Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][C:15]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(=O)C>[C:20]1([CH:17]2[CH2:16][C:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:14]([S:13]([OH:3])(=[O:2])=[O:1])[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C1=C(S)CCC(c2ccccc2)C1
Reactant: O
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC(c2ccccc2)C1
Temperature: 52.5 °C
Reaction time: 3 h

Procedure:
Sodium peroxyborate tetrahydrate (35.2 g) was admixed with acetic acid (200 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-5-phenyl-1-cyclohexene-1-carboxylate synthesized in Reference Example 13 (20 g) in acetic acid (200 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (500 ml) and stirred at room temperature for 1 hour and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (20 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in a mixture of acetonitrile (500 ml) and methanol (500 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (500 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 5-phenyl-2-sulfo-1-cyclohexene-1-carboxylate as a white powder (40.4 g) containing inorganic substances.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]1([CH2:11][NH:12][C:13]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].CN(C)[CH:28]=[O:29]>>[CH:6]1([CH2:11][NH:12][C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH:28]=[O:29])=[CH:20][NH:21]3)=[CH:17][CH:16]=2)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C(NCC1CCCC1)c1ccc2cc[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2cc(C(=O)NCC3CCCC3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
N,N-Dimethylformamide (DMF)(20 ml) was cooled to 0° under an atmosphere of nitrogen and treated cautiously with phosphorus oxychloride (6.6 ml). This solution was stirred at 0° for 15 minutes, warmed to room temperature, and treated with a solution of 6-(N-cyclopentylmethylcarbamoyl)indole (14.3 g) in DMF (100 ml). The yellow mixture was stirred for 2 hours and then brought to pH 14 by the addition of ice and 20% (w/v) aqueous sodium hydroxide. The mixture was heated to reflux for 5 minutes and allowed to cool. The precipitate which formed was collected by filtration and triturated with ether to give 6-(N-cyclopentylmethylcarbamoyl)-3-formylindole (9.6 g, 60%) as a tan powder; mp 224°-225°.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([N:26]([CH2:34][C:35]([F:38])([F:37])[F:36])C(=O)OC(C)(C)C)[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1.[CH:41](=O)[CH3:42].[BH4-].[Na+].CO>C1COCC1>[CH2:41]([NH:1][C@@H:2]1[CH2:6][N:5]([C:7]2[C:11]([NH:12][C:13]([C:15]3[N:16]=[C:17]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:34][C:35]([F:37])([F:36])[F:38])[CH:21]=4)[O:18][CH:19]=3)=[O:14])=[CH:10][N:9]([CH3:39])[N:8]=2)[C:4](=[O:40])[CH2:3]1)[CH3:42]
Reactant: CC=O
Reactant: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2C[C@@H](N)CC2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCN[C@H]1CC(=O)N(c2nn(C)cc2NC(=O)c2coc(-c3ccnc(NCC(F)(F)F)c3)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4-(4-((3-((4S)-4-amino-2-oxopyrrolidin-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-1,3-oxazol-2-yl)pyridin-2-yl)(2,2,2-trifluoroethyl)carbamate (42 mg) in THF (1.0 mL) was added acetaldehyde (37 μL), and the mixture was stirred overnight at room temperature. Sodium borohydride (28 mg) and methanol (0.20 mL) were added thereto, and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in TFA (0.70 mL), and the solution was stirred at room temperature for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/hexane to give the title compound (14 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH:24](OCC)=[O:25]>C1COCC1>[CH:24]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]2=[O:23])=[O:25]
Reactant: CCOC=O
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CNC=O)cc2c1=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A suspension of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (400 mg, 1.14 mmol) in ethyl formate (27.4 mL, 340.7 mmol) and THF (25 mL) was stirred at 60° C. for 16 h. Subsequently the solvent was evaporated and the residue dried in vacuo for 2 h. The crude product was purified by flash-master chromatography (DCM 100-90/MeOH 0-10, %-gradients) to yield N-(6-formylaminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (316 mg, 0.831 mmol, 73%) as a light-yellow solid. 1H-NMR (DMSO-d6, 400 MHz) 3.17 ppm (s, 3H, SO2—CH); LC-MS rt=2.32 min; MS: m/z 380.9 [M+H]+ Column: SunFireC18, 4.6*50 mn, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[C:16]1([CH2:22][S:23](Cl)(=[O:25])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:27]1([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1>>[CH:27]1([C:30]2[CH:36]=[CH:35][C:33]([N:34]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:23]([CH2:22][C:16]5[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=5)(=[O:25])=[O:24])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: Nc1ccc(C2CC2)cc1
Product: O=C1N(c2ccc(C3CC3)cc2)CCC12CCN(S(=O)(=O)Cc1ccccc1)CC2

