Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12](O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.CC(=O)OCC>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(C2CC=Cc3ccccc32)cc1Cl
Temperature: 100 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
To a solution of the crude alcohol 2 (53 g) in toluene (500 mL) was added silica gel coated with sulfuric acid (3%, 14 g). The mixture was heated to 100° C. and monitored by TLC (prod Rf (25 EA/hex)=0.58). After three hours, the mixture was filtered. The organic phase was washed with water and sodium bicarbonate solution, dried (Na2SO4), and evaporated to give the alkene 3 (42 g, 84%) as a pale-brown solid. TLC Rf (25 EA/hex)=0.58. GC-MS Rt=13.55 min, m/z=274 (M+). 1H NMR (CDCl3, δ): 7.4-6.7 (m, 7H), 6.54 (d, J=9.6 Hz, 1H), 6.0 (m, 1H), 4.08 (t, J=8.0 Hz, 1H), 2.7 (m, 1H), 2.5 (m, 1H). 13C NMR (CDCl3, δ, mult): 143.6, 136.3, 133.8, 132.2, 130.2, 130.2, 128.1, 127.7, 127.2, 126.4, 129.7, 127.4, 42.8(1), 31.6(2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[NH:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[N+:21]([O-])=O)=[O:8])=[CH:5][CH:4]=1.C1COCC1.O.O.[Sn](Cl)Cl.C([O-])(=O)C.[NH4+]>CCOC(C)=O.O.CO>[NH2:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[NH:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)Nc2cc(-c3ccc[nH]3)ccc2[N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl[Sn]Cl
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C(=O)Nc2cc(-c3ccc[nH]3)ccc2N)cc1
Temperature: 55 °C
Yield: 12 %

Procedure:
A solution of nitro compound 146 (0.1326 g, 0.39 mmol) in a 8.5:5:1 mixture of THF:MeOH:H2O (14.5 mL) was treated with tin(II) chloride dihydrate (0.602 g, 2.67 mmol) and ammonium acetate (0.818 g, 10.6 mmol) then heated to 55° C. for 60 min. The reaction mixture was cooled to room temperature, diluted with AcOEt, washed with 5% KHSO4, saturated NaHCO3, brine, dried over MgSO4, filtered and concentrated. The title compound 147 was obtained after purification by chromatotron (14.7 mg, 12% yield, eluent: 50% AcOEt in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:13]([CH2:14]O)=[CH:12][CH:11]=[CH:10][N:9]=1.[CH2:33]([N:35](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>O.CS(C)=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:13]([CH2:14][C:33]#[N:35])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: COc1cc(COc2ncccc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(COc2ncccc2CC#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a mixture of [2-[-3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol (540 mg), triethylamine (0.350 mL) and ethyl acetate (50 mL) was dropwise added methanesulfonyl chloride (0.145 mL) under ice-cooling and the mixture was stirred at room temperature for 0.5 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give an oil. To a mixture of this oil and dimethyl sulfoxide (10 mL) was added a solution of sodium cyanide (160 mg) in water (1 mL) at room temperature and the mixture was stirred at room temperature for 2 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from ethyl acetate-hexane to give crystals (438 mg, 79%) of 2-[2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile. melting point: 108-109° C.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20]C)=[CH:4][C:5]2[CH2:6][CH2:7][C@H:8]3[C@H:16]4[C@@H:12]([C@@H:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:18]=2[CH:19]=1.CC(C[AlH]CC(C)C)C.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[CH2:6][CH2:7][C@H:8]3[C@H:16]4[C@@H:12]([CH:13]([OH:17])[CH2:14][CH2:15]4)[CH2:11][CH2:10][C@@H:9]3[C:18]=2[CH:19]=1
Reactant: COc1cc2c(cc1F)[C@H]1CC[C@H]3[C@@H](CC[C@@H]3O)[C@@H]1CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cc2c(cc1F)[C@H]1CC[C@@H]3C(O)CC[C@H]3[C@@H]1CC2

Procedure:
The solution of 0.53 g of 2-fluoro-3-methoxy-gona-1,3,5(10)-trien-17β-ol in 50 ml of toluene is mixed with 5 ml of 20% solution of DIBAH in toluene and heated for 2 hours to 80° C. After cooling, water is added drop by drop until the reaction has run its course, then it is dispersed between water and ethyl acetate, the ethyl acetate phase is washed with concentrated common salt solution and dried with sodium sulfate. After evaporation, a residue remains that is chromatographed on silica gel with hexane-ethyl acetate, and the yield is 0.32 g (63% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:32])[O:26][C@H:27]3[CH2:31][CH2:30][O:29][CH2:28]3)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=2)[N:10]=1.CCOCC.C(Cl)[Cl:40]>>[ClH:40].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[N:18]=[C:17]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:32])[O:26][C@H:27]3[CH2:31][CH2:30][O:29][CH2:28]3)[CH2:20]2)[C:16]2[C:11](=[CH:12][C:13]([CH3:33])=[CH:14][CH:15]=2)[N:10]=1
Reactant: ClCCl
Agent: Cc1ccc2c(N3CC[C@@H](NC(=O)O[C@H]4CCOC4)C3)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCOCC
Product: Cl
Reaction time: 0.5 h

Procedure:
To a solution of (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (160 mg, 0.35 mmol) in 2 mL CH2Cl2 was added 2 M HCL solution in ether (0.176 mL, 0.35 mmol) resulting in precipitation of a solid. After the addition of 10 mL ether, the reaction was stirred for 30 minutes, filtered and the resulting solid was dried to obtain (S)-tetrahydrofuran-3-yl (R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate hydrochloride (130 mg, 76%)). LC/MS: m/z 453.3 (M+H)+ at 2.13 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.57 (s, 2H), 7.43-7.49 (m, 1H), 6.83-6.89 (m, 2H), 5.08 (s, 1H), 4.23-4.42 (m, 4H), 3.62-3.73 (m, 5H), 2.24-2.34 (m, 1H), 2.04-2.11 (m, 2H), 1.86-1.92 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:35])[C:15](=N)[CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2.[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].[OH-].[Na+].ClCCl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:35])[CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCC(=N)N(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Reaction time: 8 h
Yield: 102.8 %

Procedure:
1 g of the product obtained in Step 1 (containing 46% amidine) is dissolved in 15 mL of methanol and then 86 mg (2.26 mmol, 1.2 equivalents) of sodium tetraborohydride are added at ambient temperature. Stirring is carried out overnight at ambient temperature, and then 5 mL of 20% aqueous sodium hydroxide solution and 20 mL of dichloromethane are added. Vigorous stirring is carried out for 15 minutes. The organic phase is then extracted, washed with water, dried over MgSO4, filtered and then evaporated to dryness. There is obtained 1 g of an oil which is purified by flash chromatography on 100 g of silica (eluant=dichloromethane/ethanol/NH4OH: 90/10/1) to yield 210 mg of the title product in the form of an oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[N:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:33].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>C1COCC1>[CH3:34][N:35]1[CH2:36][CH2:37][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH:47][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]6[N:24]([C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=[C:26]([CH3:28])[CH:27]=6)=[O:22])=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:33])=[CH:43][CH:42]=2)[CH2:39][CH2:40]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)cc2)n(C(C)(C)C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2ccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)cc2)n(C(C)(C)C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
