 13C NMR (CDCl3) δ 172.0, 148.8, 141.0, 131.0, 130.5, 127.5, 124.5, 119.0, 92.9, 85.5, 50.7, 34.3, 29.8; ESI-MS m/z 288.1 (M+Na+).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([SH-:9]C(=S)OCC)=[CH:5][CH:4]=1>C(O)C.[OH-].[Na+]>[F:16][C:2]([F:1])([F:15])[C:3]1[N:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1
Reactant: CCOC(=S)[SH-]c1ccc(C(F)(F)F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: FC(F)(F)c1ccc(S)cn1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of O-ethyl S-[6-(trifluoromethyl)pyridin-3-yl]dithiocarbonate (2.67 g, 10.0 mmol) in ethanol (30 ml), 1 N aqueous sodium hydroxide (30 ml) was added, and the resulting mixture was stirred for 2 hours at 50° C. The reaction mixture was cooled to room temperature, and washed with methylene chloride. Subsequently, the aqueous layer was acidified with 1 N hydrochloric acid, and was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure, to obtain 6-(trifluoromethyl)pyridin-3-thiol as a crude product.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=2)[CH2:7][C:6]([CH3:19])([CH3:18])[C:5]1=[O:20].[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=3)=[CH:27][NH:28]2)=[CH:24][CH:23]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:31]3[CH2:32][CH2:33][N:34]([CH2:2][CH2:3][N:4]4[C:13]5[C:8](=[CH:9][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][CH:12]=5)[CH2:7][C:6]([CH3:19])([CH3:18])[C:5]4=[O:20])[CH2:35][CH:36]=3)=[CH:27][NH:28]2)=[CH:24][CH:23]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: CC1(C)Cc2cc(S(C)(=O)=O)ccc2N(CCCl)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC1(C)Cc2cc(S(C)(=O)=O)ccc2N(CCN2CC=C(c3c[nH]c4cc(F)ccc34)CC2)C1=O
Temperature: 25 °C

Procedure:
1-(2-Chloroethyl)-3,4-dihydro-3,3-dimethyl-6-methylsulfonyl-2(1H)-quinolinone (1.0 g, 0.0032 mol), 6-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.684 g, 0.0032 mol), sodium iodide (0.15 g, 0.001 mol) and potassium carbonate (1.38 g, 0.010 mol) were suspended in acetonitrile (45 ml). The reaction mixture was heated at reflux under nitrogen for 20 hr. The product mixture was then cooled to room temperature. The solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (50 ml). The organic layer was then dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed to afford 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3,4-dihydro-3,3-dimethyl-6-methylsulfonyl-2(1H)-quinolinone as a yellow foam. δ(1H NMR, DMSO, ppm): 1.28 (6H, s), 2.68 (2H, m), 3.14 (2H, s), 3.40 (3H, s), 3.55 (3H, br), 3.96 (1H, br), 4.06 (1H, br), 4.30 (1H, d), 4.60 (2H, t), 6.36 (1H, s), 7.11 (1H, dt), 7.35 (1H, dd), 7.78 (2H, m), 8.00 (3H, m), 11.56 (1H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4](C(=O)C)[CH2:3]1.Cl.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CC(=O)N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)CNc2cc(N3CCOCC3)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3,3-Dimethyl-6-morpholinoindolin-1-yl)ethanone was dissolved in acetonitrile (100 mL) and treated with 5 N HCl (50 mL) at 95° C. After 2 h, the mixture was cooled to rt. The reaction was carefully neutralized with saturated NaHCO3 solution to pH 10 and extracted with EtOAc (100 mL×4). The combined organics were washed with water, brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc/hexane, 0/1 to 1/0) to give 4-(3,3-dimethylindolin-6-yl)morpholine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.80 (1H, d, J=7.8 Hz), 6.14 (1H, dd, J=8.0, 2.2 Hz), 6.09 (1H, d, J=2.0 Hz), 5.28 (1H, s), 3.65-3.73 (4H, m), 3.13 (2H, d, J=2.0 Hz), 2.92-2.99 (4H, m), 1.17 (6H, s). Mass Spectrum (ESI) m/e=233.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](F)[C:17]=2[F:19])[C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10]1.[NH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][NH:30][CH2:31]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[CH2:29][N:30]([C:16]1[C:17]([F:19])=[C:18]3[C:13]([C:12](=[O:22])[C:11]([C:23]([OH:25])=[O:24])=[CH:10][N:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:14][C:15]=1[F:21])[CH2:31]2
Reactant: Nc1cccc2c1CNC2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1cccc2c1CN(c1c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4F)c3c1F)C2
Yield: 31.9 %

