Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+].C>CC(C)=O.CC(O)C>[Cl:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8](=[O:12])[O:9][C:10]=2[CH:11]=1
Reactant: O=c1ccc2ccc(O)cc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=c1ccc2ccc(OCCCCl)cc2o1

Procedure:
A mixture of 16.8 g (0.104 mole) of 7-hydroxycoumarin, 31.6 g (0.2 mole) of 1-bromo-3-chloropropane and 41.5 g (0.3 mole) of anhydrous potassium carbonate in 500 ml of acetone was heated at reflux for 24 hr. The mixture was filtered with difficulty to give a milky filtrate. The filtrate was treated wich charcoal and filtered through celite to give a clear filtrate. The filtrate was concentrated under reduced pressure to give a solid residue. The solid was triturated with petroleum ether (30°-60° C.), collected by filtration, and dried to yield 19.1 g (77%) of fluffy, white solid. An analytical sample, m.p. 100°-102° C., was obtained on recrystallization from 2-propanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])=[C:17]([CH3:19])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:31]1[CH2:34][CH:33]([C:35]2[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=2)[CH2:32]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:39]([C:38]1[CH:37]=[CH:36][C:35]([CH:33]2[CH2:32][N:31]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([CH3:29])=[C:20]([C:16]4[N:15]=[C:14]([CH:11]5[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]5)[NH:18][C:17]=4[CH3:19])[CH:21]=3)=[O:24])[CH2:34]2)=[CH:42][CH:41]=1)#[N:40]
Reactant: N#Cc1ccc(C2CNC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1-c1[nH]c(C2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of 3-(2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoic acid (compound 182.2, 506 mg), 4-(azetidin-3-yl)benzonitrile hydrochloride (compound 5.2, 296 mg, 1.52 mmol), EDCI (315 mg, 1.65 mmol), HOBt (107 mg, 0.64 mmol) and DIEA (877 μL, 5.08 mmol) in DMF (25 mL) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (50 mL). The organic phase was washed with brine (3×10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 8% methanol in dichloromethane to give 476 mg (69%) of the title compound as a foam. m/z (ES+) 540 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:5]=2[S:4][NH:3]1.[N+](=[CH2:16])=[N-]>C(O)(C)C.CCOCC>[CH3:16][O:12][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[C:2](=[O:1])[NH:3][S:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1ccc2c(=O)[nH]sc2c1
Reactant: C=[N+]=[N-]
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(=O)c1ccc2c(=O)[nH]sc2c1
Reaction time: 0.17 h

Procedure:
A solution of 19.5 g (0.1 mole) of 3-oxo-1,2-benzisothiazoline-6-carboxylic acid in 40 ml of isopropanol is treated with an excess of a solution of diazomethane in ether added at 0° C. with stirring over a period of 10 minutes. The reaction mixture is evaporated to dryness and the 3-oxo-1,2-benzisothiazoline-6-carboxylic acid methyl ester is obtained as an oil.
Reaction SMILES: [Br-].[O:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Zn+])=[CH:6][CH:5]=1)[CH3:3].I[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([C:20]2[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:23][CH:24]=2)=[C:15]([CH3:34])[CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:3][O:2][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][C:13]2[CH:14]=[C:15]([CH3:34])[C:16]([C:20]3[N:21]=[C:22]([NH:25][C:26](=[O:33])[C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[S:23][CH:24]=3)=[C:17]([CH3:19])[CH:18]=2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cc1

Procedure:
A THF solution of 4-methoxylbenzylzinc(II) bromide (4.0 mL, 2.0 mmol) was added to a degassed solution of N-(4-(4-iodo-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide (435 mg, 1.0 mmol) and tetrakistriphenylphosphine palladium (57.8 mg, 0.10 mmol) in THF (5.0 mL). The reaction mixture was heated at reflux for 16 h under N2 then poured into saturated aqueous NaHCO3. The mixture was extracted with ethyl acetate, washed with brine, dried MgSO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give N-(4-(4-(4-methoxybenzyl)-2,6-dimethylphenyl)thiazol-2-yl)isonicotinamide: 1H NMR (500 MHz, CDCl3) δ 8.69 (d, J=5.2 Hz, 2 H), 7.66 (d, J=4.9 Hz, 2 H), 7.11 (d, J=8.4 Hz, 2 H), 6.86 (d, 2 H), 6.80 (s, 1 H), 6.75 (s, 2 H), 3.80 (s, 2 H), 3.78 (s, 2 H), 1.98(s, 6 H); ESI-MS: m/z 399.9 (M+H)+.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]1=2.[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3/[C:3](=[CH:2]\[C:23]3[CH:24]=[C:19]([OH:18])[CH:20]=[CH:21][CH:22]=3)/[C:9]=12
Reactant: BrC=C1c2ccccc2CCc2cccnc21
Reactant: OB(O)c1cccc(O)c1
Product: Oc1cccc(/C=C2\c3ccccc3CCc3cccnc32)c1
Yield: 63.7 %

