Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19](O)=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O.C1C=CC=CC=1>CN(C)C=O>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[C:13]2[C:8]([C:9](=[O:22])[C:10]([C:19]([Cl:25])=[O:20])=[CH:11][O:12]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2c(=O)c(C(=O)O)coc2c1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc2c(=O)c(C(=O)Cl)coc2c1OC(C)=O

Procedure:
A mixture of 7,8-diacetoxychromone-3-carboxylic acid (9.5 g), thionyl chloride (2.6 ml), dimethylformamide (0.1 ml) and benzene (300 ml) was refluxed for one and half hours, and there were further added thionyl chloride (2.6 ml) and dimethyl formamide (0.1 ml). The whole was then refluxed for further one hour. Then the solvent was removed therefrom by distillation, and the residue was triturated with n-bexane. The solid matter thus obtained was collected by filtration. There was thus obtained the desired product (9.3 g).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[N:31](COCC[Si](C)(C)C)[CH:32]=[CH:33][C:26]=34)[CH:22]=[N:21]2)[CH2:7][N:6]([C:8]2[CH:19]=[CH:18][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>>[C:1]([CH2:3][C:4]1([N:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]4[NH:31][CH:32]=[CH:33][C:26]=34)[CH:22]=[N:21]2)[CH2:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:18][CH:19]=2)[CH2:7]1)#[N:2]
Reactant: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-{3-(Cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-isopropylbenzamide was dissolved in dichloromethylene (5 mL). To the solution was added trifluoroacetic acid (TFA) (2.5 mL). The mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. The residue was dissolved in methanol (10 mL). To the solution was added ethylenediamine (1 mL). The mixture was stirred at room temperature for 4 hours, and was purified by RP-HPLC (pH=10) to afford the desired product (0.415 g). LCMS (M+H)+: m/z=440.1. The high purity (99.6%) of the product was obtained by re-crystallization from acetone-ether, 1H NMR (400 MHz, CDCl3): δ 9.57 (s, 1H), 8.31 (d, J=4.9 Hz, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.70 (m, 2H), 7.39 (d, J=3.4 Hz, 1H), 7.18 (d, J=4.9 Hz, 1H), 6.70 (d, J=3.4 Hz, 1H), 6.55 (m, 2H), 5.79 (d, J=7.8 Hz, 1H), 4.47 (d, J=8.3 Hz, 2H), 4.38 (d, J=8.3 Hz, 2H), 4.27 (m, 1H), 3.45 (s, 2H), 1.25 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:13])[CH3:12])=[CH:8][C:7]=2[CH:14]=1.C(O[K])(C)(C)C.[CH2:23](Br)/[CH:24]=[C:25](/[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])\[CH3:26].O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[O:10][C:9]([C:11](=[O:13])[CH2:12][CH2:23][CH:24]=[C:25]([CH3:26])[CH2:27][CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31])=[CH:8][C:7]=2[CH:14]=1
Reactant: COc1cc2cc(C(C)=O)oc2cc1OC
Reactant: CC(C)=CCC/C(C)=C/CBr
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(=O)CCC=C(C)CCC=C(C)C)oc2cc1OC
Reaction time: 2 h

