Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]1([S:44]([NH2:47])(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH3:25][C:9]1([CH3:24])[CH2:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[NH:11][CH:10]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:47][S:44]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)(=[O:46])=[O:45])[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)c3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 119.7 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)-benzoic acid (150 mg, 0.44 mmol, 1.0 eq.) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol, 3.0 eq.) in tetrahydrofuran (3 mL) was heated to 60° C. for 2 h, then was cooled to room temperature and treated with benzenesulfonamide (89.6 mg, 0.57 mmol, 1.3 eq.). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol, 3.3 eq.) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred overnight. Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 252 mg of methyl 3,3-dimethyl-2-(3-(phenylsulfonylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was pure enough for next step without further purification. MS (ESI+APCI) M+1=479.2.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7]C(=O)[CH2:5][CH2:4]1.[CH:10](OC)([O:13][CH3:14])[O:11][CH3:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:12][O:11][C:10]1([O:13][CH3:14])[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: COC(OC)OC
Reactant: O=C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC1(OC)CCNCC1
Reaction time: 24 h

Procedure:
Into 3.26 ml of methanol were dissolved 0.10 g of 4-piperidone hydrochloride monohydrate, 0.36 ml of trimethyl orthoformate and 5 mg of p-toluenesulfonic acid monohydrate, and the reaction was conducted at room temperature for 24 hours. The reaction mixture was evaporated under reduced pressure to remove the solvent. The residue was dissolved into 1 ml of N,N-dimethylacetamide and admixed with 1.5 ml of triethylamine to give a solution of 4,4-dimethoxypiperidine.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]([C:13]([O:15]C)=[O:14])=[CH:3]1.Cl>[OH-].[Na+]>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]([C:13]([OH:15])=[O:14])=[CH:3]1
Reactant: COC(=O)c1cc(=O)n(-c2ccccc2)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Yield: 55.1 %

Procedure:
Methyl 5-oxo-1-phenyl-2,5-dihydro-1H-pyrazole-3-carboxylate (0.35 g; 1.60 mmol) in 5 ml of 2M NaOH solution was heated at 60° C. for 2 h after which the reaction mixture was made acidic with 1.5 ml of concentrated HCl which caused the product to form a yellow precipitate. Filtering gave 0.18 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 5.97 (s, 1H), 7.33-7.37 (m, 1H), 7.48-7.52 (m, 2H), 7.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1
Reactant: Clc1ncnc2cc(Br)ccc12
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ncnc3cc(Br)ccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
226.0 g (01.64 mol) of 4-methoxybenzyl alcohol in 0.5 l of toluene were added dropwise to a suspension of 80.0 g (2.0 mol) of sodium hydride [60% in paraffin oil] in 3.0 l of toluene between 15° C. and 20° C. The mixture was subsequently stirred at room temperature for a further 1 h. 165.9 g (1.64 mol) of 7-bromo-4-chloroquinazoline were then added in portions, and the reaction mixture was stirred for 48 h. Conventional work-up gave 194.8 g of 7-bromo-4-(4-methoxybenzyloxy)quinazoline as solid.
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=[O:11])[C:4](=[O:5])[CH:3]=1.N1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:10]([CH:6]1[C:4](=[O:5])[CH:3]=[C:2]([CH3:1])[O:9][C:7]1=[O:8])(=[O:11])[CH:12]=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:1][CH2:2][CH2:3][CH2:4][CH3:6]
Reactant: C1CCNCC1
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC=CC(=O)C1C(=O)C=C(C)OC1=O
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 30.2 g (0.18 mole) of dehydroacetic acid and 30.0 g (0.19 mole) of decyl aldehyde in 300 ml of chloroform was added dropwise 4.8 g of piperidine at room temperature. The mixture was refluxed for 7 hours, while removing the water formed on the reaction with the aid of a Soxhlet extractor charged with anhydrous sodium sulfate. After the reaction, the reaction mixture was extracted with 600 ml of chloroform. The organic layer was separated, washed with 2N HCl and then with water, and dried over anhydrous sodium sulfate. The extract was concentrated under a reduced pressure and 60 ml of ether/hexane (1/2) was added to the residue. The mixture was allowed to stand overnight. The precipitated crystal was recovered by filtration and recrystallized from tetrahydrofuran to obtain 9.5 g (yield: 17%) of 3-(2-dodecenoyl)-6-methyl-2H-pyran-2,4(3H)-dione in the form of a white crystal, m.p. 112°-113° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[O:18])[CH2:13][CH2:12]2)[N:3]=1.[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(O)C.Cl>[CH3:9][NH:8][C:6]1[CH:7]=[C:2]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:29])([F:28])[F:30])=[O:18])[CH2:13][CH2:12]2)[N:5]=1
Reactant: NCc1ccccc1
Reactant: CNc1cc(Cl)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Agent: Cl
Solvent: CC(C)O
Product: CNc1cc(NCc2ccccc2)nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)n1

