Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](Cl)(=[O:20])[CH3:19].O>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:20])[CH3:19])=[CH:16][CH:17]=1
Reactant: Fc1ccccc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1ccc(-c2ccccc2F)cc1
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, methylene chloride (100 ml) was added to aluminum chloride (20.1 g) and then, to thereto was added dropwise at room temperature a solution obtained by dissolving 2-fluorobiphenyl (20.0 g) and acetyl chloride (10.7 ml) in methylene chloride (100 ml). After stirring for 4 hours, a small amount of water was added to the reaction mixture, and then the mixture was subjected to extraction with chloroform. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a recrystallization method from ethanol, to obtain 1-(2'-fluoro-biphenyl-4-yl)-ethanone (17.53 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[F:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1cccc(F)c1
Product: Fc1cccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4c3)CC2)c1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 3-fluorobenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-fluorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: N=C(N)N
Reactant: COc1ccc2nccc(-n3cc(C(=O)Cl)c4ccccc43)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2nccc(-n3cc(C(=O)NC(=N)N)c4ccccc43)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 17 cm3 (8.5 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.812 g (8.5 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.67 g (1.79 mmol) of 3-chlorocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride, suspended in 40 cm3 of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the product obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.37 g of 3-guanidinocarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 266° C. Mass spectrum (EI): m/e 359 (M+•), m/e 301.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]2.[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20]([C:22]([CH3:33])([CH3:32])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=O)[CH:21]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:15][C:16]1[CH:17]=[CH:18][C:19]([O:34][CH3:35])=[C:20]([C:22]([CH3:32])([CH3:33])[CH2:23][C:24]([OH:31])([C:27]([F:30])([F:29])[F:28])[CH:25]=[N:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[N:7]3)[CH:21]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: NC(=O)c1ccc2c(N)cccc2n1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(C=Nc1cccc2nc(C(N)=O)ccc12)C(F)(F)F

Procedure:
A solution that consists of 290 mg (1.55 mmol) of 5-aminoquinoline-2-carboxylic acid amide, 616 mg (2.0 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal and 3.80 ml of concentrated acetic acid in 30 ml of toluene is refluxed for 20 hours in a water separator. Then, the solvent is removed in a vacuum. After the residue is purified on silica gel with hexane/ethyl acetate (0-70%), 438 mg (59% of theory) of the product is obtained.
Reaction SMILES: [Ag:1].[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([OH:8])=[O:7])[OH:5]>>[C:2]([OH:14])(=[O:13])[CH2:3][C:4]([CH2:9][C:10]([OH:12])=[O:11])([C:6]([O-:8])=[O:7])[OH:5].[Ag+:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: [Ag]
Product: O=C(O)CC(O)(CC(=O)O)C(=O)[O-]
Product: [Ag+]

Procedure:
Water was introduced into a reverse osmosis unit, passing through a semi-permeable membrane to remove impurities and producing deionized water. Anhydrous 99% pure citric acid was mixed with the water to produce 200 gallons of a 20% (wt/vol) (796 g citric acid per gallon water) solution. The 200 gallons of 20% citric acid were directed into an ion chamber containing having positive and negative electrodes, each consisting of 200 troy ounces of 999 fine silver. The positive and negative electrodes were spaced at least 2.0 mm apart, allowing the citric acid solution to pass between the two electrodes. An ion generation controller (IGC) power supply including a positive and a negative conductor was attached to the positive and negative electrodes. The IGC applied a current of 5 amps at 17 volts, pulsed every 9 seconds, with a polarity change at 1 minute intervals. Throughout the process, the electrode gap was adjusted in order to maintain the 5 amp-17 volt output. The electric current flow caused an ion current to flow between the positive and negative electrodes, producing free silver ions within the diluted citric acid solution. The silver ions reacted with the citric acid in the citric acid solution to produce the silver dihydrogen citrate solution. The 20% citric acid solution was recirculated through the ion chamber at 50 gallons per minute for 144 hours until the desired silver ion concentration was obtained. The silver dihydrogen citrate solution was then allowed to sit in order to allow any solids formed during the procedure to precipitate. The resulting product was a silver dihydrogen citrate solution having a silver ion concentration of 2400 ppm. Hereafter, this solution is referred to as a stock solution. The stock solution can be used immediately per the following examples or stored for later use.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=1)[OH:30].C(N(CC)CC)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([C@@H:29]([OH:30])[CH2:28][NH:27][CH:22]2[CH2:21][CH2:20][N:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)(=[O:11])=[O:10])=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)[CH:36]=[CH:35][CH:34]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)cc1

