Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][NH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]([O:32][CH2:33][C@H:34]1[O:39][C@H:38](Br)[C@H:37]([O:41][C:42]([CH3:44])=[O:43])[C@@H:36]([O:45][C:46]([CH3:48])=[O:47])[C@@H:35]1[O:49][C:50]([CH3:52])=[O:51])=[O:31].[OH-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl>[C:42]([O:41][C@@H:37]1[C@@H:36]([O:45][C:46](=[O:47])[CH3:48])[C@H:35]([O:49][C:50](=[O:51])[CH3:52])[C@@H:34]([CH2:33][O:32][C:30](=[O:31])[CH3:29])[O:39][C@H:38]1[O:28][C:21]1[C:20]([CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:15]=2)=[C:24]([CH:25]([CH3:26])[CH3:27])[NH:23][N:22]=1)(=[O:43])[CH3:44]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccc(OCCCOCc2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOCc3ccccc3)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of 4-{[4-(3-benzyloxypropoxy)phenyl]-methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (5.08 g), acetobromo-α-D-glucose (5.49 g) and benzyltri(n-butyl)ammonium chloride (2.08 g) in dichloromethane (40 mL) was added 5 mol/L aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3-1/5). The purified material was further purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/2-1/4) to give the title compound (2.75 g).
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11](OCC)=[O:12])[C:6]1=[O:16])(=O)C.[NH3:17]>CO>[OH:4][CH:5]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]([NH2:17])=[O:12])[C:6]1=[O:16]
Reactant: CCOC(=O)CN1CCC(OC(C)=O)C1=O
Reactant: N
Solvent: CO
Product: NC(=O)CN1CCC(O)C1=O
Reaction time: 1 h

Procedure:
0.40 g of ethyl (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetate is treated with 45 ml of a saturated solution of ammonia in methanol. The mixture is left to stand at room temperature for 1 hour and then evaporated. The residue is treated four times with acetonitrile and in each case again evaporated. There is obtained (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide which melts at 163°-164° after recrystallization from methanol/diethyl ether (1:3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH2:26][CH2:27][O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)=[CH:32][C:30]=3[CH:31]=2)=[O:24])=[CH:18][CH:17]=1)=[O:15])=O)(C)(C)C.Cl>CO.C(OCC)(=O)C>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH2:26][CH2:27][O:28][C:29]3[CH:35]=[CH:34][C:33]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)=[CH:32][C:30]=3[CH:31]=2)=[O:24])=[CH:20][CH:21]=1)=[O:15]
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4C(=O)OC(C)(C)C)cc2)CCO3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=O)C4CCCCN4)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
In methanol (100 ml) and ethyl acetate (150 ml) was dissolved N-(4—(1—(tert-butoxycarbonyl)piperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.0 g), and to the mixture was added hydrochloric acid (17 ml). The mixture was stirred at room temperature for 2 hours, concentrated and neutralized with sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give crude crystals, which were recrystallized from ethanol-ethyl acetate-hexane to give N-(4—(piperidin-2-ylcarbonyl)phenyl)-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 156) (0.6 g) as colorless crystals.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([CH:6]([CH2:34][CH3:35])[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:13][CH:12]=1)=[O:10])[CH3:5].CO.O1CCCC1>O>[CH2:34]([CH:6]([CH2:4][CH3:5])[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[C:18]2[CH2:21][C:22]2[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=2[O:32][CH3:33])=[CH:13][CH:12]=1)=[O:10])[CH3:35]
Reactant: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)O)cc3OC)c2c1
Reaction time: 18 h
Yield: 73.7 %