Procedure:
Light brown solid. MS (ESI): 425.19 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), phenyl-methanesulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][C@@H:7]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:6]2)#[N:2].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[N:2])=[CH:12][CH:11]=2)[CH2:6][C@H:7]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8]1)=[O:28]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2
Product: N#Cc1ccc2c(c1)C[C@H](NS(=O)(=O)c1ccccc1)CN2C(=O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 1G and 3-chlorobenzoyl chloride by procedures analogous to those described in Example 160. HPLC: 100% at 6.3 min(retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O−10% MeOH−0.1% H3PO4 and B=10% H2O−90% MeOH−0.1% H3PO4); Flow rate at 2.5 mL/min, UV detection at 220 nm). MS (ES): m/z 452 [M+1]+. Chiral HPLC 100% e.e.; retention time=50.4 min; Conditions: AD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 70 min at 1 mL/min.
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1.CN(C)C=O.O.ON1C2C=CC=CC=2N=N1>O>[NH:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:2]=[C:3]1[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:27](=[O:28])[CH2:26][C:25](=[O:29])[NH:24][C:23]3[C:30]4[C:35]([CH:36]=[CH:37][C:22]2=3)=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][CH:16]=1)=[O:13]
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CC(=O)N(c2ccc(NC(=O)c3nc4ccccc4[nH]3)cc2)c2ccc3ccccc3c2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.1 %

Procedure:
1H-Benzimidazole-2-carboxylic acid monohydrate (14 mg, 0.077 mmol), 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (23 mg, 0.072 mmol) obtained in Example 1, (3), dimethylformamide (1.4 mL), and 1-hydroxybenzotriazole monohydrate (11 mg, 0.08 mmol) were mixed, and the mixture was stirred at room temperature for 3 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogencarbonate, and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1), and then recrystallized from ethyl acetate/hexane to give the title compound (15 mg, yield 43%) as slightly yellow crystals.
Reaction SMILES: CC(C1C(OC)=C(C(C)(C)C)C=C(P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)[C:18]2[CH:23]=[CH:22][C:21]3OCO[C:20]=3[C:19]=2[C:27]2C3OCOC=3C=[CH:29][C:28]=2P(C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C2C=C(C(C)(C)C)C(OC)=C(C(C)(C)C)C=2)C=1)(C)C.C(=[O:92])C1C=CC=CC=1.C([Si](OC)(OC)OC)=C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.O.CO>[C:19]1([CH:27]([OH:92])[CH:28]=[CH2:29])[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccc3c(c2-c2c(P(c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)c4cc(C(C)(C)C)c(OC)c(C(C)(C)C)c4)ccc4c2OCO4)OCO3)cc1C(C)(C)C
Agent: C=C[Si](OC)(OC)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: C=CC(O)c1ccccc1
Temperature: 25 °C
Yield: 99 %