Procedure:
A mixture of 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) (0.288 g, 0.8 mmol) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol hydrochloride (which was obtained in Example 1) (0.832 g, 4.0 mmol) was dissolved in 50 mL of methanol and the pH was adjusted to 5 with triethylamine. After stirred at room temperature for one day acetic acid (1 mL) and NaCNBH3 (50 mg, 0.8 mmol) were then added. The reaction was stirred for another day, the solvent was removed, and the residue was purified by thin layer chromatography (10% methanol/CH2Cl2) to give the title compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.95–2.10 (m, 2 H), 2.50–3.10 (m, 5 H), 3.50–3.70 (m, 2 H), 3.79 (s, 3 H), 4.80–4.90 (m, 1 H), 6.79 (d, J=9.0 Hz, 2 ) 6.89 (d, J=9.0 Hz, 2 H), 7.05 (d, J=9.0 Hz, 2 H), 7.30–7.50 (m, 4 H), 7.60 (d, J=9.0 Hz, 2 H), 9.60 (brs, 1 H); MS (ES) m/z: 516.2 (MH+); HRMS Calcd. for C26H31ClN3O4S (MH+); 516.1724. Found: 516.1713.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:15][CH2:16]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:25])[CH3:26])[CH2:20][CH2:19]2)[CH:31]=[C:30]([O:43][CH3:44])[C:29]=1[OH:45]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CN(C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N[C@H]4CC[C@H](N(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure F, {6-bromo-4-[trans-4-(dimethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (50 mg, 0.120 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (51 mg, 0.180 mmol) to afford the desired product (22 mg, 37%) as a yellow-green solid: 1H NMR (300 MHz, CD3OD) δ 9.18 (s, 1H), 8.36 (s, 1H), 8.09 (d, J=10.4 Hz, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.25 (d, J=2.0 Hz, 1H), 4.24 (s, 1H), 3.99 (s, 3H), 3.35 (s, 1H), 2.86 (s, 7H), 2.46 (s, 2H), 2.21 (s, 2H), 1.73 (d, J=10.4 Hz, 4H), 1.28-1.06 (m, 4H); ESI MS m/z [C28H32ClN3O3+H]+; HPLC 97.5% (AUC), tR=10.92 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH2:31]([N:33]=[C:34]=[S:35])[CH3:32].O.[Cl-].[Na+]>CN(C)C=O>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:14]1[CH2:13][CH2:12][N:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:34]([NH:33][CH2:31][CH3:32])=[S:35])=[CH:3][CH:4]=2)=[O:10])[CH2:16][CH2:15]1
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Reactant: CCN=C=S
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=S)Nc1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 514.0 mg (1.26 mmol) of N-(4-aminophenyl)-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide obtained in Example 221 in 10 ml of dimethylformamide was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring at room temperature. To the resulting mixture was added 0.13 ml (1.51 mmol) of ethyl isothiocyanate, followed by overnight stirring. The reaction mixture was poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.
Reaction SMILES: C([NH:4][C:5](C(OCC)=O)([CH2:11][C:12]1[C:13]([O:22][CH3:23])=[N:14][O:15][C:16]=1[C:17]([O:19]CC)=[O:18])[C:6]([O:8]CC)=[O:7])(=[O:3])C>Cl>[OH2:3].[NH2:4][CH:5]([CH2:11][C:12]1[C:13]([O:22][CH3:23])=[N:14][O:15][C:16]=1[C:17]([OH:19])=[O:18])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1onc(OC)c1CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Agent: Cl
Product: COc1noc(C(=O)O)c1CC(N)C(=O)O
Product: O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of ethyl 2-acetamido-2-(ethoxycarbonyl)-3-[5-(ethoxycarbonyl)-3-methoxyisoxazol-4-yl]propionate (1.2 g, 3.0 mmol) in 0.5 M HCl (100 mL) was boiled under reflux for 48 h. The mixture was cooled, washed with dichloromethane (100 mL) and diethyl ether (2×100 mL), filtered and concentrated in vacuo. Water was added (5 mL) and the pH adjusted to about 3 by addition of NaOH (0.1 M and 1 M). The aqueous phase was reduced in vacuo (2 mL) and a precipitate collected by filtration. The precipitate was stirred in water (2 mL) at room temperature for 24 h affording Comp. 1 after filtration (70 mg, 10%): mp 222-225° C. (dec); 1H NMR (DMSO-d6) δ2.88 (dd, 1 H), 3.01 (dd, 1 H), 3.85-3.96 (m, 1 H), 3.90 (s, 3 H); 13C NMR (DMSO-d6) d 22.70, 52.38, 57.32, 103.25, 159.43, 165.95, 170.66 (2 C); MS ((M+H)+) m/z 231. Anal. (C8H10N2O6.0.25H2O) calcd, C, 40.94; H, 4.51; N, 11.94; found, C, 41.01; H, 4.37; N, 11.91.
