Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])=[O:4].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:66]([O:73][C:74](=[O:80])[CH2:75][CH2:76][CH2:77][CH2:78][NH2:79])[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][C@H:10]([C:18]([NH:20][CH2:21][C:22]([NH:79][CH2:78][CH2:77][CH2:76][CH2:75][C:74]([O:73][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:80])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)O
Reactant: NCCCCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)NCCCCC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-Gly-Gly-Phe-Gly-OH (SEQ ID NO. 1) (575 mg), HOSu (182 mg), and DCC (326 mg) were dissolved in DMF (20 ml), and the solution was stirred for 30 minutes. The resulting solution was added with a solution of p-toluenesulfonic acid salt of 5-aminopentanoic acid benzyl ester (500 mg) and triethylamine (0.184 ml) dissolved in DMF (10 ml), and the mixture was stirred at room temperature for three days. The reaction mixture was concentrated, and the residue was purified by column chromatography (CH2Cl2:MeOH=20:1) to obtain 560 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1). The Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOBzl (SEQ ID NO. 1) (560 mg) was dissolved in methanol (60 ml) containing 50% of water, and the solution was added with 5% Pd—C (water content; 50%, 1.5 g) and stirred overnight under hydrogen at ordinary pressure. After the catalyst was removed from the reaction mixture by filtration, the mixture was concentrated to dryness to obtain 300 mg of Boc-Gly-Gly-Phe-Gly-NH—(CH2)4—COOH (SEQ ID NO. 1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][NH:21][CH3:22])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[N:36]1[CH:40]=[N:39][C:38]([CH3:41])=[N:37]1>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH2:24][CH2:25][O:26][C:27]2[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=2[N:36]2[CH:40]=[N:39][C:38]([CH3:41])=[N:37]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCBr)n1
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCN(C)CCNc2nc(Cl)nc3c2CCC3c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a solution of N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methylethane-1,2-diamine (0.2 g, 0.623 mmol) in DMF (3 mL) was added TEA (0.095 g, 0.935 mmol) followed by 1-(2-(2-bromoethoxy)-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (Preparation J, 0.245 g, 0.233 mmol) at room temperature. The reaction mixture was stirred at rt for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (5 mL) and silica (1 g). The resultant slurry of the compound in silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, with 10% methanol in chloroform) to get N1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N2-methyl-N2-(2-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)ethyl)ethane-1,2-diamine (0.04 g, 13.12%) as a dark brown solid. LC-MS (M+H)+=567.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, s), 7.14-7.08 (3H, m), 6.99-6.95 (2H, m), 6.41 (1H, s), 6.32 (1H, d, J=8.4 Hz), 4.39 (2H, br s), 4.14 (1H, t, J=8.8 Hz), 3.93-3.88 (4H, m), 3.22-3.09 (6H, m), 2.55-2.54 (1H, m), 2.46 (3H, s), 1.99-1.98 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=2[F:21])=[CH:4][C:3]=1[N:22]1[C:30](=[O:31])[NH:29][C:28]2[C:23]1=[N:24][C:25]([CH2:34][OH:35])=[N:26][C:27]=2[O:32][CH3:33].CC([OH:39])C.O.C(OCC)(=O)C>CC(C)=O>[C:34]([C:25]1[N:24]=[C:23]2[C:28]([NH:29][C:30](=[O:31])[N:22]2[C:3]2[CH:4]=[C:5]([O:10][CH2:11][C:12]3[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]([F:20])[C:13]=3[F:21])[C:6]([O:8][CH3:9])=[CH:7][C:2]=2[Cl:1])=[C:27]([O:32][CH3:33])[N:26]=1)([OH:39])=[O:35]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CO)nc32)cc1OCc1c(OC)ccc(F)c1F
Reactant: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(C(=O)O)nc32)cc1OCc1c(OC)ccc(F)c1F
Reaction time: 0.17 h

