Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][CH:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:27]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>ClCCl.O>[C:35]([N:8]1[CH2:7][C:6]2[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)=[N:13][N:14]=[C:10]2[CH2:9]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC(c4ccccc4)CC3)n1-2
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC(c3ccccc3)CC2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the compound from example 5 (200 mg, 0.53 mmol) in dichloromethane (5 mL) was added triethylamine (110 μL, 0.79 mmol). The solution was cooled to 0° C. and acetic anhydride (59.6 μL, 0.63 mmol) was added. The reaction mixture was then stirred for 1 hour, before it was diluted with water (10 mL) and the phases were separated. The organic phase was washed with brine (10 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was azeotroped with ethyl acetate to give the product as a white, crystalline solid, 206 mg (93%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>N1C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Brc1ccc(Br)nc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Yield: 39.5 %

Procedure:
A mixed solution of 2,5-dibromopyridine (6.36 g, 26.8 mmol), 1-(tert-butoxycarbonyl)piperazine (5.00 g, 26.8 mmol) and pyridine (100 ml) was stirred at 125° C. for 12 hours, and the solvent was distilled away under reduce pressure. The residue was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the titled compound 3.62 g (39.5%) as solid product.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:9]=3[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:23]([O-:28])([N+]([O-])=O)=[O:24]>C(Cl)(Cl)Cl>[N+:23]([C:11]1[O:10][C:9]2[C:12]3[C:17]([C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)([O-:28])=[O:24]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(O)c1cc2c(-c3ccccc3)coc2c2ccccc12
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc2c(-c3ccccc3)c([N+](=O)[O-])oc2c2ccccc12
Temperature: 20 °C
Reaction time: 24 h

Procedure:
The product of step A is dissolved partially in 125 ml. of hot chloroform, and 1 g. of dinitrogen tetraoxide is added. The mixture is stirred at 20° C. for about one day. The mixture is evaporated to provide a residue which is triturated with isopropyl alcohol. The residue is separated by filtration and recrystallized from acetic acid to provide light yellow crystals of 2-nitro-3-phenylnaphtho-[1,2-b]furan-5-carboxylic acid, m.p. 286°-288° C. (dec.).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16](=[O:18])[CH3:17])([O:3]C)=[O:2].[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21].[Na]>C(O)C>[C:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH:15]1[C:20](=[O:21])[C:19](=[O:25])[CH2:17][C:16]1=[O:18])([OH:3])=[O:2]
Reactant: COC(=O)CCCc1ccccc1CCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: O=C(O)CCCc1ccccc1CC1C(=O)CC(=O)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A solution of 96 g (0.44 mol) of 4-[2-(3 -carbomethoxypropyl)phenyl]-2-butanone, 10, and 129 g (0.88 mol) of diethyl oxalate was added dropwise at room temperature to a solution made by dissolving 20.2 g (0.88 g-atm) sodium in 200 ml absolute ethanol. After the addition was complete, the reaction was stirred 1 hour at room temperature and 1 hour at 50° C. It was then concentrated, the residue taken up in H2O, and acidified with 70 ml concentrated HCl. The precipitated material was extracted into ether and washed twice with H2O. The acidic material was then extracted out of this ether phase with aqueous sodium carbonate solution. Upon acidification of the sodium carbonate solution a red oil separated. This oil was heated overnight in a solution of 200 ml concentrated HCl and 200 ml methanol. The reaction mixture was diluted with 300 ml H2O and extracted with ether. Evaporation of the ether gave 70 g of red oil. This was chromatographed on 400 g silicic acid and eluted with benzene:ethanol. Like fractions were combined and crystallized. Recrystallization from benzene gave 23 g of the trione acid 11, mp 123° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([C:15]2[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=2)[NH2:18])=[N:11][CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][C:30]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=S)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:32][C:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])=[N:18][C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:10]2[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:16]=1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccnc1-c1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(=Nc1cccc(-c2ncccc2O[Si](C)(C)C(C)(C)C)c1)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 88.8 %