A small screw cap test tube was charged with 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 65, 100 mg, 0.225 mmol) and THF (2 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47 mg, 0.25 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 42% (59 mg, 0.0955 mmol) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:18])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([Si](C)(C)C)=[CH:8]2>CC#N>[CH3:1][NH:2][C:3](=[O:18])[CH2:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2
Reactant: CNC(=O)Cc1ccc2[nH]c([Si](C)(C)C)cc2c1
Solvent: CC#N
Product: CNC(=O)Cc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
N-Methyl-2-(trimethylsilyl)-1H-indole-5-acetamide (8) (2.5 g, 0.00961 mol) was dissolved in CH3CN (50 mL) and HF (1.9 g of a 50% aqueous solution, 0.048 mol) was added. The mixture was stirred at RT for 1.5 h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. The organic phase was extracted with saturated aqueous NaHCO3 and then with brine, dried over MgSO4, filtered and evaporated in vacuo. Silica gel chromatography (10-100% EtOAc gradient in hexane) of the concentrate afforded the product (0.86 g, 47.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:38]=[C:37]([NH:39][S:40]([NH2:43])(=[O:42])=[O:41])[CH:36]=[C:35]5[C:31]=4[CH:32]=[CH:33][NH:34]5)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(N)(=O)=O)cc5[nH]ccc35)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(NS(N)(=O)=O)cc6[nH]ccc56)c34)n(-c3ccccc3)c(=O)c12
Yield: 80 %

Procedure:
N-[4-(4-{[(1S)-1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-1H-indol-6-yl]sulfamide (48 mg, 0.06 mmol) was treated with trifluoroacetic acid (1.0 ml, 12.98 mmol) and a solution of ammonia (7N in methanol, 5.0 ml, 35.0 mmol) according to the method described in Example 27. The title compound was obtained (33 mg, 80% yield) without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[C:4]([OH:11])[CH:3]=1.[CH2:12]([O:14][C:15](=[O:21])[C:16](OCC)=O)[CH3:13].[O-]CC.[Na+]>C(O)C.CCOCC>[C:15]([C:16]1[O:11][C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8](=[O:9])[CH:10]=1)([O:14][CH2:12][CH3:13])=[O:21]
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(C)cc2o1
Temperature: 0 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of 10.7g (71.25 mmoles) of 2-hydroxy-4-methylacetophenone and 31.24g (214 mmoles) of diethyloxalate in 25 ml of ethanol is added dropwise to a solution of sodium ethoxide (formed by adding 6.55g of sodium metal to 120 ml of ethanol). The mixture is refluxed for 4 hours, cooled to 0° C. and diluted with 500 ml of ether. The precipitate which forms on standing overnight is filtered off and redissolved in water and the solution acidified (pH approximately 1) with 1N hydrochloric acid. The mixture is extracted with ethyl acetate which is dried and concentrated in vacuo. The residue is dissolved in 100 ml of ethanol and 3 ml of concentrated hydrochloric acid. This solution is refluxed for 1.5 hours, then concentrated in vacuo. The residue is poured into ice water and the precipitate which formed on standing overnight is filtered off and dissolved in ethyl acetate. The ethyl acetate solution is dried and concentrated in vacuo. The residue is purified by flash column chromatography through silica gel and recrystallization from ether/hexanes to give 8.75g of 2-carboethoxy-7-methyl-4-oxo-4H-1-benzopyran as a white crystalline solid having an m.p. of 62°-4° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C(=O)C)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([C:22]2([C:28](=[O:30])[CH3:29])C=CC=CC2)CCCC[CH:17]=1>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[C:28]([OH:30])([CH:22]=[C:16]=[CH2:17])[CH3:29]
Reactant: CC(=O)C1(C2=CCCCC2)C=CC=CC1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Product: C=C=CC(C)(O)c1ccccc1-c1ccccc1

Procedure:
When Example 1 is repeated using p-phenyl-acetophenone and 1'-cyclohexenyl acetophenone in place of the p-tert butylbenzaldehyde, there is obtained 2-(p-biphenylyl)-3,4-pentadien-2-ol m.p. 65° to 66°, and 2-(p-1'-cyclohexenylphenyl)-3,4-pentadien-2-ol, respectively.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[CH3:12][O:13]S(OC)(=O)=O.[OH-].[Na+]>CO.O>[CH3:1][C:2]1[C:3]([CH2:12][OH:13])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COS(=O)(=O)OC
Reactant: COc1c(C)c[n+]([O-])cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(C)cnc(CO)c1C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
3.5-Dimethyl-4-methoxypyridine-N-oxide (61.2 g) obtained in Example 2 was dissolved in CH3OH (458 ml). Dimethylsulfate (38 ml 0.4 moles) was added dropwise during 15 minutes and pH adjusted to 5.0 using 10M NaOH. The mixture was stirred for 15 minutes and thereafter refluxed for 1 hour. An additional amount of dimethylsulfate (3.8 ml, 0.04 moles) was added dropwise and the mixture was refluxed for 1.5 hours. Stirring was continued overnight at room temperature. Thereafter the mixture was heated to reflux and (NH4)2S2O8 (91.2 g, 0.4 moles) dissolved in water (169 ml) was added during 1.75 hours, followed by refluxing for 1.5 hours and stirring at room temperature overnight. Thereafter CH3OH (452 ml) was added. Precipitated salts were filtered off and discarded. After evaporation of CH3OH, the remaining water phase (pH 0.6) was adjusted to pH 10.0 using 10M NaOH (145 ml). The water phase was extracted three times with CH2Cl2. The combined CH2Cl2 phases were dried over Na2SO4, evaporated and dried, yielding 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine (44.2 g). The identity of the product was confirmed with 1H and 13C NMR and the purity checked with gas chromatography.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:24][N:23]([C:25]3[CH:30]=[C:29]([CH:31]([CH3:33])[CH3:32])[CH:28]=[CH:27][C:26]=3[CH3:34])[CH2:22][CH2:21][C:4]=2[N:5]=[C:6]([C:8]2[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:20])=[N:11][N:12]3C=O)[N:7]=1.[F:35][CH2:36][CH2:37][OH:38].[H-].[Na+]>C1COCC1>[CH3:20][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[C:6]2[N:7]=[C:2]([O:38][CH2:37][CH2:36][F:35])[C:3]3[CH2:24][N:23]([C:25]4[CH:30]=[C:29]([CH:31]([CH3:32])[CH3:33])[CH:28]=[CH:27][C:26]=4[CH3:34])[CH2:22][CH2:21][C:4]=3[N:5]=2)[NH:12][N:11]=1
Reactant: OCCF
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4c3c(C)nn4C=O)nc(Cl)c2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)ccc4[nH]nc(C)c34)nc(OCCF)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-chloro-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)-3,5-dimethyl-1H-indazole-1-carbaldehyde (30 mg, 0.063 mmol) in THF (3 mL) was added 2-fluoroethanol (16.2 mg, 0.25 mmol) and NaH (15.1 mg, 0.63 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 4 h. LC-MS showed reaction complete. The reaction mixture was concentrated and the residue was partitioned between saturated aqueous NH4Cl solution and DCM. The layers were separated and the aqueous layer was extracted further with DCM. The organics were combined and concentrated. The residue was purified by FCC (0-100% EtOAc/heptane) to provide 2-(3,5-dimethyl-1H-indazol-4-yl)-4-(2-fluoroethoxy)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.47 (d, J=8.59 Hz, 1H), 7.34 (s, 1H), 7.15 (d, J=7.71 Hz, 1H), 7.06 (d, J=1.39 Hz, 1H), 6.92 (dd, J=1.52, 7.71 Hz, 1H), 4.71-4.81 (m, 2H), 4.67 (s, 2H), 4.13 (s, 2H), 3.33-3.39 (m, 2H), 3.05 (t, J=5.56 Hz, 2H), 2.88 (td, J=6.93, 13.80 Hz, 1H), 2.32 (s, 3H), 2.27 (s, 3H), 1.98 (s, 3H), 1.25 (d, J=6.82 Hz, 6H); MS (ESE) m/z 474.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH2:13])(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(N)(=O)=O)c1
Yield: 100.2 %

Procedure:
A solution of 1.5 g (7.42 mmol) of 3-nitrobenzenesulfonamide in 50 ml of EtOH containing 150 mg of 10% palladium on carbon was placed on a Parr hydrogenator under H2 for 1 h. The reaction was filtered through a pad of celite washing with EtOH, and the filtrate was concentrated in vacuo to give 1.28 g (100%) of 3-aminobenzenesulfonamide which was used immediately in the next reaction. The tide compound was prepared as in example 21 from 3-aminobenzenesulfonamide using intermediate C. Recrystallization from MeOH/Et2O provided 1.46 g (67%) of title compound as an off-white solid: mp 240°-242° C.; 1H NMR (D2O, 300 MHz) δ 7.86 (d, 1 H, J=8.1 Hz), 7.75 (s, 1 H), 7.63 (t, 1 H, J=8.1 Hz), 7.51 (d, 1 H, J=8.1 Hz), 2.30 (s, 3 H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C@@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC[C@H](O)CC(=O)OC
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (104 mg, 97%), MS (ISP) m/z=431.5 [(M+H)+], mp 217° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (S)-methyl 3-hydroxy-pentanoate.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1[CH:4]=O.[C:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)(=[O:19])[CH3:18].C[O-].[Li+].Cl>CN(C)C=O.CO.O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:3]=1/[CH:4]=[CH:18]/[C:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)=[O:19]
Reactant: COc1cc(O)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: C[O-]
Agent: Cl
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COc1cc(O)c(/C=C/C(=O)c2ccc(C(=O)O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.3 %

Procedure:
2-Hydroxy-4-methoxy-5-thiophen-2-yl-benzaldehyde (Ex-29B, 0.10 g, 0.43 mmol) and 4-acetylbenzoic acid (0.070 g, 0.43 mmol) were dissolved in a dimethylformamide-methanol solution (2.8 mL, 7:3). After complete dissolution, lithium methoxide (0.065 g, 1.7 mmol) was added and the resulting red slurry was stirred in the dark at room temperature for 18 h. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethyl alcohol (5 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. Note: the compound appears to decompose with heating. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.025 g (15%) of the title compound as a dark yellow solid, mp 125° C. (dec). 1H-NMR (300 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.18–8.22 (m, 3H), 8.09 (d, 2H, J=8.1 Hz), 8.05 (s, 1H), 7.87 (d, 1H, J=14.7 Hz), 7.60 (d, 1H, J=3.0 Hz), 7.49 (d, 1H, J=4.2 Hz), 7.11 (dd, 1H, J=4.2, 3.0 Hz), 6.67 (s, 1H), 3.90 (s, 3H). MS (ESI) m/z=381 ([M+H]+, 100%). Anal. Calcd. for C21H16O5S.EtOH: C, 64.77; H, 5.20; S, 7.52. Found: C, 64.68; H, 5.00; S, 7.77.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:28]1([O:33][CH2:32][CH2:31][O:30]1)[CH3:29])[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[C:11]([C:23]([OH:25])=[O:24])=[C:12]([CH2:15]SC3SC(C)=NN=3)[CH2:13][S:14][C@H:9]12)=[O:6]>O1CCCC1.O.C(O)(=O)C.[Zn]>[CH3:1][O:2][N:3]=[C:4]([C:28]1([O:33][CH2:32][CH2:31][O:30]1)[CH3:29])[C:5]([NH:7][CH:8]1[C:26](=[O:27])[N:10]2[CH:11]([C:23]([OH:25])=[O:24])[C:12](=[CH2:15])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(C)s3)CS[C@H]12)C1(C)OCCO1
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C=C1CS[C@@H]2C(NC(=O)C(=NOC)C3(C)OCCO3)C(=O)N2C1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
Zinc powder (500 mg.) and copper sulfate 5-hydrate (50 mg.) were added to a solution of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 500 mg.) in tetrahydrofuran (6 ml.), water (2 ml.) and acetic acid (1 ml.), and stirred at room temperature for 2 hours. The resultant mixture was filtered and washed with tetrahydrofuran (5 ml.). The filtrate and the washings were combined and treated in a similar manner to that of Example 10-(3) to give a mixture (160 mg.) of 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methylenecepham-4-carboxylic acid (syn isomer) and 7-(2-methoxyimino-3,3-ethylenedioxybutyramido)-3-methyl-3-cephem-4-carboxylic acid (syn isomer).