Procedure:
To a solution of 9-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-2-hydroxymethyl-6-methoxy-7,9-dihydro-8H-purin-8-one (0.14 g) in acetone (5 mL) was added this solution in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes, and then stirred at room temperature overnight. To the reaction mixture was added 2-propanol (2 mL), and the mixture was stirred at room temperature for 20 minutes. To the mixture were added water and ethyl acetate, and the insoluble material was removed by filtration. The insoluble material was washed with water, ethyl acetate and diethyl ether successively. The filtrate and washings were combined, and the organic layer was separated. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=1/1) to give the title compound (4 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][CH3:14])[C@@H:10]([CH2:15][O:16][C:17]2[C:18]3[C:32]([Cl:33])=[CH:31][NH:30][C:19]=3[N:20]=[C:21]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[N:22]=2)[CH2:9]1)=O)(C)(C)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[Cl:33][C:32]1[C:18]2[C:17]([O:16][CH2:15][C@@H:10]3[C@@H:11]([O:13][CH3:14])[CH2:12][NH:8][CH2:9]3)=[N:22][C:21]([NH:23][C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)=[N:20][C:19]=2[NH:30][CH:31]=1
Reactant: CO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1COc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[C@H]1CNC[C@@H]1COc1nc(Nc2cnn(C)c2)nc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 122.7 %

Procedure:
To a solution of (3R,4R)-3-[5-chloro-2-(1-methyl-1H-pyrazol-4-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxymethyl]-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (12.40 g, 26 mmol) in DCM (60 mL) at 0° C. was added TFA (10.1 mL, 208 mmol) and the resulting solution was stirred at ambient temperature for 2.5 hrs. The volatiles were removed and to the residue was added ethyl ether (150 mL). The resulting suspension was stirred for 2 hrs then filtered to afford a light pink solid. This was washed with ethyl ether (30 mL) and dried to give the title compound (15.69 g, quant) as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H) 9.09 (s, 3H) 7.85 (s, 1H) 7.54 (s, 1H) 7.09 (d, J=2.32 Hz, 1H) 4.48 (d, J=6.48 Hz, 2H) 4.11 (br. s., 1H) 3.81 (s, 3H) 3.46-3.60 (m, 1H) 3.35-3.45 (m, 2H) 3.32 (s, 3H) 3.15 (dq, J=12.01, 6.02 Hz, 1H) 2.88 (m, J=6.42, 6.42 Hz, 1H). m/z (APCI+) for parent molecule C16H20ClN7O2 378.2 (M+H)+ with Cl isotope pattern.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:16]=2[O:15][CH2:14][CH2:13]1>>[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3([OH:28])[CH2:23][CH2:24][N:25]([C@@H:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=5)[C@H:7]4[OH:11])[CH2:26][CH2:27]3)[C:16]=2[O:15][CH2:14][CH2:13]1
Reactant: OC1(c2cccc3c2OCCO3)CCNCC1
Reactant: O=C1CCc2cc(F)ccc21
Product: O[C@@H]1c2ccc(F)cc2C[C@H]1N1CCC(O)(c2cccc3c2OCCO3)CC1

Procedure:
Prepared using, in succession, the methods described in Examples 1 and 2, but using 5-fluoroindan-1-one in Step 1 of Example 1, and using 4-(2,3-dihydro[1,4]benzodioxin-5-yl)-4-hydroxypiperidine in Step 2 of Example 1.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.N>C(O)C.ClCCl.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[NH2:22][C:21]1[CH:20]=[CH:19][C:4]([CH:5]=[C:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2ccc([N+](=O)[O-])c(F)c2)CC1
Agent: [Fe+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccc(N)cc2)CC1
Temperature: 85 °C
Yield: 70.1 %

