Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]C.C([Sn](=O)CCCC)CCC>CO>[CH2:1]([O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23]
Reactant: CCCCCCCCCCCCO
Reactant: COC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CO
Product: CCCCCCCCCCCCOC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
30.6 g (0.1 mol) of methyl-2-methyl-3-(3',5'-di-tert.-butyl-4'-hydroxyphenyl)-propionate and 18.6 g (0.1 mol) of 1-dodecanol are placed in a 4-necked glass flask and heated to 100° C., then 0.25 g=1 mol % of dibutyltin oxide is added and the mixture is heated further to 180° C., with methanol being split off. The reaction mixture is maintained at 180° C. for 6 hours.
Reaction SMILES: [CH2:1]1[C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH3:23]>C(#N)C>[CH2:22]([N:3]1[CH2:2][CH2:1][C:7]2=[CH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[N:6]2[CH2:5][CH2:4]1)[CH3:23]
Reactant: CCBr
Reactant: c1ccc2c(c1)cc1n2CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCc2cc3ccccc3n2CC1
Temperature: 40 °C
Reaction time: 22 h

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (280 mg, 1.5 mmol) in acetonitrile (15 mL) is treated with powdered potassium carbonate (622 mg, 4.5 mmol) and bromoethane (0.12 mL, 1.65 mmol, filtered through a pad of celite). The resulting milky suspenesion is heated to 40° C. After 22 hrs, the volatiles are removed under reduced pressure, diluted with water (20 mL), and extracted twice with ethyl acetate (20 mL). The combined organics are washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give a crude oil. This material is purified by LC (230-400 silica gel) eluting with 5% methanol/dichloromethane to afford 226 mg of 3-ethyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole as a white solid, mp 44-46° C. IR (drift) 2931, 2808, 1466, 1413, 1373, 1348, 1323, 1315, 1243, 1132, 1104, 776, 749, 732, 688 cm−1.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH2:24]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH:23]=[CH2:22]
Reactant: Cc1ccc(Nc2nc(=O)c3cccnc3s2)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Li+]
Product: C=CCn1c(=Nc2ccc(C)cc2)sc2ncccc2c1=O
Yield: 52.2 %

Procedure:
The reaction procedure of Example 11 was followed except that 900 mg (3.34 mmol) of 2-(4-methylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 27 mg of lithium hydride and 404 mg of allyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 539 mg of 3-allyl-2,3-dihydro-2-[(4-methylphenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from a mixture of ether and hexane) as a low polarity substance and 248 mg of 2-[N-allyl-N-(4-methylphenyl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (recrystallized from ether) as a high polarity substance.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Br[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN(C=O)C>[CH2:10]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 15.6 %

Procedure:
Step 1 A solution of imidazolidin-2-one (500 mg, 5.81 mmol) in DMF (30 mL) was stirred on ice and treated with sodium hydride, 60% oil dispersion (264 mg, 6.60 mmol). The mixture was stirred at rt for 50 min, then was treated with (bromomethyl)benzene (0.691 mL, 5.81 mmol). After 2 h, the mixture was poured into water and extracted three times with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography (eluting with EtOAc) to provide 1-benzylimidazolidin-2-one as a white solid (160 mg, 16%). 1H NMR (400 MHz, chloroform-d) δ 7.22-7.39 (5 H, m), 4.53 (1 H, br. s.), 4.37 (2 H, s), 3.25-3.46 (4 H, m).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[N+:28]([C:31]1[CH:32]=[C:33]([S:37]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1cccc([N+](=O)[O-])c1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 42 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with 3-nitrobenzenesulfonyl chloride under the conditions used in example 2 giving 42% of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[CH2:9].[N+](=[CH2:12])=[N-]>CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:9]1
Reactant: C=[N+]=[N-]
Reactant: C=Cc1ccncc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: Brc1cnccc1C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-bromo-4-vinylpyridine (Z, 0.4 g, 2.2 mmol) in ether (20 mL) was added palladium acetate (catalytic) and diazomethane (required for preparation, N-nitroso-N-methylurea-1.03 g, 10.0 mmol; 40% potassium hydroxide, 10 mL; ether, 20 mL) portion wise at 0° C. for 10 min. The reaction mixture was stirred at 0° C. for 0.5 h. The reaction mixture was filter through CELITE bed and concentrated under vacuum to afford the crude compound to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ: 8.62 (s, 1H), 8.34-8.33 (d, J=5.2 Hz, 1H), 6.72-6.71 (d, J=4.8 Hz, 1H), 2.25-2.18 (m, 1H), 1.17-1.12 (m, 2H), 0.80-0.76 (m, 2H). MS (M+2): 200.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:28][C:29]1[O:30][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[N:32][N:33]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:19]3[N:18]=[N:17][N:16]([CH2:28][C:29]4[O:30][C:31]([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)=[N:32][N:33]=4)[C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: ClCc1nnc(-c2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3c2nnn3Cc2nnc(-c3ccccc3)o2)c1
Reaction time: 16 h