Procedure:
A solution of lithium hydroxide monohydrate (150 mg) in water (4 ml) was added to a solution of methyl 4-(7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl)-3-methoxybenzoate (310 mg) in 1:1 methanol:tetrahydrofuran (15 ml). The mixture was stirred for 18 h. After most of the solvent was evaporated, water (7 ml) was added. The mixture was acidified with 1N hydrochloric acid and the precipitate was filtered, triturated with 25 ml of 10:1 ether:methanol, ground to a powder and vacuum dried at 100° C for 12 h to give 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoic acid (221 mg, 74%) as a colorless solid; mp 198.0°-199.0° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[C:3]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Br[C:27]1[CH:36]=[C:35]2[C:30]([CH2:31][CH:32]([CH3:51])[N:33]([C:37]3[CH:42]=[C:41]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[N:40]=[C:39]([NH2:50])[N:38]=3)[CH2:34]2)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[NH2:50][C:39]1[N:38]=[C:37]([N:33]2[CH:32]([CH3:51])[CH2:31][C:30]3[C:35](=[CH:36][C:27]([C:5]4[CH:4]=[C:3]([C:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[O:17])[N:2]([CH3:1])[CH:6]=4)=[CH:28][CH:29]=3)[CH2:34]2)[CH:42]=[C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)[N:40]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1Cc2ccc(-c3cc(C(=O)OCc4ccccc4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (78.5 mg, 0.230 mmol), 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.080 g, 0.19 mmol) (Peak 1, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (4.07 mg, 0.00575 mmol), and sodium carbonate (0.0406 g, 0.383 mmol) in 1,4-dioxane (0.88 mL) and water (0.1 mL) was vacuumed and refilled with N2 for 3 times and then stirred at 90° C. overnight. LCMS monitored reaction. After cooling down to r.t., the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on a silica gel column with methanol in methylene chloride (0-10%) to afford the desired product. LCMS (M+H)+: m/z=552.1.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:34]=[CH:35][C:36]=1[F:37].Cl>>[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH2:25][CH:26]4[CH2:27][CH2:28][CH2:29]4)[C:15]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:16])[CH2:4]3)[CH2:43][CH2:42]2)[CH:34]=[CH:35][C:36]=1[F:37]
Reactant: O=C[C@H]1CN([C@H](CC2CCC2)C(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1F
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)c(F)c3)CC2)[C@@H](c2ccccc2)C1
Yield: 50.4 %

Procedure:
The title compound was prepared from 26 mg (0.06 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 25, Step B) and 17.5 mg (0.06 mmol) of 4-(3-(3,4-difluorophenyl)propyl)piperidine.HCl (from EXAMPLE 119, Step C) using a procedure analogous to that described in EXAMPLE 1, Step J to provide 18.6 mg (47%) of the title compound: RF: 0.33 (1:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 1.15-3.29 (m, 33H), 5.17 (ABq, 2H), 6.8-7.4 (m, 13H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:9][CH:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][O:2][C:3]1[C:4]([O:9][CH:10]2[CH2:15][CH2:14][CH:13]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1OC1CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: COc1cccnc1OC1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-methoxy-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[F:12][C:8]1[C:9]([N+:1]([O-:4])=[O:2])=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(F)c1-c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(F)c(-c2ccncc2)c1F
Reaction time: 0.75 h
Yield: 88 %

Procedure:
A mixture of cold (0° C.) concentrated nitric acid (20.4 ml) and concentrated sulfuric acid (20.4 ml) was added in portions to a stirred solution of 10 g 4-(2,6-difluorophenyl)-pyridine in 56 ml concentrated sulfuric acid at 0° C. After 45 minutes at 0° C., the mixture was poured onto ice and the resulting solution was neutralized with solid sodium bicarbonate. It was then extracted twice with ethyl acetate and the organic extracts were dried and evaporated to give the product as white solid of m.p. 110°-112° C. (10.9 g, 88% yield). NMR (CDCl3, 60 MHz): 8.8 (m, 2H), 8.2 (m, 1H), 7.0-7.6 (m, 3H).
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH:55]3[CH2:60][CH2:59][CH2:58][C:57]([CH3:62])([CH3:61])[CH2:56]3)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[N:6]1([S:10]([NH:13][C:49](=[O:50])[C:48]2[CH:52]=[C:44]([CH:41]3[CH2:42][CH2:43]3)[C:45]([O:54][CH:55]3[CH2:60][CH2:59][CH2:58][C:57]([CH3:62])([CH3:61])[CH2:56]3)=[CH:46][C:47]=2[F:53])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)O)cc2C2CC2)C1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a white solid (0.035 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ11.58 (s, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.03 (d, J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 4.04 (t, J=7.7 Hz, 4H), 2.21-2.11 (m, 2H), 2.06-1.96 (m, 2H), 1.76-1.70 (m, 1H), 1.65-1.53 (m, 2H), 1.38-1.14 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 425.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[H-].[Na+]>CN(C=O)C>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:7][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O-:3])=[O:2]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COCc1ccccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 1 h