Procedure:
To a solution of 1-(5,6 dimethoxy benzofuran-2-yl)ethanone A2 (1 g, 4.545 mmol) in anhydrous Toluene added tBuOK (0.51 g, 4.545 mmol) at 0° C. under argon atmosphere and then stirred at the same temperature for 15 min to this reaction mixture geranyl bromide added drop wise. Resulting suspension stirred at the same temperature for 2 hrs. 50 ml water was added to the reaction mixture and layers were separated. Aqueous layer was extracted with ethylaectate. The combined organic extract were washed with brine and dried over Na2SO4, evaporated under reduced pressure. Chromatography of the residue on silica gel (5% EtOAc/hexanes) afforded the ketone A3 (1.69 g) in 70% yield pale yellow liquid: 1H NMR (500 MHz, CDCl3) δ 7.425 (s, 1H), 7.365 (s, 1H), 7.06 (s, 1H), 5.12-5.16 (m, 1H), 5.08-5.04 (m, 1H), 3.96 (s, 3H), 3.93 (s, 3H), 2.97-2.89 (t, 2H), 2.50-2.40 (m, 2H), 2.17-2.00 (m, 4H), 1.66 (s, 3H), 1.63 (s, 3H), 1.64 (s, 3H), 1.58 (s, 3H), ppm. Mass: ESI [M+Na]+: 379.2; Elemental anal. calcd. for C22H28O4; C, 74.13; H, 7.92. found C, 74.0; H, 5.25.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.C(N(CC)CC)C.[CH2:26]([Si:28](Cl)([CH2:31][CH3:32])[CH2:29][CH3:30])[CH3:27]>ClCCl>[CH3:1][O:2][CH2:3][C:4]1([CH2:17][O:18][Si:28]([CH2:31][CH3:32])([CH2:29][CH3:30])[CH2:26][CH3:27])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: COCC1(CO)c2ccccc2-c2ccccc21
Reactant: CC[Si](Cl)(CC)CC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[Si](CC)(CC)OCC1(COC)c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
1 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (4.2 mmol) was dissolved in 20 ml of dichloromethane. The solution was cooled in ice-water bath, and 0.87 ml of triethyl amine (6.2 mmol) was added thereto. After stirring for 5 minutes, 0.91 ml of triethylsilyl chloride (5.4 mmol) was added drop-wise, and the mixture was stirred for further 2 hours, followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, and the organic layer separated was dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated to give 1.24 g of concentrate (yield 84%).
Reaction SMILES: [F:1][CH2:2][C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[O:24][CH2:23][CH:22]([NH:25][C:26](=O)[CH2:27][CH3:28])[CH2:21][C:18]3=[N:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)[CH3:4].B.C1COCC1>C1COCC1>[F:1][CH2:2][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]3[O:24][CH2:23][CH:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:21][C:18]3=[N:19][CH:20]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)[CH3:4]
Reactant: CCC(=O)NC1COc2cc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cnc2C1
Agent: B
Solvent: C1CCOC1
Product: CCCNC1COc2cc(NS(=O)(=O)c3ccc([C@H](C)CF)cc3)cnc2C1
Yield: 45.4 %

Procedure:
Following the same procedure as described in example 34, N-{7-[4-((S)-2-fluoro-1-methyl-ethyl)-benzenesulfonylamino]-3,4-dihydro-2H-pyrano[3,2-b]pyridin-3-yl}-propionamide (100 mg, 0.27 mmol) in THF (15 ml) was treated with 1M BH3.THF (2.3 ml, 2.3 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 97:3) gave the title compound (50 mg, 52%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]4[CH2:26][CH2:25][C:24]5[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=5[C:22](=[O:31])[O:21]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.Br[Mg][CH2:34][CH2:35][CH2:36][CH2:37][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([OH:21])[CH2:26][CH2:25][C:24]4[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=4[C:22]4([OH:31])[CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Br[Mg]CCCC[Mg]Br
Reactant: O=C1OC(c2cccc(OCc3ccc4ccc(Cl)cc4n3)c2)CCc2ccccc21
Solvent: C1CCOC1
Product: OC(CCc1ccccc1C1(O)CCCC1)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Reaction time: 0.5 h

Procedure:
To the lactone of Step 4 (1.004 g, 2.335 mmol) in 5 mL of anhydrous THF at r.t., a suspension of 0.70M 1,4-di(bromomagnesio)butane in THF (J. Org. Chem., 45, 1828 (1980); 5.3 mL, 3.7 mmol) was added dropwise and the mixture was stirred for 30 min and was quenched at 0° C. with cold 25% aq NH4OAc. The title cyclopentanol was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 15:85 and 20:80. Yield: 1.006 g, 88%.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([OH:43])(=[O:42])[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34]O>O1CCCC1>[C:36]1([CH:33]2[CH2:34][O:43][C:32]2=[O:42])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(O)C(CO)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OCC1c1ccccc1
Temperature: -10 °C
Yield: 83.8 %

Procedure:
Diethylazodicarboxylate (DEAD) (1.89 milliliter (mL), 12.0 millimole (mmol)) was added dropwise to a stirred solution of triphenylphosphine (3.18 gram (g), 12.0 mmol) in dry tetrahydrofuran (THF) (40 mL) at −78° C. under nitrogen (N2). Tropic acid (2.00 g, 12.0 mmol) in dry THF (40 mL) was then added dropwise, and the resulting mixture was stirred and slowly warmed to −10° C., at which point the solution was homogeneous. After concentration and purification by flash chromatography on silica gel (petroleum ether/ethyl acetate (EtOAc) 85:15), 3-phenyloxetan-2-one (1.49 g, 84%) (see Mulzer, J.; Kerkmann, T. J. Am. Chem. Soc. 1980, 102, 3620-3622) was isolated as a yellow oil: 1H NMR (270 MHz, CDCl3) δ 7.3 (m, 5H), 4.8 (dd, J=5.0, 1.7 Hz, 1H), 4.5 (dd, J=5.0, 1.7 Hz, 1H), 4.2 (dd, J=5.0, 5.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:30][CH:29]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: CN(CCO)c1ccc(C(=O)[O-])cc1
Product: CN(CCO)c1ccc(C(=O)Nc2ccc(C(=O)c3ccc(NC(=O)c4ccc(N(C)CCO)cc4)cc3)cc2)cc1