Procedure:
tert-Butyl 4-(3-fluoro-4-nitrobenzylidene)piperidine-1-carboxylate (2.97 mmol, 1 g), iron(II) sulfate heptahydrate (20.42 mmol, 5.68 g) and ammonia (10.02 mmol, 11.39 ml) were combined in ethanol (20 mL) and heated at 85° C. overnight. The reaction mixture was diluted with dichloromethane and water then filtered through celite. The organic phase of the filtrate was dried and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting with dichloromethane to 3% methanol/dichloromethane) to afford the intermediate tert-butyl 4-(4-aminobenzylidene)piperidine-1-carboxylate (600 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH:51]=O)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[NH:53]1[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C.C(O)(C(F)(F)F)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:42][C:43]4([O:49][CH2:50][CH2:51][N:53]5[CH2:58][CH2:57][S:56](=[O:60])(=[O:59])[CH2:55][CH2:54]5)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]4)[C:40]=3[CH3:41])=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)OC(C)(C)C)cnn1CC1(OCC=O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cnn1CC1(OCCN2CCS(=O)(=O)CC2)CCCCC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 167F (72 mg) and thiomorpholine 1,1-dioxide (13.5 mg) in dichloromethane (3 mL) was added sodium triacetoxyborohydride (32 mg). The mixture was stirred overnight. The mixture was dissolved in ethyl acetate (200 mL) and washed with 2N aqueous NaOH and brine, and dried over Na2SO4. Filtration and evaporation of the solvent gave crude product which was dissolved in dichloromethane (2 mL) and TFA (2 mL). After stirring overnight, the solvent was evaporated. The residue was purified by reverse phase chromatography using a Gilson system, eluting with 20-80% acetonitrile in 0.1% TFA water solution to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6). δ ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 5H), 6.97 (d, 1H), 4.96 (s, 2H), 4.10 (s, 3H), 3.53 (m, 8H), 3.02 (t, 2H), 2.13 (s, 3H), 1.43 (m, 10H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:6]=2[CH:19]=1.[N:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:7]1[C:6]2[CH:19]=[C:2]([C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[CH:3]=[CH:4][C:5]=2[NH:11][CH2:10][CH2:9][NH:8]1
Reactant: OB(O)c1ccncc1
Reactant: Fc1ccccc1C1NCCNc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccccc1C1NCCNc2ccc(-c3ccncc3)cc21
Temperature: 160 °C
Yield: 40.2 %