Procedure:
To a solution of cis-4-{[4-chloro-6-(methylamino)-2-pyrimidinyl]amino}-N-{[2-(trifluoromethyl)phenyl]methyl}cyclohexanecarboxamide (50.0 mg, 0.11 mmol) and benzylamine (59.0 mg, 0.55 mmol) in 2-propanol (3 mL) was added one drop of concentrated HCl. The mixture was irradiated in the microwave for 3 hours at 170° C., at which time LCMS indicated the formation of the desired product. The crude reaction mixture was filtered and purified directly by preparative HPLC (gradient; 30-80% CH3CN:H2O (0.1% TFA)), to afford the title compound (30 mg, 0.58 mmol, 52%). MS (ES+) m/e 513 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[NH:9][C:8]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[S:6]1(=[O:19])=[O:18].[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)CC)C.O>CN(C=O)C>[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:10](=[O:11])[NH:9][C:8]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=3[S:6]2(=[O:19])=[O:18])[CH2:28][CH2:27]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: COc1ccc2c(c1)S(=O)(=O)N(CCCBr)C(=O)N2
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)S(=O)(=O)N(CCCN1CCN(c3ncccn3)CC1)C(=O)N2
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
0.01 mol of 2-(3-bromopropyl)-7-methoxy-1,2,4-benzothiadiazin-3(4H)one 1,1-dioxide, 0.012 mol of 1-(2-pyrimidinyl)piperazine and 0.01 mol of triethylamine are dissolved in 30 ml of DMF and the solution is heated at 60° C., with stirring, for 1.5 hours. Then 15 ml of water are added and the reaction mixture is cooled to 0° C. The substance which crystallises out during this is filtered off with suction, stirred with isopropanol, again filtered off with suction and dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: O=C(NCc1ccccc1)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6z (95% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and benzyl isocyanate as a white solid. IR(CHCl3) 3289, 1713, 1536 cm−1; 1H-NMR (CDCl3) δ4.63 (d, J=5.8 Hz, 2H), 7.22-7.40 (m, 6H), 7.58 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 9.15 (br s, 1H); ESIMS m/e 319 and 321 (M++1, 35Cl and 37Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:7]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])[CH3:6])=[O:4].Cl.N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+]>O.CCOCC>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:16](=[O:20])[CH2:17][O:18][CH3:19])[C:8]1[C:13]([N:14]=[N+:26]=[N-:27])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15])[CH3:6])=[O:4]
Reactant: COCC(=O)N(c1c(C)cccc1N)C(C)C(=O)OC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COCC(=O)N(c1c(C)cccc1N=[N+]=[N-])C(C)C(=O)OC
Temperature: 0 °C

Procedure:
10.0 g of N-(1'-methoxycarbonyl-ethyl)-N-methoxyacetyl-2-methyl-6-aminoaniline were strirred up with 75 g of ice and 15 ml of conc. hydrochloric acid at 0° to 5° C. until a clear solution was formed. At 0° to 5° C. where then added dropwise, within 10 minutes, 2.5 g of sodium nitrite dissolved in 10 ml of water. The reddish-brown solution was stirred for a further 30 minutes at the above temperature, and 100 ml of ether were subsequently added. There was thereupon added dropwise at 0° to 5° C., within 15 minutes, a solution of 2.5 g of sodium azide in 10 ml of water, and the temperature was allowed to rise in the course of 30 minutes to room temperature. The reaction mixture was extracted with ether; the organic phase was then washed with sodium hydrogen carbonate/water, dried with magnesium sulfate, and the solvent was evaporated off. The resulting oil was dried at 40° C. in vacuo; nD26 : 1.5396. nD28.5 : 1.5389.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:16])=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:17]([O:19][C:20]1[C:21](=O)[C:22](=[O:27])[C:23]=1[O:24]CC)[CH3:18]>C(O)C>[CH2:17]([O:19][C:20]1[C:23](=[O:24])[C:22](=[O:27])[C:21]=1[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([N:10]2[CH2:14][CH2:13][C@@H:12]([OH:15])[CH2:11]2)=[O:9])[C:3]=1[OH:16])[CH3:18]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccc(C(=O)N2CC[C@@H](O)C2)c1O
Solvent: CCO
Product: CCOc1c(Nc2cccc(C(=O)N3CC[C@@H](O)C3)c2O)c(=O)c1=O
Temperature: 60 °C
Yield: 66.2 %