Procedure:
Following procedures essentially as described in Example 219, combine 11-bromomethylene-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (250 mg, 0.87 mmol) and (3-hydroxyphenyl) boronic acid (133 mg, 0.96 mmol). Purify to provide product 166 mg (63%) as an off-white solid. LC/MS: 300.1 (M+H). 1H NMR (DMSO, 400 MHz): δ9.22 (s,1H), 8.40 (d,1H), 7.49 (d,1H), 7.34 (d,1H), 7.24 (d,1H), 7.21 (d,3H), 7.15 (s,1H), 7.04 (t,1H), 6.92 (d,1H), 6.90 (d,1H), 6.52 (d,1H), 6.40-6.42 (m,2H), 3.4-2.8 (m,4H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1>[C:15]1([CH2:14][CH2:13][C:12]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NC(=O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of methyl 4-aminobenzoate (825 mg, 5.46 mmol) in anydrous pyridine (16 mL) was added dropwise hydrocinnamoyl chloride (990 μL) at 0° C. After 5 min the temperature was allowed to warm up to rt. After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 1200 mg) was added and the resulting mixture was stirred overnight at rt. After rinsing the resin and filtration, water (200 mL) was added to the filtrate and a white solid precipated out. Filtration and washing with water gave a solid which was dried under vacuo at 60° C. overnight. The title compound (1.40 g) was obtained as a white solid (90%) in 98.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:18]=[N:19][C:20]([C:23]4([C:30]#[N:31])[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]4)=[CH:21][CH:22]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1.ClC1C=CC=CC=1Cl>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4([C:30]#[N:31])[CH2:24][CH2:25][CH:26]([O:29][C:32](=[O:38])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[O:15])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCC(OC(=O)CCC(=O)O)CC3)nc2)cnn1-c1ccc(Cl)cc1
Temperature: 150 °C
Reaction time: 7 h
Yield: 40.7 %

Procedure:
1-(4-Chlorophenyl)-N-[6-(1-cyano-4-hydroxycyclohexyl)pyridin-3-yl]-5-methyl-1H-pyrazole-4-carboxamide (0.42 g), succinic anhydride (0.11 g) and p-toluenesulfonic acid hydrate (5 mg) were added to 1,2-dichlorobenzene (4 ml) and stirred at 150° C. for seven hours. The reaction solution was treated with water and the precipitated solid was recrystallized from aqueous isopropanol to give the titled compound (0.21 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[O:19])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:36])C=1.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[C:18]([NH:20][CH:21]2[CH2:22][CH2:23][S:24](=[O:36])[CH2:25][CH2:26]2)=[O:19])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCSCC2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCS(=O)CC2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-(tetrahydro-2H-thiopyran-4-yl)acetamide (Example 193, 0.25 g, 0.63 mmol), in ethyl acetate (5 mL) was added m-chloroperbenzoic acid (0.19 g, 0.76 mmol) at 0° C. After stirred at 0° C. for 3 h, the mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 50:50 to 0:100 then ethyl acetate/methanol 100/0 to 70/30) to give the title compound (0.14 g, 55%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24]Cl)=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5].[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31]1>>[OH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][N:31]1[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:20]=[CH:19][C:18]2[NH:17][C:16]3[C:11](=[CH:12][C:13]([NH:21][C:22](=[O:26])[CH2:23][CH2:24][N:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]4[CH2:29][OH:28])=[CH:14][CH:15]=3)[C:10](=[O:27])[C:9]=2[CH:8]=1)=[O:5]
Reactant: O=C(CCCl)Nc1ccc2[nH]c3ccc(NC(=O)CCCl)cc3c(=O)c2c1
Reactant: OCC1CCCCN1
Product: O=C(CCN1CCCCC1CO)Nc1ccc2[nH]c3ccc(NC(=O)CCN4CCCCC4CO)cc3c(=O)c2c1