Procedure:
CuF2.2H2O (3 mg, 0.020 mmol) and (R)-DTBM-SEGPHOS (47 mg. 0.04 mmol) were added to methanol (0.7 mL) under an argon atmosphere, and the mixture was refluxed for 2 hours. Thereafter, the reaction mixture was allowed to stand for cooling to room temperature, and the volatile matter was removed in vacuo. Toluene (0.5 mL) was added to the resulting residue, and the operation for removal of the volatile matter was again carried out twice in vacuo (this catalyst preparation method is designated as “B”; hereinafter the same). The resulting CuF-phosphine complex was dissolved in DMF (1 mL), to which were then added benzaldehyde (67 μL, 0.67 mmol) and vinyltrimethoxysilane (206 μL, 1.34 mmol) at room temperature, and the mixture was stirred at 40° C. for 30 minutes. The reaction mixture was allowed to stand for cooling to room temperature, to which was then added tetrabutylammonium fluoride (TBAF) (1M/THF, 0.5 mL), and the mixture was stirred for 10 minutes. After adding water, the mixture was extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate/hexane: 1/9 to 1/4), thereby obtaining desired 1-phenyl-2-propen-1-ol in a yield of 99%. Its optical purity was measured by HPLC and found to be 94% ee. Furthermore, its absolute configuration was determined in terms of an angle of rotation by comparison with an already reported value. As a result, the product was found to be an (S)-form.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B21, vide infra) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N.J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28].C(N(C(C)C)CC)(C)C>C1COCC1>[C:30]1([O:29][C:27]([N:10]2[C:9]3[C:21]4[C:6]([CH2:7][C:8]=3[C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:11]2)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=4)=[O:28])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)Oc1ccccc1)C2

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (1.5 g g, 4.2 mmol), Phenyl chloroformate (Compound 55a) (0.76 mL, 6.3 mmole) and THF (10 mL) was added Diisopropylethylamine (DIPEA) (1.4 mL, 8.4 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The solvent was dried over sodium sulfate and removed via rotovap to give a crude material (Compound 433). MS m/z 446.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([C:11]2[N:12]([CH3:20])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=[N:7][CH:6]=1)C.[Li+].[OH-]>CO>[NH4+:7].[OH-:3].[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[C:11]1[C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)c1cncc(-c2cc3ccccc3n2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(-c2cncc(C(=O)O)c2)cc2ccccc21
Product: [NH4+]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 0.1 %

Procedure:
To a solution of 5-(1-methyl-1H-indol-2-yl)-nicotinic acid ethyl ester (Example 102, 0.156 g, 0.55 mmol) and MeOH (5 mL) is added aqueous 1M LiOH (1.4 mL, 1.39 mmol). The reaction is stirred at room temperature for 2.5 h. Purification by reverse phase HPLC with Xbridge Shield RP18 column and a 0.1% aqueous NH4OH in acetonitrile gradient gives 5-(1-methyl-1H-indol-2-yl)-nicotinic acid. MS (ESI) m/z 253.34 (M+H)+.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.CN1C(C[N:26]2[C:30]([SH:31])=[N:29][N:28]=[N:27]2)=NN=N1.[C:32](O)(=O)[CH3:33].B(F)(F)F.CCOCC>O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH:5]([S:31][C:30]3[NH:29][N:28]=[N:27][N:26]=3)[CH2:33][C:32]3[N:26]([CH3:30])[N:27]=[N:28][N:29]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cn1nnnc1Cn1nnnc1S
Reactant: CC(=O)O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O
Product: Cn1nnnc1CC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 1.54 g. of 7-aminocephalosporanic acid and 1.0 g. (5 mmole) of 1-(1-methyl-1H-tetrazol-5-ylmethyl)-1H-tetrazol-5-thiol in 7.0 ml. of glacial acetic acid was heated in an oil bath to a temperature of about 65°-70° C. To the hot reaction mixture were added 3.6 ml. of boron trifluoride etherate, and the reaction mixture was heated at a temperature of 65°-70° C. for one hour with stirring. The reaction mixture was then cooled to room temperature and 10 ml. of water were added. The reaction mixture was stirred for 15 minutes after water addition, was filtered, and then chilled in an ice bath. The pH of the cold mixture was adjusted to pH 4.5 with concentrated ammonium hydroxide. The precipitate which formed was filtered, washed repeatedly with water, with acetone, and finally with diethyl ether. The off-white solid product was vacuum dried for one hour at 40° C. There was obtained 1.5 g. (80% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O>CC(C)=O>[F:30][C:29]([F:32])([F:31])[CH2:28][O:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(O)c1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1cccc(OCC(F)(F)F)c1
Temperature: 50 °C
Yield: 97 %