Procedure:
A mixture of 3.63 g (16 mmol, 1 eq) of (3-amino-2-hydroxyphenyl)-((R)-3-hydroxypyrrolidin-1-yl)methanone and 3.40 g (20 mmol, 1.2 eq) of 3,4-diethoxy-3-cyclobutene-1,2-dione in 70 ml of ethanol was heated at 60° C. for 16 hours. The reaction medium was filtered and the filtrate was chromatographed on silica gel (column puriFlash IR-50SI-300G, Spot II with solid deposition) eluted with dichloromethane/methanol (gradient). 3.67 g of 3-ethoxy-4-[2-hydroxy-3-((R)-3-hydroxypyrrolidine-1-carbonyl)phenylamino]cyclobut-3-ene-1,2-dione were obtained in the form of a beige solid. Yield=66%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=2)/[C:8]([OH:10])=[O:9])[N:6]=1.C1(N=C=NC2CCCCC2)CCCCC1.O[N:54]1[C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=2[N:56]=[N:55]1>O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH:13]([C:22]([O:24][CH:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([OH:21])[CH:15]=2)/[C:8]([O:10][N:54]2[C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=3[N:56]=[N:55]2)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)O)cs1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Nc1nc(/C(=N/OC(C(=O)OC(c2ccccc2)c2ccccc2)c2ccc(O)c(O)c2)C(=O)On2nnc3ccccc32)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
A mixture of 2-(2-aminothiazol-4-yl)-2-(Z)-[diphenylmethyloxycarbonyl(3,4-dihydroxyphenyl)methyl]oxyiminoacetic acid (IIa) (779 mg, 1.5 mmol) [for the preparation of compound IIa see: Japan Kokai 88-99078 published 4/30/88], dicyclohexylcarbodiimide (DCC, 352 mg, 1.71 mmol), N-hydroxybenzotriazole (261 mg, 1.71 mmol) in tetrahydrofuran (THF) (6 ml) was stirred at room temperature for 1 hr and the resulting precipitate was filtered off. The filtrate was concentrated under reduced pressure to provide 1.00 gram (100%) of the activated ester IIIa.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21].[OH-].[Li+]>CO>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CCCCCOc1ccc2c(c1)[nH]c1ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCCOc1ccc2c(c1)[nH]c1ccccc12
Yield: 96.7 %

Procedure:
Ethyl 6-(9H-carbazol-2-yloxy)-hexanoate (270 mg, 0.8 mmol) and 1 N aqueous lithium hydroxide (2 ml, 2 mmol) in 15 ml methanol was heated to reflux for 1h. The solvent was removed, the residue was acidified by 1 ml 2N aqueous hydrochloric acid. The precipitate was collected to give 6-(9H-carbazol-2-yloxy)-hexanoic acid (230 mg, 93%) as a colorless solid. MS (M−H+)296.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:7]=2[CH:15]=1.[Cl:16][CH2:17][CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([NH:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][Cl:16])=[CH:26][CH:25]=3)=[N:8][C:7]=2[CH:15]=1
Reactant: COc1ccc2sc(S(C)(=O)=O)nc2c1
Reactant: Nc1ccc(OCCCl)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2sc(Nc3ccc(OCCCl)cc3)nc2c1
Reaction time: 2 h