Procedure:
Chloroamide 13 (1.0 g, 2.5 mmol) was treated with 2-hydroxymethylpiperidine (5 mL) according to the general aminolysis procedure to give the desired product JM-ACO-11 (888 mg, 63%) as a pale yellow/green solid.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[OH2:32].C(N(CC)CC)C>C(#N)C>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]/[OH:19])/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:32])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: O
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC[C@H]1OC(=O)/C(=C\O)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17-hydroxy-wortmannin (20 mg, 0.047 mmol) is dissolved in 4 mL acetonitrile and 2 mL water with 0.5 mL triethylamine. The reaction mixture is stirred at room temperature overnight. The title compound is isolated by preparative HPLC using Nova-Pak HRC 18, 60A, 6 um, 19×300 mm column (Waters) at UV 254 nm (Mobile Phase A is 100 ml acetonitrile with 900 ml water, and 0.2 ml trifluoroacetic acid. Mobile Phase B is 900 ml acetonitrile with 100 ml water and 0.2 ml trifluoroacetic acid. The gradient is 0-5 min at 20% B and 80% A, 5-35 min from 20% B to 70% B at flow rate 20 mL/min). The fraction at 12 min peak is collected and extracted with CH2Cl2. The organic layer is dried over anhydrous sodium sulfate and rotavaped to dryness. A total of 5 mg of yellow solid is obtained by precipitation from 1 mL CH2Cl2 and 3 mL heptane and drying using nitrogen gas and then a speecdvac. LC/MS shows [M+H] 449.31 and [M−H] 447.26.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([F:10])=[CH:8][N:9]=1)[CH:5]=O.[F:11][C:12]1[CH:26]=[CH:25][CH:24]=[CH:23][C:13]=1[CH2:14]P(=O)(OCC)OCC.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:14]/[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[F:11])[C:7]([F:10])=[CH:8][N:9]=1
Reactant: CCOP(=O)(Cc1ccccc1F)OCC
Reactant: O=Cc1cc(Br)ncc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccccc1/C=C/c1cc(Br)ncc1F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinaldehyde (2 g, 9.80 mmol) and diethyl 2-fluorobenzylphosphonate (2.66 g, 10.78 mmol) in tetrahydrofuran (80 mL) at 0° C., was added potassium tert-butoxide(1M in tetrahydrofuran, 12.75 mL, 12.75 mmol) dropwise over a couple of minutes. When addition was complete, the reaction was allowed to stir at 0° C. for 45 min and quenched by addition of saturated ammonium chloride. The reaction was diluted with ether, washed with water (4×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%→15% EtOAc/Hex) gave 450 mg as an oil with solid crystallizing from the mixture. The material was triturated with hexanes (2×) to give a fine white powder. 1H NMR (CDCl3) δ: 8.26 (d, J=1.5 Hz, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.64 (td, J=7.6, 1.5 Hz, 1H), 7.54 (d, J=16.8 Hz, 1H), 7.30-7.41 (m, 1H), 7.17-7.26 (m, 2H), 7.11-7.17 (m, 1H). 13C NMR (CDCl3) δ: 161.0, 156.7, 138.8, 136.6, 135.5, 131.0, 129.3, 127.9, 124.6, 123.7, 119.4, 116.3. 19F NMR (CDCl3) δ: −116.72 (br. s., 1F), −136.08 (br. s., 1F).
Reaction SMILES: [CH2:1]([P:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.N>>[N+:15]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][P:8]2(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=P1(Cc2ccccc2)CCCCC1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 1-benzylphosphorinane-1-oxide (5.39 g) were added nitric acid (1.94 ml) and sulfuric acid (15 ml) at 0° C., and the mixture was stirred at 50-60° C. for 2hours. The reaction mixture was added to crushed ice-water, neutralized with ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-(4-nitrobenzyl)-phosphorinane-1-oxide (2.47 g) as pale yellow crystals.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(OC(=O)C)(=O)C.[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13].[H-].[Na+]>S(=O)(=O)(O)O.O>[C:12]([CH2:14][N:15]1[C:20]2[CH:21]=[C:22]([N+:1]([O-:4])=[O:2])[C:23]([F:25])=[CH:24][C:19]=2[O:18][CH2:17][C:16]1=[O:26])#[N:13]
Reactant: N#CCN1C(=O)COc2cc(F)ccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 95.2 %