Procedure:
To a suspension of 3-(3-tert-butyldimethylsilyloxypyridin-2-yl)-aniline (303 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (335 mg) and diisopropylethylamine (0.405 ml) in dichloromethane (10 ml) was added 1-methyl-2-chloropyridinium iodide (335 mg), and the mixture was stirred for 18 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 35 g, 20% ethyl acetate in n-hexane) to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-tert-butyldimethylsilyloxypyridin-2-yl)phenyl)guanidine (486 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH3:30])[C:26](=O)[CH3:27])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].B>O1CCCC1>[ClH:15].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH3:30])[CH2:26][CH3:27])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(CC)C(C)=O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCCN(CC)CC
Product: Cl

Procedure:
A solution of 0.84 g. of 2-[3-(N-ethylacetamido)propyl]-5-chloro-3-phenylisoindole-1-carboxylic acid ethyl ester in 5 ml. of tetrahydrofuran is added dropwise under argon at room temperature to 3 ml. of a 1-M solution of borane in tetrahydrofuran. Subsequently, the mixture is heated at reflux for 4 hours, then treated at 15°-20° C. with 0.8 ml. of 6-N hydrochloric acid and the tetrahydrofuran is removed by distillation at atmospheric pressure. The residue is partitioned between 3 ml. of water and 5 ml. of ether and cooled in an ice-bath. The crystallized hydrochloride is isolated and purified in a manner analogous to that described in Example 5, and there is obtained 5-chloro-2-[3-(diethylamino)-propyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride having a melting point of 203°-206° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[C:6](OCC)=[O:7])C.[BH4-].[Li+].C1(C)C=CC=CC=1>C1COCC1>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([CH:5]([CH2:4][OH:3])[CH2:6][OH:7])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C(=O)OCC)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C(CO)CO)CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 1-tert-butoxycarbonylpiperidine-4-ol, triethylamine, benzenesulfonyl chloride and methylene chloride was stirred for two days at room temperature to give 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate. A mixture of the obtained 1-tert-butoxycarbonylpiperidine-4-ylbenzenesulfonate, diethyl malonate, 20% sodium ethoxide-EtOH solution and EtOH was stirred for 22 hours heated to reflux to give diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate. A mixture of the obtained diethyl[1-(tert-butoxycarbonyl)piperidine-4-yl]malonate, lithium borohydride, toluene and THF was stirred for 18 hours at 60° C. to give 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol. A mixture of the obtained 2-(1-tert-butoxycarbonylpiperidine-4-yl)propane-1,3-diol, 4M HCl-dioxane solution and MeOH was stirred for one hour at room temperature to give 2-piperidine-4-ylpropane-1,3-diol hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].CCN(CC)CC.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl>[CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[NH:1][C:17](=[O:20])[CH2:18][CH3:19])=[O:5]
Reactant: CCC(=O)Cl
Reactant: Nc1ccccc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1ccccc1C=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.6 %