Procedure:
Compound 330 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-(N-2-hydroxylethyl-N-methylamino)benzoate. [M+H]+ calcd for C33H35N4O5: 567.26; found: 567.04.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][C:17]2[C:16]([NH:19][C:20]([NH2:22])=[S:21])=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.Br[CH:24]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:25](OC)OC>CCO.Cl>[C:30]1([C:24]2[S:21][C:20]([NH:19][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]4[C:17]=3[CH2:18][CH:9]([OH:8])[CH2:10][CH2:11]4)=[N:22][CH:25]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cccc(NC(N)=S)c2C1
Reactant: COC(OC)C(Br)c1ccccc1
Agent: Cl
Solvent: CCO
Product: OC1CCc2cccc(Nc3ncc(-c4ccccc4)s3)c2C1
Temperature: 25 °C

Procedure:
A mixture of the product of Example 24A (200 mg, 0.594 mmol) and the product of Example 24B (146 mg, 0.596 mmol) was refluxed for 2 hours in a mixture of EtOH (6 mL) and 1N HCl (1 mL). After cooling to room temperature, the mixture was quenched with saturated NaHCO3 solution and was extracted with EtOAc. The extracts were dried over Na2SO4, filtered evaporated under reduced pressure, and chromatographed on silica gel (95:5 to 92:8 CH2Cl2:CH3OH eluant). The title compound was afforded as a pale tan solid, 53 mg (28%). 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 7.57 (m, 2H), 7.46-7.49 (m, 2H), 7.33-7.38 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H), 6.88 (d, J=7.4 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 3.82 (m, 1H), 2.71-2.98 (m, 4H), 1.83-1.93 (m, 1H), 1.57-1.66 (m, 1H). MS (ESI+) m/z 323 (M+H). Anal. calcd. For C19H18N2OS: C, 70.78; H, 5.63; N, 8.69. Found: C, 70.91; H, 5.37; N, 8.33.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][CH2:6][C:7]1[N:8]([C:20]2[S:21][CH:22]=[C:23]([C:25](=[O:27])[NH2:26])[N:24]=2)[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)C.[Li+].[OH-]>CO.C1COCC1>[C:25]([C:23]1[N:24]=[C:20]([N:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:10][CH:11]=[C:7]2[CH2:6][CH2:5][C:4]([OH:28])=[O:3])[S:21][CH:22]=1)(=[O:27])[NH2:26]
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1nc(C(N)=O)cs1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(CCC(=O)O)n2-c2nc(C(N)=O)cs2)cc1
Reaction time: 24 h

Procedure:
To 3-[1-(4-Carbamoyl-thiazol-2-yl)-5-(4-methoxy-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (0.15 mmol) in a 2:1 mixture of methanol/THF was added 2M LiOH (0.30 mmol). The reaction mixture was stirred for 24 hours. The solvent was removed in vacuo. The residue was diluted with water (2 mL) and extracted with ethyl ether. The pH of the aqueous layer was adjusted to 2 with 1N HCl. The resulting suspension was filtered off; the solid was washed with water and dried to give the final compound. Yield: 36 mg, 69%.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.NC1C=C([Cl:21])C=CC=1O.Cl.CN(CCCl)CCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[N:1]1([C:7]2[CH:12]=[C:11]([Cl:21])[CH:10]=[CH:9][C:8]=2[OH:13])[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: Nc1cc(Cl)ccc1O
Reactant: Oc1ccccc1N1CCNCC1
Agent: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCCO
Product: Oc1ccc(Cl)cc1N1CCNCC1

Procedure:
The derivative 45A is prepared according to the same procedure described for 43A, using the following reactants: 2-amino-4-chlorophenol (3 g; 20.9 mmol); N-methylbis(2-chloroethyl)amine hydrochloride (4.2 g; 22 mmol); sodium carbonate (1.1 g; 10.5 mmol); 1-butanol (42 ml).
Reaction SMILES: [CH2:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)[CH2:2][CH3:3].C1C(=O)N([Br:16])C(=O)C1>C(=O)([O-])[O-].[Na+].[Na+]>[Br:16][C:6]1[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[CH:8][CH:7]=1
Reactant: CCCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1ccc(Br)s1
Temperature: 0 °C