Procedure:
98% nitric acid (0.71 g) was added dropwise to acetic anhydride (11.3 ml) at a temperature of 0° C. Subsequently a few drops of concentrated sulfuric acid were added thereto as catalyst, and the mixture was stirred for a while at 0° C. 4-cyanomethyl-7-fluoro-2H-1,4-benzoxazin-3(4H)-one (2.06 g) was added little by little thereto and stirred continuously at 0° C. for 30 minutes. A solution consisting of sodium hydride (10 g) and water (88 ml), cooled previously to 0° C., was added dropwise at 0° C. to neutralize the reaction liquor. The liquor was extracted with methylisobutyl ketone, and the extraction liquor was washed with water and a table salt solution, then dried with anhydrous sodium sulfate. The solvent was distilled off to give the desired 4-cyanomethyl-7-fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (2.39 g). mp. 204°-206° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].Cl.[CH3:9][NH:10][O:11][CH3:12].CN1CCOCC1.CN(C)CCCN=C=NCC.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH3:12][O:11][N:10]([CH3:9])[C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CNOC
Reactant: CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCC(=O)N(C)OC
Yield: 84.8 %

Procedure:
Part A: To a magnetically stirred solution of valeric acid (10.9 ml, 0.1 mol) in dichloromethane (200 ml) was successively added: N-methyl-N-methoxy-amine.hydrochloride (10.14 gram, 0.104 mol), N-methylmorpholine (22.9 ml, 0.208 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (EDCI) (19.92 gram, 0.104 mol) and HOBt (14.04 gram, 0.104 mol) and the resulting mixture was reacted for 20 hours at room temperature. The obtained suspension was successively washed with water, aqueous citric acid (a solution of 24 gram citric acid in 250 ml H2O) and 5% aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated to give pentanoic acid methoxy-methyl-amide (12.31 gram, 85% yield) as a colorless oil. 1H-NMR (400 MHz, CDCl3) δ 0.93 (t, J=7, 3H), 1.31-1.43 (m, 2H), 1.57-1.66 (m, 2H), 2.42 (br t, J=7, 2H), 3.18 (s, 3H), 3.69 (s, 3H).
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[C:8]([F:12])[CH:9]=[C:10]([F:11])[C:4]=2[O:3]1.[Li]C(CC)C.[I:19]I.[NH4+].[Cl-]>O1CCCC1>[F:13][C:2]1([F:1])[O:6][C:5]2[CH:7]=[C:8]([F:12])[C:9]([I:19])=[C:10]([F:11])[C:4]=2[O:3]1
Reactant: Fc1cc(F)c2c(c1)OC(F)(F)O2
Reactant: II
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cc2c(c(F)c1I)OC(F)(F)O2
Temperature: -70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
2,2,4,6-Tetrafluorobenzo[d][1,3]dioxole (500 mg, 2.6 mmol) was dissolved in dry tetrahydrofuran (7 mL), cooled to −70° C., treated dropwise with sec-BuLi (1.3 M; 2.1 mL, 2.7 mmol) and stirred for 1 h at −70° C. This mixture was treated dropwise with a solution of iodine (1.1 g, 4.4 mmol) in tetrahydrofuran (5 mL) over 10 min. After 2 h at −70° C., the mixture was treated with saturated NH4Cl, extracted with ethyl ether, dried (Na2SO4) and evaporated. The material was purified by reverse phase HPLC with 85% acetonitrile-water to give the title compound (250 mg; 30%): 1H NMR (400 MHz, CDCl3) δ 6.80-6.77 (d, J=8.7 Hz, 1H), 6.77-6.75 (d, J=8.7 Hz, 1H); 19F NMR (376 MHz, CDCl3) δ −48.72, −99.73, −132.62; EIMS m/z 320.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1>>[CH2:3]([CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([CH3:5])[CH2:7][C:8]1=[O:13])[CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: CC1CC(=O)CC(=O)C1
Product: C=CCC1C(=O)CC(C)CC1=O

Procedure:
By the procedure of Example 29, allyl bromide is reacted with 5-methyl-1,3-cyclohexanedione to produce 2-allyl-5-methyl-1,3-cyclohexanedione.
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[N:22]=[C:23]=S.C(N(CC)CC)C.CS(Cl)(=O)=O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[NH:22][C:23]1[NH:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:3])=[O:13])=[CH:6][C:7]=2[N:12]=1
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1ccc(N)c(N)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2[nH]c(Nc3c(Cl)cccc3Cl)nc2c1
Reaction time: 8 h