Procedure:
To a solution of 2-aminobenzaldehyde (1 g, 8.26 mmol) and Et3N (1.15 ml, 8.26 mmol) in DCM (50 ml) was added propionyl chloride (0.72 ml, 8.26 mmol) and the resulting mixture stirred at RT for 3 days. The mixture washed with water, sat. NaCl, dried over MgSO4, filtered and evaporated to afford the title compound 1.4 g (96%). 1H NMR (CDCl3): 1.30 (t, J 7.6 Hz, 3H), 2.51 (q, J 7.6 Hz, 2H), 7.23 (m, 1H), 7.62 (m, 1H), 7.69 (m, 1H), 8.78 (m, 1H), 9.94 (s, 1H), 11.19 (brs, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:54])[CH2:7][CH:6]([O:8][C:9]([CH2:11][CH2:12][N:13]2[C:20](=[O:21])[N:19]([CH2:22][CH2:23][C:24]([O:26][CH:27]3[CH2:32][C:31]([CH3:34])([CH3:33])[NH:30][C:29]([CH3:36])([CH3:35])[CH2:28]3)=[O:25])[C:17](=[O:18])[N:16]([CH2:37][CH2:38][C:39]([O:41][CH:42]3[CH2:47][C:46]([CH3:49])([CH3:48])[NH:45][C:44]([CH3:51])([CH3:50])[CH2:43]3)=[O:40])[C:14]2=[O:15])=[O:10])[CH2:5][C:4]([CH3:53])([CH3:52])[NH:3]1>C(OC(=O)C)(=O)C.C(OCC)C.C(Cl)Cl>[C:6]([N:3]1[C:2]([CH3:54])([CH3:1])[CH2:7][CH:6]([O:8][C:9]([CH2:11][CH2:12][N:13]2[C:14](=[O:15])[N:16]([CH2:37][CH2:38][C:39]([O:41][CH:42]3[CH2:43][C:44]([CH3:51])([CH3:50])[N:45]([C:9](=[O:10])[CH3:11])[C:46]([CH3:49])([CH3:48])[CH2:47]3)=[O:40])[C:17](=[O:18])[N:19]([CH2:22][CH2:23][C:24]([O:26][CH:27]3[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([C:24](=[O:25])[CH3:23])[C:29]([CH3:35])([CH3:36])[CH2:28]3)=[O:25])[C:20]2=[O:21])=[O:10])[CH2:5][C:4]1([CH3:53])[CH3:52])(=[O:8])[CH3:5]
Reactant: CC1(C)CC(OC(=O)CCn2c(=O)n(CCC(=O)OC3CC(C)(C)NC(C)(C)C3)c(=O)n(CCC(=O)OC3CC(C)(C)NC(C)(C)C3)c2=O)CC(C)(C)N1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1C(C)(C)CC(OC(=O)CCn2c(=O)n(CCC(=O)OC3CC(C)(C)N(C(C)=O)C(C)(C)C3)c(=O)n(CCC(=O)OC3CC(C)(C)N(C(C)=O)C(C)(C)C3)c2=O)CC1(C)C
Temperature: 95 °C

Procedure:
12 g of 1,3,5-tris-[2-(2,2,6,6-tetramethyl-piperidin-4-yl-oxycarbonyl)-ethyl]-isocyanuric acid (m.p. 153°-155° C.) were suspended in 120 ml of acetic anhydride, and the suspension was heated at 95° C. for 26 hours. The acetic anhydride was then distilled off as completely as possible, in a water-jet vacuum, from the clear solution formed; the residue was dissolved in 200 ml of diethyl ether/methylene chloride (9:1), the solution was washed twice with water, three times with saturated sodium hydrogen carbonate solution, and finally again twice with water. The organic phase was dried over sodium sulphate, the solvent was distilled off in vacuo, and the residue was recrystallised from diethyl ether/acetonitrile (98:2) to obtain pure 1,3,5-tris-[2-(1-acetyl-2,2,6,6-tetramethyl-piperidin-4-yl-oxycarbonyl)-ethyl]-isocyanuric acid, m.p. 126.5°-128° C.
Reaction SMILES: O[Li].O.C[O:5][C:6]([C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:7].CO.O>C1COCC1>[C:13]1([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[N:9]=[CH:10]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cn(-c2ccccc2)cn1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccccc2)cn1
Reaction time: 3 h
Yield: 87 %