Procedure:
Next, 10 g (0.079 mol, 1 eq) of the obtained 2-propylthiophene was introduced into a three-necked flask, and this was flushed with Ar. To this, 100 ml of THF was added, stirred, and cooled to 0° C. To this, 15.5 g (0.087 mol. 1 eq) of NBS was added directly. After that, the temperature was returned to the room temperature, and stirred for 12 hours. To this, 20 ml of 10% sodium carbonate aqueous solution was added, extracted with diethyl ether, water washed until pH is 7, and dehydrated with Na2SO4. After removing Na2SO4 by filtration, the solvent was removed. This was purified by silica gel chromatography, and specified substance of 2-bromo-5-propylthiophene (1 in the chemical reaction formula) was obtained. Yielding quantity was around 14 g, and yielding percentage was around 85%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[C:17]([O:21][C:22](=[O:28])[C@@H:23]1[CH2:27][CH2:26][CH2:25][NH:24]1)([CH3:20])([CH3:19])[CH3:18].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[CH3:16][C:2]1([CH3:1])[O:6][C:5](=[O:7])[CH:4]([CH:8]([C:9]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:23]2[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:28])=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[O:3]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C)C1OC(C)(C)OC1=O
Reaction time: 8 h

Procedure:
To 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid G-1 (10 mmol; prepared as described in Method F, above) in DMF (50 mL) was added proline O-t-butyl ester (10 mmol), DIEA (25 mmol) and PyBOP (10 mmol) and the solution stirred for 8 h. The reaction was diluted with ethyl acetate and washed with water, sodium bicarbonate, brine, and then dried (Na2SO4). The filtrate was concentrated and then purified on silica gel (Merck 60; ethyl acetate/hexane) to afford 1-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)-1-(2-(S)-tert-butoxycarbonylpyrrolidin-1-ylcarbonyl)pentane G-2 (5 mmol, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1.CO.B(F)(F)F.[CH2:36](N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:29][CH3:36])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:28][CH2:27][C@@H:15]3[N:16]4[C:25]5[C:24]([C@@H:14]3[CH2:13]2)=[CH:23][CH:22]=[CH:21][C:20]=5[N:19]([CH3:26])[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CN1CCN2c3c(cccc31)[C@@H]1CN(CCCC(O)c3ccc(F)cc3)CC[C@@H]12
Agent: FB(F)F
Solvent: CO
Solvent: ClCCl
Product: COC(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCN3C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-fluoro-phenyl)-4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-butan-1-ol (225 mg, 0.57 mmol) in anhydrous dichloromethane (3 mL) is added anhydrous methanol (100 μL, 2.28 mmol), and then BF3.OEt (300 μL, 2.28 mmol, 1.0 M in THF) is added dropwise at room temperature. The reaction mixture is stirred at room temperature overnight, and then poured into ice water. After the mixture is basified with triethylamine, the organic phase is separated and dried over MgSO4, and then evaporated to dryness under reduced pressure. The obtained residue is purified with a semi-preparative HPLC system to give 80 mg of pure product as a brown oil. 1H NMR (500 MHz, DMSO-d6) δ 7.31 (ddd, J=8.6, 5.6, 1.2 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 6.50 (td, J=7.6, 1.3 Hz, 1H), 6.39 (d, J=7.3 Hz, 1H), 6.32 (d, J=7.9 Hz, 1H), 4.15 (td, J=6.5, 3.5 Hz, 1H), 3.49-3.37 (m, 1H), 3.31-3.22 (m, 3H), 3.15-3.04 (m, 4H), 3.02-2.91 (m, 1H), 2.77 (s, 3H), 2.70-2.61 (m, 2H), 2.29-2.11 (m, 2H), 2.09-1.97 (m, 1H), 1.92-1.81 (m, 1H), 1.78-1.63 (m, 3H), 1.60-1.49 (m, 1H), 1.49-1.37 (m, 1H), 1.37-1.22 (m, 1H). MS (ESI) m/z 410.6 [M+H]+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:10]=1[C:9]1[CH:11]=[C:12]([NH2:15])[CH:13]=[CH:14][C:8]=1[CH2:7][CH2:6][CH2:5]2.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:15][C:12]2[CH:13]=[CH:14][C:8]3[CH2:7][CH2:6][CH2:5][N:4]4[C:10](=[N:1][CH:2]=[CH:3]4)[C:9]=3[CH:11]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)-c1nccn1CCC2
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)-c2nccn2CCC3)ncc1Cl