Procedure:
A 5-mL microwave tube was charged with provided 7-bromo-5-(2-fluorophenyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (25 mg), 4-pyridylboronic acid (50 mg), dichlorobis(triphenyl-phosphine)palladium(II) (10 mg), potassium carbonate (50 mg), dimethylformamide (3.5 mL) and water (0.5 mL). The reaction was heated to 160° C. for 360 seconds using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organic extracts were combined and dried over magnesium sulfate. The drying agent was filtered and the filtrate was concentrated to an oil. Silica gel purification provided the title compound 5-(2-fluorophenyl)-7-(4-pyridinyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine (10 mg) as a white powder. H1 NMR (d6-dmso): 8.42 (d, 2H), 7.46 (m, 2H), 7.30 (m, 3H), 7.18 (m, 2H), 7.02 (d, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.22 (br s, 1H), 3.18-3.3 (m, 1H), 2.78-2.96 (m, 3H), 2.64 (br s, 1H). Mass (ES+)=320.2 (100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:5]([Cl:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)O1.C([O-])([O-])=O.[Na+].[Na+]>C(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>[Cl:8][C:5]1[C:4]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:3][C:2]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)=[CH:7][N:6]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccc4ncccc4c3)cnc2Cl)cc1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
(Some starting materials may be obtained from AstaTech, Inc. Princeton, N.J.) A 15 mL sealed pressure tube was charged with N-(5-bromo-2-chloropyridin-3-yl)-4-methoxybenzenesulfonamide (120 mg, 0.318 mmol), 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (90 mg, 0.350 mmol) in ethanol (1.5 mL). To this was added 5 mol % of Pd(PPh3)4 (18 mg, 0.016 mmol) and Na2CO3 (2M, 0.4 mL). The flask was flushed with argon, sealed and stirred at 90° C. for 4 hours. The crude mixture was partitioned between water and ethyl acetate, extracted with ethyl acetate (3×), dried over Na2SO4 and concentrated in vacuo. The Solids were taken up in minimal methylene chloride and purified via ISCO, 40 g RediSep® (Teledyne ISCO, Lincoln, Nebr.) column with a 20-100% gradient of ethyl acetate in hexanes, to afford the desired material. MS (ESI pos. ion) m/z calc'd for C21H16ClN3O3S: 425.1; found 426.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.83 (s, 3 H) 7.12 (d, J=8.80 Hz, 2 H) 7.63 (dd, J=8.36, 4.25 Hz, 1 H) 7.72 (d, J=8.61 Hz, 2 H) 8.05 (dd, J=8.95, 1.81 Hz, 1 H) 8.10 (d, J=1.96 Hz, 1 H) 8.13-8.19 (m, 1 H) 8.32 (d, J=1.76 Hz, 1 H) 8.47 (d, J=8.51 Hz, 1 H) 8.72 (d, J=1.76 Hz, 1 H) 8.97 (dd, J=4.16, 1.32 Hz, 1 H) 10.32 (s, 1 H)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][CH2:28]C(OC(C)(C)C)=O)[CH:21]=1)[CH2:2][CH2:3][CH3:4].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH3:19])/[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:8][C:7]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][NH:27][CH3:28])[CH:21]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1cc(/C=C(\C)C(=O)OCC)ccc1-c1cccc(CNC)c1
Yield: 84 %

Procedure:
g (2.2 mmol) of ethyl (E)-3-{2-butoxy-3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-methylacrylate in 10 mL of dichloromethane and 1.5 mL of trifluoroacetic acid are stirred at room temperature for 2 hours 30 minutes. The reaction medium is evaporated to dryness and purified by chromatography on a column of silica eluted with a 98/2 and then 95/5 mixture of ethyl acetate and methanol. 1.1 g (84%) of ethyl (E)-3-(2-butoxy-3′-methylaminomethylbiphenyl-4-yl)-2-methylacrylate trifluoroacetate are obtained in the form of an orange oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].[CH3:12][CH2:13][CH:14]1[O:16][CH2:15]1>CN(C)C=O>[OH:16][CH:14]([CH2:13][CH3:12])[CH2:15][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CCC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCC(O)CN1C(=O)NC(C)(C)C1=O
Temperature: 100 °C
Reaction time: 4 h

Procedure:
256.3 g of 5,5-dimethylhydantoin (2 mols) and 2.54 g of lithium chloride in 300 ml of dimethylformamide are together stirred at 65° C. 158.8 g of 1,2-butene oxide (2.2 mols) are slowly added dropwise over the course of 2 hours at this temperature. Thereafter the mixture is stirred for a further 4 hours at 100° C. The solution is cooled to room temperature and filtered, and the filtrate is then concentrated on a rotary evaporator at 70° C/20 mm Hg and dried to constant weight at 90° C/0.1 mm Hg. A crystalline, light yellow crude product is obtained in quantitative yield (400.1 g). The substance can be purified by recrystallisation from acetone. Colourless, glistening crystals melting at 87°-88.5° C are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:19].OO>CO>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Agent: OO
Solvent: CO
Product: Cc1cccc(O)c1OCc1ccccc1
Yield: 70 %