Procedure:
178 mg of 1-(2,4-difluorophenyl)-6,7,8-trifluoro-1,4- dihydro-4-oxoquinoline-3-carboxylic acid, 81 mg of 4-aminoisoindoline, 137 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 75 mg of the target compound.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH:3]=[CH2:4].Br[CH2:7][CH2:8][CH:9]=[O:10].[OH-].[Na+]>CO>[CH2:1]([NH:5][CH2:7][CH2:8][CH:9]=[O:10])[CH2:2][CH:3]=[CH2:4]
Reactant: O=CCCBr
Reactant: C=CCCN
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCNCCC=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
But-3-enylamine (1.0 mole), the diethyl acetal of 3-bromopropionaldehyde (1.0 mole) and methanol (100 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux with stirring for a period of about 6 hours. After this time the reaction mixture is cooled to room temperature and sodium hydroxide (20 grams) is added. The reaction mixture is then stirred for an additional period of about 16 hours. The mixture is then filtered and the filtrate is distilled to yield the desired product the diethyl acetal of 3-but-3-enylaminopropionaldehyde.
Reaction SMILES: C([Li])(CC)C.[CH3:6][N:7]([CH2:9][C-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1)[CH3:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1I>C1CCCCC1.C1COCC1.C(OCC)C.[Cl-].[Cl-].[Zn+2]>[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:11]1[C-:10]([CH2:9][N:7]([CH3:8])[CH3:6])[CH:14]=[CH:13][CH:12]=1.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: CN(C)C[c-]1cccc1
Reactant: Brc1ccccc1I
Agent: [Fe+2]
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C[c-]1cccc1-c1ccccc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
46 ml (60 mmol) of a 1.3 molar solution of s-butyllithium in cyclohexane are added dropwise to a degassed solution of 12 g (49.4 mmol) of N,N-dimethylaminomethylferrocene in 40 ml of THF while cooling in ice. The solution is stirred at 0° C. for 30 minutes, and 74 ml of a 1 molar solution of ZnCl2 in diethyl ether are subsequently added dropwise, likewise at 0° C. The reaction mixture is stirred at room temperature for 1 hour, after which 3.5 g (5 mmol) of bis(diphenylphosphine)palladium(II) chloride and a solution of 28.3 g (100 mmol) of 2-bromoiodobenzene in 50 ml of THF are added and the mixture is refluxed for 3 days. The solvent is taken off on a rotary evaporator, the residue is taken up in CH2Cl2 and extracted with water. The aqueous phase is extracted 3 times with 50 ml each time of CH2Cl2 and the combined organic phases are washed twice with 30 ml each time of water. After drying over MgSO4 and removal of the solvent under reduced pressure, the residue is chromatographed on aluminium oxide. As eluant, use is made of a mixture of petroleum ether, ether and triethylamine in a ratio of 60:1:3. The yield is 6.336 g (15.92 mmol, 32%) of L7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:36]([CH3:37])[CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Reactant: CNC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield: 12%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H+]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([O:20]C)=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.O.[OH-].[Li+].C1COCC1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=[O:19])=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: COC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Yield: 88 %

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [O:1]1[CH:10]2[CH:2]1[CH2:3][C:4]1[C:9]2=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([CH:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH:2]2[OH:1])[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: c1ccc2c(c1)CC1OC21
Product: CN1CCN(C2c3ccccc3CC2O)CC1

Procedure:
Using the procedure of Example 23, Step A, 14.57 g of 2,3-epoxy-indane and 12.4 ml of N-methyl piperazine were reacted to obtain 6.447 g of [trans (±)] 2,3-dihydro-1- (4- methyl-1-piperazinyl)-1H-inden-2-o1 melting at 132° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.C[N:16](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:16])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of 4-methoxy-2-nitro-benzoic acid (14.1 g, 71.5 mmol) and some drops of DMF in DCM (150 ml) was added drop wise oxalyl chloride (19.0 g, 150 mmol) and the mixture was stirred for two hours at room temperature. The solvent was evaporated and water was added. The product was filtered of and washed with water and hexane. The product was dried in vacuum. Yield: 10 g, 71%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([O:22]C)=[O:21])[CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>CO.O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([C:20]([OH:22])=[O:21])[CH:13]=2)[O:9][N:8]=1
Reactant: COC(=O)c1cc(OC)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A stirred suspension of 3-(2-pyridyl)-5-(3-methoxycarbonyl-5-methoxyphenyl)-1,2,4-oxadiazole (191.3 mg, 0.62 mmol) in methanol-tetrahydrofuran (1:1, 10 mL) was treated with 1 M sodium hydroxide (1.5 mL, 1.5 mmol). The reaction was stirred at 50° C. for 5 hours and the solvent then removed in vacuo. The residue was dissolved in a small amount of water and then acidified (pH 4–5) by the addition of 2 N hydrogen chloride. The precipitate was collected and dried to afford 131.8 (72%) of 3-(2-pyridyl)-5-(3-carboxy-5-methoxyphenyl)-1,2,4-oxadiazole: 1H NMR (DMSO): δ −8.81 (d, 1H), 8.28 (s, 1H), 8.21 (d, 1H), 8.06 (t, 1H), 7.88 (s, 1H), 7.74 (s, 1H), 7.65 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][S:10]([NH:13][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:11])=[O:12])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(NS(=O)(=O)C=Cc1ccc([N+](=O)[O-])cc1)c1ccccc1
Yield: 76 %