Procedure:
20 g o-nitro benzylalcohol and 21.7 ml ethyl bromoacetate was dissolved in 250 ml dry DMF. Portions of 55-60% sodium hydride were added to this solution under stirring over one hour until a total amount of 8.5 g had been added. The mixture was left overnight at room temperature and then heated to 150° C. under stirring for 2 hours. The mixture was then evaporated and the residue was partitioned between diethylether and water. The organic phase was evaporated to give 14 g ethyl (o-nitro-benzyloxy)acetate as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][C:15](=[O:17])[CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)[S:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reactant: Cc1csc(N)n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc(NC(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 20 h

Procedure:
To a round-bottomed flask containing 2-(1-tert-butoxycarbonyl-piperazin-4-yl)-acetic acid×2HCl (0.100 g, 0.36 mmol) was added 2-amino-4-methylthiazole (0.045 g, 0.39 mmol) and anhydrous dichloromethane (4 ml). The reaction mixture was cooled into an ice-bath under argon, and then diisopropylethylamine (0.139 g, 1.08 mmol) was added followed by PyBOP (0.187 g, 0.36 mmol). The ice-bath was removed and the reaction mixture was allowed to stir for 20 h under argon. The solvent was removed in vacuo, the residue was absorbed on silica gel and the free running powder was placed on a 20 g isolute silica column which was eluted with 30% ethyl acetate in dichloromethane and then 60% ethyl acetate in dichloromethane. The title compound was obtained as a gummy material (0.076 g, 62%). 1H-NMR (500 MHz, DMSO-d6) 1.39 (s, 9H, C(CH3)3), 2.25 (s, 3H, CH3), 2.45 (br s, 4H, piperazine N(CH2)2), 3.27 (s, 2H, NCH2CO), 6.76 (s, 1H, thiazole 5-H), 11.78 (s, 1H, CONH);
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][P:5]([OH:7])[OH:6].[C:8]1(=[O:12])[CH2:11][CH2:10][CH2:9]1.O>C[Si](C)(C)N[Si](C)(C)C.Cl>[NH2:1][CH2:2][CH2:3][CH2:4][P:5]([C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1)(=[O:7])[OH:6]
Reactant: NCCCP(O)O
Reactant: O=C1CCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: O
Product: NCCCP(=O)(O)C1(O)CCC1

Procedure:
A suspension of 2.46 g of 3-aminopropylphosphonous acid in 20 ml of hexamethyldisilazane is heated to reflux under an inert gas for 24 hours. The resulting clear solution is cooled to 15° and 2.0 ml of cyclobutanone are added. An exothermic reaction ensues. The reaction mixture is stirred until the temperature drops to room temperature (approximately 1 hour). Water is added and the volatile materials are removed in vacuo to yield a semi-solid. This is dissolved in 2.0M aqueous hydrochloride acid and washed with 2×100 ml of dichloromethane. The aqueous layer is evaporated in vacuo to afford a solid which is passed through a DOWEX® 50 W×8 (14-40 mesh) ion-exchange column to give 3-aminopropyl(1-hydroxycyclobutyl)phosphinic acid, m.p. 174°-175° (dec).
Reaction SMILES: O([C:5]([CH3:7])=[O:6])C(C)=O.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:8][N:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5](=[O:6])[CH3:7]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccccc1
Product: CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
(CH3CO)2O (50 g, 480.77 mmol) was added to N-methylbenzenamine (10.7 g, 100.00 mmol), and the resulting solution was stirred at room temperature for 15 hours. The reaction mixture was then quenched by adding 200 mL of iced water. The resulting solution was extracted with dichloromethane (2×100 mL), and the organic layers were combined and concentrated to afford 11 g (70%) of N-methyl-N-phenylacetamide as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-Allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.97 (s, —CO2H); 7.47 (d-like, 1 arom. H); 7.40 (m, 2 arom. H); 7.18 (m, 1 arom. H); 5.99 (m, —CH═CH2); 5.37, 5.23 (2 d-like, CH═CH2); 4.03 (d-like, CH2—CH_CH2). 13C-NMR (100 MHz, d6-DMSO): 167.08 (C═O); 158.12; 133.44; 132.27; 129.67; 121.66; 119.47; 117.47; 114.78; 68.27.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:30])[N:12]([CH2:19][CH:20]1[NH:29][CH2:28][CH2:27][C:22]3(OCC[O:23]3)[CH2:21]1)[C:13]2=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11](=[O:30])[N:12]([CH2:19][CH:20]1[CH2:21][C:22](=[O:23])[CH2:27][CH2:28][NH:29]1)[C:13]2=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc(OCc3ccccc3)c2C(=O)N1CC1CC2(CCN1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCNC(CN2C(=O)c3cccc(OCc4ccccc4)c3C2=O)C1
Temperature: 65 °C
Reaction time: 6 h