Procedure:
A stirred solution of 1H-imidazole-4-carboxylic acid (0.5 g, 0.00446 mmol), concentrated sulfuric acid (0.5 mL) and MeOH (20 mL) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate and washed the organic layer with sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 325 mg (58% Yield) of 1H-imidazole-4-carboxylic acid methyl ester. A mixture of 1H-imidazole-4-carboxylic acid methyl ester (225 mg, 1.8 mmol), cuprous oxide (225 mg, 1.8 mmol), iodobenzene (736 mg, 3.6 mmol), 1,10-phenanthroline (320 mg, 1.8 mmol) and cesium carbonate (1.74 g, 5.3 mmol) in DMSO (2 mL) in a seal tube was subjected to reaction in a microwave reactor (time: 5 min, temp: 90° C., power: zero) The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. Purification by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 200 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester. LiOH.H2O (143 mg, 3.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester (231 mg, 1.1 mmol) in a mixture of THF (3 mL), MeOH (1 mL), H2O (1 mL) and stirring was continued at ambient temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added and acidified it with 10% aqueous HCl, the solid was collected to afford 180 mg (83.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][CH:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]2=3)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH:31]1[C:18]2[CH:17]([O:16][CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:32][CH2:33][CH3:34])[C:4]([OH:35])=[O:3])=[CH:8][CH:9]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][S:20][C:19]=2[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(Cc1ccc(OCCOC2c3ccccc3CSc3ccccc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
3-(4-[2-(6,11-Dihydrodibenzo[b,e]thiepin-11-yloxy)-ethoxy]-phenyl)-2-ethoxy-propionic acid ethyl ester (example 2) (220 mg, 0.44 mmol) in ethanol (5 mL) was added NaOH 1 N (0.9 mL, 0.9 mmol). The mixture was stirred at room temperature for 16 h. The ethanol was evaporated of and pH adjusted with HCl 1 N to pH 1. After extraction with dichloromethane the product was purified by chromatography, using dichloromethane/methanol (9:1) as eluent, to give 126 mg (62%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 2.85-3.10 (m, 2H), 3.32-3.42 (m, 1H), 3.52-3.65 (m, 1H), 2.85 (t, 2H), 3.95-4.05 (m, 1H), 4.10-4.22 (m, 2H), 4.5-5.1 (bs, 1H), 5.60-5.75 (bs, 1H), 6.82 (d, 2H), 7.05-7.50 (m, 10H).
Reaction SMILES: [C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19]>C(Cl)(Cl)Cl>[C:1]1([P:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])[O:17][C:18]([CH3:19])=[CH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)CCl
Reactant: COP(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C=C(C)OP(=O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Yield: 79.5 %