Procedure:
To a stirred solution of tert-butyl 3-hydroxyphenylcarbamate (2 g, 9.56 mmol) in acetone (38 mL) were added potassium carbonate (6.61 g, 47.8 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.07 mL, 14.34 mmol). The reaction mixture was heated at 50° C. overnight, cooled and filtered. The filtrate was concentrated, and the residue was dissolved in CH2Cl2, washed with brine, dried over anhydrous sodium sulfate and concentrated to yield the title compound (2.7 g, 97% yield). MS (ES): m/z=314.25 [M+Na]+.
Reaction SMILES: CC([O:4]C(/N=N/C(OC(C)C)=O)=O)C.OCCC1N=CSC=1C.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:37]1([P:30](=[O:4])([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cc1scnc1CCO
Solvent: C1CCOC1
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
DIAD (3.16 ml, 16.1 mM) was added to a stirred solution of methyl 3-nitro-5-hydroxy benzoate (2.11 g, 10.7 mM), 4-(2-hydroxy ethyl)-5-methylthiazole (1.55 ml, 12.8 mM), and triphenylphosphine (4.21 g, 16.1 mM) in THF (50 ml) under an argon atmosphere at room temperature. After 1 hr reaction mixture concentrated in vacuo, residue triturated with diethyl ether to give a colourless solid (triphenylphosphine oxide). Diethyl ether conc. to give a dark brown gum, purification on silica gel (50% to 75% EtOAc/iso-hexane) gave the product contaminated with reduced DIAD and triphenylphosphine oxide (6.8 g). The crude product was dissolved/suspended in MeOH (80 ml), 2M NaOH (20 ml, 40 mM) added, heated at 65° C. for 4 hrs then cooled and concentrated. The residue was diluted with water (140 ml)/2M NaOH (40 ml), the precipitated triphenylphosphine oxide filtered, then acidified with c. HCl to pH 1-2. The precipitate was filtered, washed with water, dried under high-vacuum to give 3-{2-(4-methyl thiazol-5-yl)ethoxy}-5-nitro benzoic acid as a colourless solid (3.12 g, 79% over 2 steps); 1H NMR δ (d6-DMSO): 2.39 (s, 3H), 3.23 (t, 2H), 4.35 (t, 2H), 7.78 (s, 1H), 7.90 (m, 1H), 8.22 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[O:26]=[S:27]1(=[O:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CO>[O:26]=[S:27]1(=[O:33])[CH2:32][CH2:31][N:30]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: O=S1(=O)CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCS(=O)(=O)CC3)n2n1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 110 mg, 0.319 mmol), S,S-dioxidothiomorpholine hydrochloride (164 mg, 0.957 mmol) and N,N-diisopropylethylamine (181 mg, 1.40 mmol) in DMF (1.28 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with methanol, and was then purified by preparatory HPLC (20-30% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (52.4 mg, 37%). 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.00 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 6.21 (s, 1H), 4.25 (br. s., 4H), 3.41 (br. s., 4H), 2.39 (s, 3H), 1.45 (s, 6H); ESI-MS: m/z 444.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][C:58]=1[O:59][CH3:60])CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][C:56]2[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[C:58]([O:59][CH3:60])[CH:57]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(COC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1OC
Temperature: 25 °C
Yield: 51 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (83 mg) was added to toluene/triethylamine=10/1 (9 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (147 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3,4-dimethoxybenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 48%).