Procedure:
A mixture of 4-nitrostyrylsulfonamide (18.2 g., 0.08 mole), benzoyl chloride (12.6 g., 0.09 mole) and phosphorus oxychloride (13.8 g., 0.09 mole) is heated at steam bath temperature for 1.5 hr. The reaction mixture diluted with 20 ml. of ethyl acetate, cooled and filtered affords 19.0 g. (76% yield) of N-(4-nitrostyrylsulfonyl)benzamide, m.p. 192°-195° C., from ethyl acetate-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:14](=[O:16])C)[CH:8]=2)[O:3]1.Cl[O-:20].[Na+].[OH-].[Na+]>O.O1CCOCC1>[CH3:18][C:2]1([CH3:1])[CH2:11][C:10]([CH3:12])([CH3:13])[C:9]2[C:4](=[CH:5][C:6]([CH3:17])=[C:7]([C:14]([OH:16])=[O:20])[CH:8]=2)[O:3]1
Reactant: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Reactant: [O-]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc2c(cc1C(=O)O)C(C)(C)CC(C)(C)O2
Temperature: 45 °C
Reaction time: 48 h

Procedure:
A mixture of 950 mg (3.9 mmol) of 2,2,4,4,7-pentamethyl-6-acetylchroman (Compound 53), 100 ml of 10% sodium hypochlorite solution, 10 ml of a solution of 1.52 g (38 mmol) of sodium hydroxide in water and 10 ml of dioxane was heated at 45° C. for 72 hours. The mixture was cooled to room temperature and washed with 2×25 ml of ether. The aqueous layer was then treated with sodium metabisulphite until it was negative to the potassium iodide-starch test. The aqueous layer was acidified to pH=2 with dilute H2SO4 and the mixture was then stored in the refrigerator for 48 hours. The mixture was extracted with 3×25 ml of ether. The ether extracts were then combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solution was then filtered and the filtrate was concentrated in-vacuo to give the title compound as a white solid. PMR (CDCl3): & 1.34 (12H, s), 1.82 (2H, s), 2.53 (3H, s), 6.64 (1H, s), 8.03 (1 H, s).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:29][O:30][C:31](=[O:35])[C@H:32]([CH3:34])[NH2:33].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[NH:8]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[C@@H:9]([C:14]([NH:33][C@H:32]([C:31]([O:30][CH3:29])=[O:35])[CH3:34])=[O:16])[CH2:10][CH2:11][S:12][CH3:13]
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)[C@H](C)NC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
Boc-(D)-methionine (50.0 g) is dissolved in dichloromethane (200 ml) and 1-hydroxybenzo-triazole hydrate (29.7 g) and (L)-alanine methyl ester hydrochloride (31.0 g) is added. The mixture is cooled to 0° C. and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43.0 g) is added in portions, maintaining the temperature of the mixture at 0-5° C. N-Methylmorpholine (42.2 g) is then added over 30 minutes, maintaining the temperature of the mixture at 0-5° C. The mixture is then stirred at 0° C. for 5 hours. The reaction mixture is washed successively with water (2×100 ml), 10% aqueous citric acid solution (100 ml), saturated aqueous sodium bicarbonate solution (100 ml), water (100 ml) and evaporated to dryness at 40° C. under reduced pressure to give Boc-(D)-Met-(L)-Ala-OMe (67.0 g estimated to contain 0.17 mol) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:12])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[CH2:10]([O:9][C:7]([C:6]1[C:5]([CH3:12])=[CH:4][S:3][C:2]=1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1scc(C)c1C(=O)OCC)C(=O)OCC
Temperature: 135 °C

Procedure:
A mixture of ethyl 2-amino-4-methylthiophene-3-carboxylate (5.23 g) and diethyl ethoxymethylenemalonate (5.71 mL) is heated to 135° C. for 3 h with a stream of nitrogen passing through the flask. The mixture is allowed to cool to room temperature. The resulting solid is recrystallized (EtOH, 250 mL) to afford 9.23 g of the title compound as yellow needles. Physical characteristics. M.p. 126-128° C.; 1H NMR (400 MHz, DMSO-d6) δ12.36, 8.08, 6.77, 4.34, 4.24, 4.15, 2.31, 1.34, 1.27, 1.25; MS (ESI+) m/z 356 (M+H)+. Anal. Found: C, 54.12; H, 5.95; N, 3.99.; S, 8.99.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[C:16](O)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].CS(O)(=O)=O>>[C:16]([O:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCCOc1ccccc1
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(=O)OCCOc1ccccc1
Temperature: 220 °C

Procedure:
To a four neck round bottom flask fitted with nitrogen inlet, mechanical stirrer, temperature probe and condenser is charged 994.13 g (2.24 moles) of the Alkoxylate from example 27 and 605.87 g (2.13 moles) of Stearic Acid. A catalytic amount of Methanesulfonic Acid (1.6 g) is charged and the reaction mixture is heated to 220° C. under nitrogen sparge. The reaction is monitored by measuring the acid value to an AV of preferably less than 5. Once the AV is reached, the temperature is cooled to 85° C. and the catalyst is neutralized with an equivalent molar amount of 45% KOH and washed once with water. The reaction is dried under vacuum yielding the desired product.