Procedure:
To 3,4-diamino-benzoic acid ethyl ester (4.0 g, 22.2 mmol) in 100 mL dichloromethane was added 1,3-dichloro-2-isothiocyanato-benzene (4.5 g, 22 mmol) in 50 mL dichloromethane. After stirring overnight and refluxing for another 6 hrs, the solvent was evaporated. After adding 200 mL dichloromethane, triethylamine (7 mL, 50 mmol) and 4-dimethylaminopyridine (100 mg, 0.82 mmol) have been added, methanesulfonyl chloride (1.7 mL, 22 mmol) in 50 mL dichloromethane was added to the reaction mixture. After stirring for 2 h, another portion of methanesulfonyl chloride (1.7 mL, 22 mmol) was added. After stirring at room temperature overnight, the solvent was evaporated. The residue was mixed with 150 mL methanol and 40 mL 4N NaOH (aq), stirred over night, another 20 mL 4N NaOH (aq) added and refluxed for 2 h. The solvent was removed, the residue mixed with water and methanol and the mixture neutralized with 4 N HCl (aq). The mixture was filtered, washed with water and dried.
Reaction SMILES: CN(C)C=O.[Cl:6][CH:7](Cl)[CH3:8].C(Cl)(=O)C(Cl)=O.[N:16]1[C:21]2[CH:22]=[CH:23][S:24]C=2C(=O)[NH:18][CH:17]=1>O>[Cl:6][C:7]1[C:8]2[S:24][CH:23]=[CH:22][C:21]=2[N:16]=[CH:17][N:18]=1
Reactant: CC(Cl)Cl
Reactant: O=c1[nH]cnc2ccsc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ncnc2ccsc12
Reaction time: 2.5 h
Yield: 99 %

Procedure:
After dimethylformamide (15.4 ml, 197.13 mmol) was added into 150 ml of dichloroethane with lowering the temperature to 0° C., oxalyl chloride (25 4 ml, 295.70 mmol) was slowly added. When white gel type started to form, 3H-thieno[3,2-d]pyrimidine-4-one (15 g, 98.57 mmol) was added. After 2.5 hours of reflex of the reaction mixture, the temperature was lowed to room temperature. After adding water, the reaction mixture was extracted using dichloromethane (3×300 ml) and dried with anhydrous magnesium sulfate. After concentrated under vacuum, trituration was carried out with 200 ml of hexane and the title compound (16.7 g, 99%) was obtained as a dark brown solid.
Reaction SMILES: CCCCCCCCC[CH2:10]/[CH:11]=[CH:12]/[CH:13]1[C:18](=[O:19])[O:17][C:15](=[O:16])[CH2:14]1.[OH-].[K+].[CH3:22][C:23]#[CH:24]>>[CH:24]([C:13]1([CH:12]=[CH:11][CH3:10])[C:18](=[O:19])[O:17][C:15](=[O:16])[C:14]1([CH:14]=[CH:13][CH3:18])[CH:10]=[CH:11][CH3:12])=[CH:23][CH3:22]
Reactant: C#CC
Reactant: CCCCCCCCCC/C=C/C1CC(=O)OC1=O
Agent: [K+]
Agent: [OH-]
Product: CC=CC1(C=CC)C(=O)OC(=O)C1(C=CC)C=CC

Procedure:
The experiments in Example 3 were repeated with tetrapropenylsuccininc anhydride (DDSA) instead of oleic acid. DDSA was supplied by Milliken Chemicals and had a neutralization number of 406 mg KOH/g. Milliken uses C12 branched-chain olefin derived from propylene tetramer to make DDSA.
Reaction SMILES: [CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])(O)[CH:18]=[CH2:19])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13].[BrH:22].O>CCOCC>[CH3:1][C:2](=[CH:14][CH:15]=[CH:16][C:17]([CH3:21])=[CH:18][CH2:19][Br:22])[C:3]#[C:4][C:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]=1[CH3:13]
Reactant: Br
Reactant: C=CC(C)(O)C=CC=C(C)C#CC1=C(C)CCCC1(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C#CC1=C(C)CCCC1(C)C)=CC=CC(C)=CCBr
Reaction time: 0.25 h

Procedure:
2.84 g of the alcohol III prepared as described in Example 1 were dissolved in 50 ml of ether and an equimolar amount of a solution of HBr in ether was added dropwise at -70° C., whilst stirring. The reaction mixture was then kept for 15 minutes at from -60° to -70° C. and thereafter for 15 minutes at -15° C. 30 ml of water were then added and the organic phase was separated off, washed neutral, dried and concentrated. 3.2 g of a residue (crude yield 93.5%) were left; the structure of the material was determined by IR, NMR and UV spectroscopy.