Procedure:
3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (100 mg, 0.328 mmol), cesium carbonate (107 mg, 0.328 mmol) and 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (64 mg, 0.328 mmol) were combined and suspended in DMF (2 mL). After 16 hours at room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride (1 mL) and extracted with EtOAc (2×25 mL). The combined organic fractions were evaporated under reduced pressure, and the resulting residue was purified by reverse phase chromatography eluting with 30-95% MeCN/H2O+0.1% TFA. The product fractions were concentrated to yield the title compound. 1H NMR (DMSO-d6) δ 8.01 (d, J=8.9 Hz, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.88 (d, J=8.9 Hz, 1H), 7.83 (m, 1H), 7.61 (m, 5H), 6.54 (s, 2H). HRMS (M+1)=463.0465.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].P(O)([O-])([O-])=O.[NH4+].[NH4+].S([O-])([O-])(=O)=O.[Mg+2]>>[O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: O=C[C@H](O)[C@@H](O)[C@H](O)CO
Temperature: 40 °C
Reaction time: 0.75 h

Procedure:
Alternatively XI protein is isolated from Streptomyces rubiginosus strain C3 derived from S. rubiginosus ATCC 21,175 using the method described in U.S. Pat. No. 4,410,627, which is incorporated herein by reference. The strain is grown by submerged aerobic fermentation on a medium with the following composition (by percent weight) dextrose 9.0%, corn steep liquor (solids) 0.06%, diammonium phosphate 0.008%, magnesium sulfate 0.06%, antifoam (pluronic PL-61) 0.003%. The medium is sterilized at 121° C. for 45 min, cooled and adjusted to pH 5 6.8-7.0. The medium is inoculated with 14% (v/v) of an inoculm comprising the contents of a seed fermenter prepared with the S. rubiginosus strain. XI protein is extracted from the S. rubiginosus strain by adding 0.35% Maquat MC 1412 (Mason Chemical Co.) and 10 ppm of hen's egg lysozyme and agitating for 5 hr at 40° C., pH 6.3 to 6.6. The mixture is then filtered to provide a solution of unpurified xylose isomerase. The crude isomerase is purified by adsorption on DEAE-cellulose, filtering and washing the adsorbed product with 0.1M NaCl solution to remove impurities, and then desorbing by contacting with 0.45M NaCl solution. The pH of all solutions is maintained at 7.5 during the purification step. The solution of partially purified isomerase obtained thereby is mixed with 3 volumes of 95% ethanol at 0° C. to precipitate the isomerase. Perlite filter aid is added, the solids recovered by filtration, and air dried to provide a soluble XI preparation containing 2500 U/g. Specific activity of the preparation thus prepared is 40 U/mg of protein.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([S:10][CH3:11])[N:4]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O>>[CH2:16]([O:9][C:7]1[N:6]=[C:5]([S:10][CH3:11])[N:4]=[C:3]([CH2:2][Cl:1])[CH:8]=1)[CH3:17]
Reactant: CCOS(=O)(=O)OCC
Reactant: CSc1nc(O)cc(CCl)n1
Product: CCOc1cc(CCl)nc(SC)n1

Procedure:
4-Chloromethyl-6-hydroxy-2-methylthio-pyrimidine [known from S. Cohen et al., J.Org. Chem. 27, 3545-3549 (1962)] is treated with diethyl sulphate analogously to the process described in Example 59 in order to produce 6-ethoxy-4-chloromethyl-2-methylthio-pyrimidine which is required as the starting material in Example 19. M.p. (after crystallization from water) 167°-171° C.; 1H-NMR (CDCl3): 1.40 (t, CH3) 2.56 (s, SCH3), 4.45 (q, CH2), 4.47 (s, CH2Cl), 6.55 (s, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH3:30][O:31][C:32](=[O:51])[C:33]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])([CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[CH3:30][O:31][C:32](=[O:51])[C:33]([O:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[F:50])([CH3:42])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:37][CH:36]=1
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: COC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Product: COC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F