Procedure:
Following a procedure analogous to Example 1741e, 5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide was converted to 2-[5-chloro-2-(5,6-dihydro-4H-1,3a-diaza-benzo[e]azulen-9-ylamino)-pyrimidin-4-ylamino]-3-chloro-N-methyl-benzamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.17 (s, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.71 (d, 1H), 7.4 (m, 3H), 7.3 (m, 2H), 4.16 (t, 2H), 2.81 (s, 3H), 2.70 (t, 2H), 2.46 (pent, 2H); MS (m/e) 494 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]CC2C=CC=CC=2)=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=1)=[O:4].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37]CC2C=CC=CC=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][NH:37][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:19][O:20][CH3:21])[CH:6]=2)[OH:4])=[CH:27][CH:28]=1
Reactant: COCc1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: Fc1ccc(CCOCCCCCNCc2ccccc2)cc1
Solvent: C1CCOC1
Product: COCc1cc(C(O)CNCCCCCOCCc2ccc(F)cc2)ccc1O
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[3-(methoxymethyl)-4-(phenylmethoxy)phenyl]ethanone (1.0 g), N-[5-(2-(4-fluorophenyl)ethoxy]pentyl]benzenemethanamine (0.91 g), and DEA (0.77 g) in THF (15 ml) was left at room temperature for 18 h, filtered and evaporated. The residue was hydrogenated over 10% Pd-C (0.5 g) and 5% Pt-C (0.5 g), filtered and evaporated. The resulting oil was purified by FCC eluting with System C (80:20:1) to give the title compound as a white solid (0.58 g) m.p. 86°-87°, t.l.c. (System C 80:20:1) Rf 0.25.
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].Br[CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24].C(=O)([O-])[O-].[K+].[K+].Cl>COCCOC>[F:1][C:2]([F:18])([C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])[CH2:3][C:4]([CH2:20][CH2:21][C:22]([F:26])=[C:23]([F:25])[F:24])([C:7]#[N:8])[C:5]#[N:6]
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: N#CC(C#N)(CCC(F)=C(F)F)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 10 h
Yield: 23.2 %

Procedure:
1.4 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 1.3 g of 1-bromo-3,4,4-trifluoro-3-butene were dissolved in 10 ml of ethylene glycol dimethyl ether, 0.97 g of potassium carbonate was added, and the mixture was stirred at room temperature for 10 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.45 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)-2-(3,4,4-trifluoro-3-butenyl)malononitrile (hereinafter, referred to as the present compound (75)).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]([NH2:19])=[S:18])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]1)=O.[ClH:44]>>[ClH:44].[ClH:44].[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:28]=[C:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[N:19]=2)=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Brc1cnc(Nc2nc(C3CCNCC3)cs2)c(OCc2ccccc2)c1
Yield: 51.4 %

Procedure:
1-(3-(Benzyloxy)-5-bromopyridin-2-yl)thiourea (200 mg, 0.59 mmol), triethylamine (0.144 ml, 1.03 mmol) and tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (253 mg, 0.82 mmol) were reacted according to the procedure in Example 1, Step D to afford the title compound (157.6 mg, 51.4% yield) as a white solid after HCl salt formation. 1H NMR (DMSO-d6) δ 10.30 (bs, 1H), 8.83 (bs, 1H), 8.60 (bs, 1H), 7.99 (dd, 1H), 7.67 (d, 1H), 7.59 (m, 2H), 7.45-7.33 (m, 3H), 6.75 (s, 1H), 5.30 (s, 2H), 3.32 (d, 2H), 3.05-2.85 (m, 3H), 2.11 (d, 2H), 1.79 (m, 2H). Mass spectrum (apci) m/z=445.2 (M+H-2HCl).
Reaction SMILES: [N+](=[CH2:3])=[N-].[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([OH:6])=[O:5].C(OC(=O)C)C>CCOCC>[C:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N:12]=1)([O:6][CH3:3])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCNc1nc2ccccc2c(=O)o1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)CCCNc1nc2ccccc2c(=O)o1
Reaction time: 3 h

Procedure:
A solution of diazomethane in ether is added dropwise to a solution of 2-(3-carboxy-propylamino)-4H-3,1-benzoxazin-4-one in ether. The reaction is monitored by thin layer chromatography (silica gel, 10% ethylacetate in petroleum ether) until completion. A small amount of silica gel is added to the solution. The solution is allowed to stand for 3 hours, then filtered. The filtrate is evaporated to give 2-(3-carbomethoxypropylamino)-4H-3,1-benzoxazin-4-one.