Procedure:
To a solution of the above 4-benzyloxy-2-(1,4-dioxa-8-aza-spiro[4.5]dec-7-ylmethyl)-isoindole-1,3-dione (0.22 g, 0.54 mmol) in 1,4-dioxane (4 ml) was added 4N hydrochloric acid (4 ml) and the reaction stirred in a 65° C. (oil bath) for 6 hours. The mixture was basified with saturated sodium bicarbonate until pH=8 and extracted with dichloromethane (3×20 ml). The combined organic extracts were dried (MgSO4), filtered, and the solvent evaporated in vacuo affording crude 4-benzyloxy-2-(4-oxo-piperidin-2-ylmethyl)-isoindole-1,3-dione as an oil. Which was used without further purification or characterization.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].[C:9]1([P:15](Cl)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.O1CCOCC1.O1CCOCC1>[NH2:2][O:3][P:15](=[O:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
Into a 500-mL three neck round-bottom flask, was placed a solution of hydroxylamine hydrochloride (30.0 g, 432 mmol) in H2O/dioxane (90/45 mL). The solution was cooled to 0-5° C., then sodium bicarbonate (36.5 g, 434 mmol) was added portion-wise over 10 min and the mixture was stirred at 0-5° C. for 30 min. A solution of diphenylphosphinoyl chloride (41.0 g, 173 mmol) in dioxane (45 mL) was added drop-wise at 0-5° C. over 30 min, then the resulting mixture was stirred for an additional 2 h at ambient temperature. The resulting solids were collected by filtration and washed with water (200 mL), NaOH (0.25 M, 200 mL) and PE (200 mL). The product was dried to yield the title compound as a white solid (20 g, crude).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=[O:12])[CH2:4][CH2:3][CH2:2]1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:14][S:15]([C:7]1[CH:6]=[C:5]2[C:10](=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=1)[O:1][CH2:2][CH2:3][CH2:4]2)(=[O:17])=[O:16]
Reactant: O=C(O)c1cccc2c1OCCC2
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)cc2c1OCCC2
Temperature: 10 °C
Reaction time: 1 h

Procedure:
930 ml of chlorosulphonic acid were introduced into a 1-liter round-bottomed flask and 165 g of chroman-8-carboxylic acid were then added in small amounts, while maintaining the temperature between 0° C. and 10° C. by cooling. The solution was stirred for 1 hour at 10° C., and then allowed to stand overnight at ambient temperature. It was then poured in small amounts onto ice, while stirring and maintaining the temperature at 0° C. by cooling externally and by introducing ice into the flask.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.C(N(CC)CC)C.[C-]#N.[K+]>C(#N)C.O>[CH:8]12[CH2:9][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:1][C:2]2=[O:3]
Reactant: C=C1OC(=O)C2CCC1C2
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CC(=O)C2CCC1C2
Yield: 74.2 %

Procedure:
Analogously to Example P3, 2.76 g (20 mmol) of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one are stirred for 15 hours at room temperature in the presence of 2.23 g (22 mmol) of triethylamine and 0.13 g (2 mmol) of potassium cyanide in 10 ml of acetonitrile. The mixture is heated at 55° for a further 30 minutes and then taken up in water and the neutral components are removed at pH 10 using ethyl acetate. The aqueous phase, acidified to pH 2, is extracted with ethyl acetate, dried over sodium sulfate and concentrated by evaporation, yielding 2.05 g (74.3%0) of pure bicyclo[3.2.1]octane-2,4-dione having a melting point of 129-130° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([NH2:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].Cl[C:22]([S:24]Cl)=[O:23]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:5]([CH2:12][CH2:13][C:14]2[O:15][C:22](=[O:23])[S:24][N:16]=2)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(Cl)SCl
Reactant: CC(C)(C)c1cc(CCC(N)=O)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCc2nsc(=O)o2)cc(C(C)(C)C)c1O
Temperature: 60 °C

Procedure:
A suspension of 13.45 grams of 3-[4-hydroxy-3,5-di- tert-butylphenyl]propionamide in 150 ml of toluene is admixed with 20.22 grams of chlorocarbonyl sulfenyl chloride added dropwise. After heating the reaction mixture at 60° C. for 20 hours, the solvent is removed under reduced pressure. The residue is recrystallized from heptane to give the title compound as a pale yellow crystalline solid: mp 82°-86° C.