Procedure:
The titled compound is prepared, according to the procedure of Example 1, Step A, using toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (0.888 g, 2.12 mmole) and 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methylester (0.645 g, 2.12 mmole) to produce an oil (0.95 g, 81%). Mass [EI+] 551 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[C:38](Cl)=[O:39]>>[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]=1[C:38]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=2)[CH2:10][CH2:9]1)=[O:39]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCO)CC2)c1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Product: Cc1onc(-c2ccccc2)c1C(=O)OCCCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-{3-[1-(6-hydroxyhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 532.1 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].[ClH:38]>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][C@@H:11]([C:13]([NH:15][CH2:16][C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])=[O:14])[CH3:12])=[O:9])[CH3:7])=[O:4].[ClH:38]
Reactant: C[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: C[C@H](NC(=O)CN)C(=O)N[C@H](C)C(=O)NCC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To Boc-Gly-Ala-DAla-Gly-Gly-OBzl prepared as in Example 33C (17.2 g, 33.0 mmol) in glacial acetic acid (480 ml) was added 6 N HCl (120 ml) and the reaction mixture was stirred at room temperature for 24 h. Concentration in vacuo followed by coevaporation with water (2×250 ml) and toluene (2×250 ml) afforded 12.9 g (100% yield) of the product as a white powder: 1H NMR (D2O) δ 1.36 (d, J=6.9 Hz, 3 H), 1.38 (d, J=7.2 Hz, 3 H), 3.84 (s, 2 H), 3.96 (s, 2 H), 3.99 (s, 2 H), 4.30-4.36 (m, 2 H).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]2[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([C:19]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:20]=3[CH:21]=[CH:22][CH:23]=[N:24]4)[CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1([C@H](NC2C([N+]([O-])=O)=CN=C(Br)C=2)C)C=CC=CC=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.[C:61](=O)([O-])[O-:62].[K+].[K+]>CN(C=O)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@H:7]([N:9]2[C:10]3[CH:11]=[C:12]([C:19]4[CH:28]=[CH:27][CH:26]=[C:25]5[C:20]=4[CH:21]=[CH:22][CH:23]=[N:24]5)[N:13]=[CH:14][C:15]=3[NH:16][C:61]2=[O:62])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](Nc1cc(-c2cccc3ncccc23)ncc1[N+](=O)[O-])c1ccccc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[C@@H](Nc1cc(Br)ncc1[N+](=O)[O-])c1ccccc1
Agent: OB(O)c1cccc2ncccc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Temperature: 85 °C
Yield: 77 %

Procedure:
((1R)-1-Phenylethyl)(5-nitro-2-(5-quinolyl)(4-pyridyl))amine. ((1R)-1-Phenylethyl)(2-bromo-5-nitro(4-pyridyl))amine (5.6 g, 1.75 mmol) and 5-quinolineboronic acid (393 mg, 2.27 mmole) were dissolved in DMF (25 ml). Nitrogen gas was bubbled into solution for 2 min. Potassium carbonate (970 mg, 7.00 mmol) in water (5 mL) was then added followed by tetrakis(triphenylphosphine)palladium (0) (0.175 mmol). The solution was then heated to 85° C. under nitrogen for 1 h. The solution was condensed under reduced pressure and the crude product was diluted with ethyl acetate and filtered through a plug of silica-gel. The resultant filtrate was condensed under reduced pressure to afford the title compound (502 mg, 77%). MS (ESI) m/z 371 [M+1]+.
Reaction SMILES: Br[C:2]1([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>C(#N)C>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[C:10]3[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:12])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Br)Cc1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
The mixture of rac-3-bromo-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (1 g, 2.703 mmol), piperazine-1-carboxylic acid tert-butyl ester (0.604 g, 3.24 mmol) and DIPEA (0.419 g, 3.24 mmol) in acetonitrile (20 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and extracted with dichloromethane. The organic layer was dried over Na2SO4, filtered and concentrated to give 1.1 g of rac-4-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperazine-1-carboxylic acid tert-butyl ester. MS m/z 476 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:7]([OH:28])=[CH:8][C:9]2[O:14][C:13]([CH3:16])([CH3:15])[C@@H:12]([OH:17])[C@H:11]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:10]=2[CH:27]=1)=[O:4].[Cl-].[NH4+]>CO.[OH-].[Na+]>[OH:17][C@H:12]1[C@H:11]([NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:27]=[C:6]3[C:7]([O:28][CH2:2][C:3](=[O:4])[NH:5]3)=[CH:8][C:9]=2[O:14][C:13]1([CH3:16])[CH3:15]
Reactant: CC1(C)Oc2cc(O)c(NC(=O)CCl)cc2[C@@H](NCCc2ccccc2)[C@@H]1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc3c(cc2[C@@H](NCCc2ccccc2)[C@@H]1O)NC(=O)CO3
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2-chloro-N-{(±)-trans-3,7-dihydroxy-2,2-dimethyl-4-[(2-phenylethyl)amino]-3,4-dihydro-2H-1-benzopyran-6-yl}-acetamide (187 mg, 0.46 mmol) in methanol (2 mL), sodium hydroxide aqueous solution (1 mol/L, 1.8 mL) was added at room temperature, and the resulting mixture was stirred for 3 hours. Upon the completion of the reaction, saturated ammonium chloride aqeuous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with 1 mol/L sodium hydroxide aqueous solution and then with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=1/3) and the aimed product was obtained (yield: 61%).
Reaction SMILES: [Cl:1][P:2]1([Cl:12])[N:7]=[P:6](Cl)([Cl:8])[N:5]=[P:4]([Cl:11])([Cl:10])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][C:17]([O-:18])=[CH:16][CH:15]=1.[Na+]>O1CCCC1>[F:13][C:14]1[CH:20]=[CH:19][C:17]([O:18][P:6]2([Cl:8])[N:7]=[P:2]([Cl:12])([Cl:1])[N:3]=[P:4]([Cl:11])([Cl:10])[N:5]=2)=[CH:16][CH:15]=1
Reactant: [O-]c1ccc(F)cc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(OP2(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N2)cc1
Temperature: -78 °C