Procedure:
2-Benzyloxy-3-methylbenzaldehyde prepared by the above 2-(1) 20.0 g (88.4 mmol) was dissolved in methanol 100 ml and thereto was added sulfuric acid 20.0 g (203 mmol) and then added 30% hydrogen peroxide 30.1 g (265 mmol). The mixture was refluxed for 2 hours. After disappearance of the raw material, the solution was concentrated in vacuo, neutralized with a saturated sodium bicarbonate solution and extracted with methylene chloride. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (n-hexane-ethyl acetate) to give 2-benzyloxy-3-methylphenol 13.3 g (yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:44])[NH:4][C@H:5]([C:19](=[O:43])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:45]([O:47][P:48](OCC)([O:50][CH2:51][CH3:52])=[O:49])[CH3:46].P(Cl)(OCC)(OCC)=O.[H-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:44])[NH:4][C@H:5]([C:19](=[O:43])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][O:27][P:48]([O:50][CH2:51][CH3:52])([O:47][CH2:45][CH3:46])=[O:49])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOP(=O)(OCC)OCC
Reactant: COC(=O)N[C@H](C(=O)NCCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The PL-100 compound (product of step F, 203 mg, 0.325 mmol) was dissolved in dry tetrahydrofuran (3 mL) and 0.2 mL triethylphosphate under N2 atmosphere. The mixture was stirred at this temperature for 15 min, followed by the addition of diethyl chlorophosphate (0.061 mL, 0.423 mmol). Sodium hydride (60% in mineral oil) (17 mg, 0.423 mmol) was added at 0° C. The solution was stirred for 1 h at 0° C. and 12 h at room temperature. 20 mL of Amberlite XAD-2 was added to the solution and the beads were thoroughly mixed with the solvent. To the mixture was added ice water 0.2 mL, and the THF evaporated off. The beads were then washed with distilled water 6 times 100 mL then extracted three times with ethyl acetate (30 mL). The combined phase was evaporated and the residue was dried under high vacuum. The crude product was purified by flash chromatography using ethyl acetate/hexane (8/2), then EtOAc 100% as eluent. The yield of this reaction is 152 mg 61%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH2:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1.[CH2:24]([OH:35])[C@H:25]([OH:34])[C@H:26]1[O:31][C:29](=[O:30])[C:28]([OH:32])=[C:27]1[OH:33].C>CO>[O:30]=[C:29]1[O:31][C@H:26]([C@H:25]([CH2:24][OH:35])[OH:34])[C:27]([O-:33])=[C:28]1[OH:32].[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[CH:17][CH2:18][O:19][C:14]=3[C:13]([O:20][CH3:21])=[C:12]([O:22][CH3:23])[CH:11]=2)=[CH:4][N:3]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: COc1cc(Cc2cnc(N)nc2N)c2c(c1OC)OCC=C2
Solvent: CO
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O

Procedure:
To 2,4-diamino-5-(7,8-dimethoxy-2H-1-benzopyran-5-ylmethyl)pyrimidine (5.00 g, 15.9 mmol) in 450 mL of boiling methanol was added a solution of L(+)-ascorbic acid (2.80 g, 15.9 mmol) in 50 mL of methanol. The solution was treated with charcoal, filtered, and evaporated to dryness. Further drying at 40° C. in a vacuum oven gave 7.58 g (97.2%) of the title compound. Anal. Calcd for C16H18H4O3.C6H8O6.H2O: C, 51.97; H, 5.55; N, 11.02. Found: C, 51.95; H, 5.57; N, 11.02.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.F[CH2:11][C:12](NC1C=CC=CC=1)=[O:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH3:11][C:12]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[F:9])=[O:13]
Reactant: O=C(CF)Nc1ccccc1
Agent: Nc1ccc(Cl)cc1F
Product: CC(=O)Nc1ccc(Cl)cc1F

Procedure:
U.S. Pat. No. 4,138,242 (Goddard, Feb. 6, 1979) relates to herbicidal compounds and their preparation from 4-chloro-2-fluoroaniline. The 4-chloro-2-fluoroaniline is prepared through the chlorination of 2-fluoroacetanilide to yield 4-chloro-2-fluoroacetanilide and the subsequent formation of the desired aniline.