Procedure:
A mixture of 5-methoxy-2-methylsulphonylbenzothiazole (1,105 g.), 4-(2-chloroethoxy)aniline (780 g.) and toluene (5 liters) is boiled for 2 hours under reflux with simultaneous removal of water. A further quantity of 4-(2-chloroethoxy)aniline (156 g.) is then added and the mixture boiled under reflux for 4 hours. The mixture is cooled, the solid filtered off, washed with ethanol (about 3 liters) and dried to give 5-methoxy-2-[4-(2-chloroethoxy)anilino]benzothiazole m.p. 176°- 178°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a 0° C. solution of 4-(4-bromophenyl)phenol (1.0 g, 4.0 mmol) and pyridine (0.65 mL, 8 mmol) in CH2Cl2 (20 mL) was added chloro-tert-butyldimethylsilane (0.72 g, 4.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 days, then diluted with water and extracted with CH2Cl2. The organic layer was washed with a 2N HCl solution, a 1N KOH solution, dried (MgSO4) and concentrated under reduced pressure to yield 1-(4-bromophenyl)-4-tert-butyldimethylsilyloxybenzene (0.89 g, 61%) as a white solid: TLC (33% EtOAc/hex) Rf 0.57.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCCCCCC>CC(C)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([OH:25])=[O:24])=[C:14]([CH:17]([O:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC(=O)OC(C)C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: CC(C)=O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC(C)C1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Temperature: 5 °C
Yield: 40.5 %

Procedure:
To a cooled (5° C.), stirred solution of 0.328 g. of benzhydryl 7-(2-thienylacetamido)-3-(1-acetoxyethyl)-3-cephem-4-carboxylate in 1 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. The reaction mixture was allowed to stir with cooling for 20 minutes after which time was added 30 ml. of n-heptane. The reaction mixture was evaporated in vacuo to a low volume, 20 ml. of n-heptane was added, and the resulting mixture was stirred with cooling for five minutes. The solid obtained by filtration of the resulting solution was dissolved in acetone, and the acetone solution was then filtered and evaporated to near dryness. The residue was dissolved in ethyl acetate, and the resulting solution was extracted three times with cold aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with ethyl acetate, and acidified with 1N.HCl. The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave 94 mg. (40.5 percent) of the title product:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[N:10]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:42](=[O:43])[CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[O:34][CH3:33])[CH2:15][CH2:14]3)[N:10]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Fc1ccc(-c2nc(C3CCNCC3)n(-c3ncccn3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CCC(c2nc(-c3ccc(F)cc3)nn2-c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of INTERMEDIATE 9 HCl salt (15.0 mg, 0.035 mmol) and triethylamine (22.9 mg, 0.23 mmol) in DMF (0.25 ml) was added (2-methoxyphenyl)acetic acid (7.8 mg, 0.045 mmol), followed by addition of HATU (17.2 mg, 0.045 mmol). After stirring at ambient temperature for 1.5 hour, the reaction mixture was quenched with 2 mL of a mixture of 1,4-dioxane and water (1:1). The mixture was purified by RP-HPLC (10 to 100% ACN/Water, both containing 0.1% TEA) to give the title compound as a white powder after lyophilization. LC-MS (m/z): 473.11 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=[O:6].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>O1CCCC1>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[O:11][CH3:12])[C:5]([NH2:7])=[O:6])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: COc1ccc(C(N)=O)cc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Solvent: C1CCOC1
Product: COc1ccc(C(N)=O)cc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
3-Amino-4-methoxy-benzamide (1.00 g, 0.00602 mol) in tetrahydrofuran (40 mL) was treated with 2,4,5-trichloro-pyrimidine (0.8278 mL, 0.007221 mol), and the reaction was stirred overnight at room temperature, then for 4 hours at 50° C. The mixture was partitioned between water and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The organics were dried (MgSO4) and concentrated, and the product was isolated by chromatography (Silica, MeOH/dichloromethane 0-3%), followed by crystallization from methanol to give 3-(2,5-dichloro-pyrimidin-4-ylamino)-4-methoxy-benzamide as a white solid (1.26 g, 64%). LC/MS (ESI+): 313.04 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(OCC)(=O)C.[C:21](O)([CH3:24])([CH3:23])[CH3:22]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(O)c([N+](=O)[O-])c1
Reaction time: 24 h
Yield: 22 %

Procedure:
0-t-Butyl-N,N-diisopropyl-isourea (3.65 gm, 20 mmol) was added to a solution of 4-hydroxy-3-nitrobenzene-acetic acid (3.61 gm, 18.3 mmol) in t-butanol (18 mL) and stirred for 24 hours. Ethyl acetate (100 mL) was added and the solution washed successively with water 3×25 mL), 1N sodium bicarbonate solution 3×25 mL), and saturated salt solution (25 mL). The product was isolated as a yellow oil (1.02 gm, 22% yield) and used without further purification: 1H-NMR δ (CDCl3) 1.44 (9H, s), 3.52 (2H, s), 7.08 (2H, d, J=8 Hz), 7.51 (1H, dd, J=8, 3 Hz), 8.00 (1H, d, J=3 Hz).