Procedure:
60 parts of hexachlorocyclotriphosphazene were charged into a reactor together with 500 parts of tetrahydrofuran, and the mixture cooled at -78° C. The previously prepared sodium p-fluorophenoxide solution was added dropwise and reacted as in Example 1. The resultant product was worked up as in Example 1 to yield p-fluorophenoxypentachlorocyclotriphosphazene (b.p. 107° C at 0.02 Torr).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][OH:18])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5].N1C=CC=CC=1.Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13]([CH2:17][O:18][C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37])=[C:12]2[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)=[O:5]
Reactant: O=C(Nc1cccc2c(-n3ccnc3)c(CO)cnc12)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1-n1ccnc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.7 %

Procedure:
To a suspension of 8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-4-(imidazol-1-yl)quinoline (800 mg) in dichloromethane (10 ml) were dropwise added pyridine (230 mg) and phenyl chloroformate (333 mg) at ambient temperature, and the mixture was stirred for 1 hour at ambient temperature. The mixture was washed with saturated ammonium chloride solution, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 8-(2,6-dichlorobenzoylamino)-4-(imidazol-1-yl)-3-(phenoxycarbonyloxymethyl)quinoline (100 mg).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([CH3:19])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][C:13]1[CH:12]=[C:11]([N:5]2[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]2)[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: Cc1cc(F)ccc1C#N
Reactant: FC(F)(F)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C#N
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a solution of 4-(trifluoromethyl)-1H-pyrazole (1.0 g, 7.0 mmol) and 4-fluoro-2-methylbenzonitrile (1.16 g, 8.50 mmol) in acetonitrile (8 mL) was slowly added potassium carbonate (1.96 g, 14.2 mmol) at room temperature. The reaction was heated to 80° C. and stirred overnight. The reaction was cooled to room temperature and poured into water. The layers were separated and the aqueous was extracted with ethyl acetate (3×15 mL). The combined organics were washed with water, dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)benzonitrile (710 mg, 40%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.26 (s, 1H), 7.94 (s, 1H), 7.72-7.74 (m, 2H), 7.61-7.64 (m, 1H), 2.64 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C(O)(=O)C.ClCCl>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+].[Fe]>[Br:1][C:2]1[C:3]([O:11][CH3:12])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: COc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1cccc(N)c1Br
Temperature: 25 °C
Yield: 90 %

Procedure:
(Prepared by a modification of reported procedure WO Patent: WO2006/7700). To a solution of 2-bromo-3-nitro-anisole synthesized above (10.3 mmol, 1.0 eq.) in absolute ethanol and glacial acetic acid at room temperature was added iron powder (42.1 mmol, 4.1 eq). The resultant mixture was heated to reflux for 1.5 hours, and then cooled to room temperature. The reaction mixture was diluted with water, and solid sodium carbonate was added until the pH was 6-7. Dichloromethane was added, and the mixture was filtered through celite. The dried (sodium sulfate) organics were concentrated to afford 2-bromo-3-methoxy-aniline (I-10, X═Br, R1═CH3) as an oil. Yield: 90%; 1H NMR (400 MHz; CDCl3): 3.87 (s, 3H), 4.16 (br s, 2H), 6.31 (dd, J=8.0, 1.2 Hz, 1H), 6.42 (dt, J=8.0, 0.8, 0.4 Hz, 1H), 7.05 (t, J=8.0 Hz, 1H) ppm.