Reaction SMILES: [O:1]([C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6])[CH3:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.ClCCl>N1C=CC=CC=1>[CH3:2][O:1][C:3]1[CH:4]=[C:5]([NH:6][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(NS(=O)(=O)c2ccc(C)cc2)cc(OC)c1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 3,5-dimethoxylaniline (24.0 g, 156.9 mmol) and p-toluenesulfonyl chloride (29.8 g, 156.9 mmol) in anhydrous pyridine (70 mL) was stirred and heated to reflux for 30 min under argon atmosphere. The reaction mixture was cooled to room temperature and poured into 400 mL of ice-cold water. Dichloromethane was added to extract the product. The organic layer was separated and washed with water, 5% HCl aqueous solution, water and brine and dried with anhydrous Na2SO4. Removal of solvent provided yellow solid crude, which was purified by re-crystallization in diethyl ether to afford 42.6 g (89.0%) of the title compound as light yellow crystalline solid. mp 103-104° C.
Reaction SMILES: [F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O+](CC)CC)[CH3:7].[C:13]1([C:19]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:28](=[O:38])[CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])[CH2:26]3)[C:22](=[O:39])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCOCC>ClCCl>[F:1][B-:2]([F:5])([F:4])[F:3].[CH2:6]([O:38][C:28](=[N+:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:20][CH2:21][C:22]2=[O:39])[CH2:26]1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH3:7]
Reactant: CC[O+](CC)CC
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(Cc1ccccc1OC)=[N+]1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
Triethyloxonium tetrafluoroborate (2.35 g) is added to a solution of (3aRS,7aRS)-7,7-diphenyl-2-[(2-methoxyphenyl)acetyl]perhydro-4-isoindolone (5 g) in dichloromethane (10 cc). The reaction mixture is left stirring for 20 hours at room temperature; it is then treated with ether (100 cc) and the precipitate obtained is drained, washed with ether (100 cc) and dried. (3aRS,7aRS)-2-[1-Ethoxy-2-(2-methoxyphenyl)ethylidene]-4-oxo-7,7-diphenylperhydroisoindolium tetrafluoroborate (5.75 g) is obtained in the form of a yellow powder, which is used in the crude state for the following manipulation.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10](#[N:15])/[CH:11]=[CH:12]/[C:13]#[N:14].[CH2:16]([O:18][CH:19]=[CH2:20])[CH3:17]>>[CH2:16]([O:18][CH2:19][CH2:20][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[CH3:17].[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10](#[N:15])/[CH:11]=[CH:12]/[C:13]#[N:14]
Reactant: C=COCC
Agent: C=Cc1ccc(O)cc1
Agent: N#C/C=C/C#N
Product: C=Cc1ccc(OCCOCC)cc1

Procedure:
Using 9.0 g of poly(p-hydroxystyrene/fumaronitrile) obtained according to (2) above and 2.8 g of ethylvinyl ether, the procedure of (3) of Preparation Example 1 was carried out for reaction and after-treatments to obtain 8.3 g of poly(p-1-ethoxyethoxystyrene/p-hydroxystyrene/fumaronitrile) as white powdery crystal. P-1-ethoxyethoxystyrene unit/p-hydroxystyrene unit molar ratio in the polymer≈3:7 (1H NMR). Mw≈20,000; Mw/Mn=1.85 (GPC with polystyrene calibration).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[F:7][C:8]1[C:30]([CH:31]=C)=[CH:29][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:26]([CH3:28])[CH3:27])[N:22]=[C:23]([CH3:25])[N:24]=1)[N:13]=3.CC(C)=[O:35].O>CC(O)(C)C.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[F:7][C:8]1[C:30]([CH:31]=[O:35])=[CH:29][C:11]2[C:12]3[N:16]([CH2:17][CH2:18][O:19][C:10]=2[CH:9]=1)[CH:15]=[C:14]([C:20]1[N:21]([CH:26]([CH3:28])[CH3:27])[N:22]=[C:23]([CH3:25])[N:24]=1)[N:13]=3
Reactant: CC(C)=O
Reactant: C=Cc1cc2c(cc1F)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1nc(-c2cn3c(n2)-c2cc(C=O)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Osmium tetraoxide (1.8 mL of a 2.5% solution in tBuOH) and sodium periodate (1.51 g, 7.08 mmol) were added to a solution of 8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-9-vinyl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.0 g, 2.83 mmol) in an acetone-water mixture (5:1, 60 mL). The reaction mixture was stirred vigorously for 24 h at RT. The mixture was diluted with EtOAc (100 mL), washed with water and brine, dried (Na2SO4) and concentrated in vacuo to give the title compound (968 mg, 2.72 mmol, 96%) as a pale yellow oil. The product was taken on without further purification. LCMS (Method J): RT=2.78 min, [M+H]+ =356