Procedure:
Methyl diphenylphosphinite (4.92 g, 22.7 mmol) was dissolved in chloroform (2 ml) in a 15 ml round bottom flask under inert atmosphere (constant flow of dry argon). The solution was then cooled to −78° C. by immersion of the reaction vessel into a dry ice/acetone bath. The methyl diphenylphosphinite was observed to freeze out of solution. To the reaction vessel at reduced temperature, a solution of chloroacetone (1.8 ml, 22.5 mmol) in chloroform (1 ml) was added. The reaction vessel was allowed to warm to room temperature over three hours with constant stirring and argon flow. As the methyl diphenylphosphinite melted into the solution, the reaction proceeded. After the completion of the three hour reaction time, the crude product was obtained by removal of the chloroform. Recrystallization from hot hexane followed by drying for 12 hours in a vacuum oven (60° C. 6 mm Hg) yielded 1-methylvinyl diphenylphosphinate (4.62 g, 79.6% overall). The melting point of the recrystallized product was determined to be from about 84.1 to 85.3° C. The proton NMR of the product in CDCl3 showed the expected resonances (relative to TMS at 0.0 ppm) at 1.01 ppm correlating to the three methyl protons, at 4.29 ppm and 4.64 ppm for the two vinyl protons, and at 7.3-7.8 ppm for the ten aromatic protons. The phosphorus NMR of the product in CDCl3 showed a simple resonance relative to 85% H3PO4 at 20.00 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2.[OH:27]OS([O-])=O.[K+]>CO.O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([N:21]1[CH2:26][CH2:25][S:24](=[O:27])[CH2:23][CH2:22]1)=[N:16][N:15]=[CH:14]2
Reactant: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCSCC3)nncc2c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCS(=O)CC3)nncc2c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-3-[1-(thiomorpholin-4-yl)phthalazin-6-yl]benzamide (0.6 mmol) (Method A) in 10 mL methanol/H2O (8:2) was stirred at RT was treated with oxone® monopersulfate compound (1 mmol). The mixture was stirred at 0° C.-50° C. over 1h. The mixture was quenched with 20 mL sat. N2SO3, extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel chromatography eluting with 1-5% 2 M ammonia methanol in dichloromethane to give the title compound. Found MS(ES+): 381(M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]([CH3:24])=[CH2:23])=[O:20]>C1COCC1>[C:3]([NH:5][C:19](=[O:20])[O:21][C:22]([CH3:24])=[CH2:23])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: C=C(C)OC(=O)Cl
Reactant: CC(C)(C)C(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)OC(=O)NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
A −78° C. solution of 2,2,2-trimethylacetamide (1 g, 9.89 mmol) in THF (20 mL) was treated drop-wise with lithium bis(trimethylsilyl)amide (1.0N in THF, 11.86 mL, 11.86 mmol), stirred for 30 min, treated drop-wise with a solution of isopropenyl chloroformate (1.43 g, 11.86 mmol) in THF (5 mL), warmed to RT and stirred for 1 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with satd. NH4Cl, then brine, dried over Na2SO4 and concentrated to dryness to afford prop-1-en-2-yl pivaloylcarbamate (1.94 g, 106%) which was used without further purification.
Reaction SMILES: [Li+].[OH-].[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[S:11]([CH2:14][C:15]([O:17]C)=[O:16])(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].CCOC(C)=O>O.C1COCC1>[C:3]([O:7][C:8]([N:10]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=1)[S:11]([CH2:14][C:15]([OH:17])=[O:16])(=[O:13])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)CS(=O)(=O)N(C(=O)OC(C)(C)C)c1ccc(OC)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N(C(=O)OC(C)(C)C)S(=O)(=O)CC(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A solution of LiOH (28.1 mg, 0.669 mmol) in water (0.66 ml) was added to a solution of methyl 2-(N-(tert-butoxycarbonyl)-N-(3,4-dimethoxyphenyl)sulfamoyl)-acetate (237 mg, 0.609 mmol) in THF (3 ml), and the mixture was stirred at RT for 2 hours. EtOAc was added, and the solution was washed with HCl 1N (6 ml); the organic phase was washed with brine, dried over Na2SO4, filtered and evaporated, to give 2-(N-(tert-butoxycarbonyl)-N-(3,4-dimethoxyphenyl)sulfamoyl)acetic acid (200 mg, 0.533 mmol, 88% yield, MS/ESI+ 397.9 [MNa]+) that was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:20]=[CH:19][C:7]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:9])=[CH:6][CH:5]=1.I[CH3:22]>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:9])=[CH:19][CH:20]=1
Reactant: CI
Reactant: Cc1ccc(CCNC(=O)c2ccc(F)cc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CCN(C)C(=O)c2ccc(F)cc2)o1
Yield: 83.6 %

Procedure:
NaH (60% dispersion in oil, 65 mg, 1.63 mmol) was added portionwise to a solution of 4-fluoro-N-[2-(5-methyl-2-furanyl)ethyl]benzamide (269 mg, 1.09 mmol, 237A) in THF (5 mL). After gas evolution ceased, iodomethane (0.14 mL, 2.18 mmol) was added drop-wise. Once HPLC analysis showed the reaction to be 50% complete, the mixture was concentrated under reduced pressure and resubjected to the above conditions. After all the starting material was consumed, H2O was added and the resulting mixture was extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel eluting with 20% acetone/CHCl3 gave 238 mg (84%) of compound 425A. HPLC: 98% at 2.94 min (retention time) (Phenomenex-prime S5-C 18 column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z [M+H]=262.38.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)[CH2:2][CH3:3].[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1.O=[C:19]([CH2:26][CH2:27][CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:26]([C:19]1[NH:12][C:13]2[NH:14][N:15]=[CH:16][C:17]=2[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[CH2:1][CH2:2][CH3:3])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:27][CH3:28]
Reactant: Nc1cc[nH]n1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CCCc1ccccc1C=O
Product: CCCC1=C(C(=O)OCC)C(c2ccccc2CCC)c2cn[nH]c2N1

Procedure:
The title compound was prepared from 2-propylbenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.