Reaction SMILES: [Br:1][C:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:35]1[CH:36]=C[C:38]2[N:43](O)N=[N:41][C:39]=2[CH:40]=1.NC1C=NC=CC=1.C(Cl)CCl>CN(C)C=O>[Br:1][C:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:5]([C:6]([NH:41][C:39]2[CH:38]=[N:43][CH:36]=[CH:35][CH:40]=2)=[O:8])=[C:4]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccnc1)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Temperature: 50 °C

Procedure:
To a suspension of 4-bromo-5-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 35; 100 mg, 0.25 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.09 ml, 0.49 mmol), HOBT (45.2 mg, 0.30 mmol), 3-aminopyridine (30.1 mg, 0.32 mmol) and EDC (94 mg, 0.49 mmol). The mixture was heated at 50° C. for 5 hours to allow dissolution. The solvent was removed in vacuo and purified by MDAP to yield the title compound as a white solid. 67 mg.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[N:14](CC2C=CC(OC)=CC=2OC)[C@@H:13]1[CH2:28][N:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:30]1=[O:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:15](=[O:16])[NH:14][C@@H:13]1[CH2:28][N:29]1[C:33](=[O:34])[CH2:32][N:31]([C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[C:30]1=[O:42])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2C(=O)CN(C(=O)OC(C)(C)C)C2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)N(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)C1=O
Temperature: 90 °C
Yield: 23.1 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using tert-butyl 3-(((2R,3S)-3-(((benzyloxy)carbonyl)amino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-2-yl)methyl)-2,4-dioxoimidazolidine-1-carboxylate (900 mg, 1.70 mmol) K2S2O8 (280 mg, 2.89 mmol), and K2HPO4 (680 mg, 2.91 mmol) in ACN:water (2:1, 30 mL) while heating at 90° C. for 4 h. After cooling to rt, the mixture was filtered and the filtrate was concentrated in vacuo, removing most of the ACN. The mixture was diluted with water/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 2-6%) to afford the title compound (170 mg, 23%). LCMS: m/z=431.0 (M−1).
Reaction SMILES: [NH3:1].Cl.[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([C:16](Cl)=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]#[N:20])=[CH:6][CH:5]=1>ClCCl>[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][S:9][C:10]2[N:15]=[C:14]([C:16]([NH2:1])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]#[N:20])=[CH:6][CH:5]=1
Reactant: N
Reactant: N#Cc1ccc(C(=O)Cl)nc1SCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(N)=O)nc1SCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
Dry ammonia gas was bubbled through a solution of 6-(4-chlorobenzylthio)-5-cyanopicolinoyl chloride hydrochloride 81 (60 mg, 0.17 mmol) in dichloromethane (10 ml) for 5 min at 0° C. The mixture was stirred for 1 hr at ambient temperature and concentrated in vacuo. The crude product was purified by recrystallization in ether to afford 25 mg (48%) of the desired product 83. 1H NMR (600 MHz, DMSO-d6) δ 8.37 (d, 1H, J=7.8 Hz), 7.84 (d, 1H, J=8.4 Hz), 7.49-7.47 (m, 2H), 7.38-7.37 (m, 2H), 4.74 (s, 2H). MS: m/z Calcd 303.8 Found MH+ 304.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[OH:11].[C:12](=O)([O-])[O-:13].[K+].[K+]>C(OCC)(=O)C>[Cl:8][C:6]1[C:5]([Cl:9])=[C:4]([Cl:10])[C:3]2[O:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1O
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1[nH]c2cc(Cl)c(Cl)c(Cl)c2o1
Yield: 82 %

Procedure:
21.3 g of 2-amino-4,5,6-trichlorophenol, 27.6 g of anhydrous potassium carbonate and 150 ml of ethyl acetate were placed in a 300 ml round-bottom flask and a solution of 9.9 g of diphosgen (trichloromethyl chloroformate) dissolved in 50 ml of ethyl acetate was added dropwise to the mixture with stirring under cooling on ice-water bath. The resulting mixture was heated at reflux temperature for one hour and the reaction solution was then cooled and subjected to suction filtration to remove insoluble salts. The filtrate was concentrated to dryness under reduced pressure to afford yellowish white crystals, which were recrystallized from methanol/acetone to give 19.6 g of 5,6,7-trichlorobenzoxazolone as white crystals with a melting point of 253°-254° C.