Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH:12]1([C:15]([NH2:18])([CH3:17])[CH3:16])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH:12]1([C:15]([NH:18][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)([CH3:17])[CH3:16])[CH2:14][CH2:13]1
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC(C)(N)C1CC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CSc1ncc(C#N)c(NC(C)(C)C2CC2)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (750 mg, 4.0 mmol) in DMF (8 mL) was added 2-cyclopropylpropan-2-amine (400 mg, 4.0 mmol) and DIEA (1560 mg, 12.0 mmol). The resulting mixture was stirred at 60° C. for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (665 mg, 2.68 mmol, 66% yield) as a white solid. MS (ESI) m/z=249.2 [M+H]+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[OH:1][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([OH:21])[CH3:20]
Reactant: CC(O)CCCCCCC#CCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)CCCCCCC#CCCO
Temperature: 23 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 19 (2.9 g, 9.4 mmol) in THF (15 mL) was added 19 mL of tetra-n-butylammonium fluoride (19 mmole, 1M solution in THF). The reaction was stirred for 1 hr at 23° C. then diluted with 75 mL of water. The aqueous mixture was extracted with ether (3×50 mL) and the ether extract washed with brine (2×50 mL). Product isolation yielded 1.86 g (100%) of the diol (20). No further purification was carried out on 20.
Reaction SMILES: [C:1]1(=[N:13]O)[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[OH2:15]>>[C:1]1(=[O:15])[C:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2][NH:13]1
Reactant: O
Reactant: ON=C1CCc2oc3ccccc3c21
Product: O=C1NCCc2oc3ccccc3c21

Procedure:
A mixture of 2,3-dihydro-1H-cyclopent a[b]benzofuran-1-one oxime (1.0g) and polyphosphoric acid (ca.2 ml) was heated at 110° for 5h. Water (100 ml) was added and the suspension was extracted with ethyl acetate (3×50 ml). The combined extracts were dried and evaporated to give a solid (ca.325 mg) which was purified by FCC eluting with System B (1:1) to give the title compound, m.p. 158°-161°.
Reaction SMILES: C(=[O:5])C(C)C.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.CO>N1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:5])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC(C)C=O
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-L-menthoxyacetyloxy-2-methylpropene is prepared from isobutyraldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-L-menthoxyacetyloxy-2-methylpropene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyloxy-L-3-methylbutyrate and methyl 2-L-menthoxyacetyl-D-3-methylbutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-hydroxy-3-methylbutyric acid, methanol, and L-menthoxyacetic acid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl[CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:34](=[O:46])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[SH:47][C:48]1[CH2:52][O:51][C:50](=[O:53])[CH:49]=1>ClCCl>[O:53]=[C:50]1[CH:49]=[C:48]([S:47][CH2:11][C:12]2[CH2:13][S:14][C@@H:15]3[C@H:35]([NH:36][C:37](=[O:45])[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:34](=[O:46])[N:16]3[C:17]=2[C:18]([O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:52][O:51]1
Reactant: O=C1C=C(S)CO1
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSC3=CC(=O)OC3)CS[C@H]12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
N,N-Diisopropylethylamine (0.52 ml) was added to a stirred solution of diphenylmethyl 3-chloromethyl-7β-phenylacetamidoceph-3-em-4-carboxylate (1.59 g) and 4-mercapto-2(5H)-furanone (400 mg) in dichloromethane (30 ml). The mixture was stirred at room temperature for 2 hours and then washed successively with aqueous citric acid solution, water, sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. The title compound (1.64 g) was isolated by column chromatography of the residue using gradient elution (Kieselgel, 1:1 going to 3:7 hexane:ethyl acetate), m.p. 178°-180° C. from ethyl acetate/hexane (Found: C, 64.89; H, 4.61; N, 4.57; S, 10.30: C33H28N2O6S2 requires; C, 64.69; H, 4.61; N, 4.57; S, 10.47). υmax (CHCl3) 3400, 1780, 1745, and 1680 cm-1. δH (CDCl3) 3.36 (1H, d, J 18.3Hz), 3.57 (1H, d, J 18.3Hz), 3.62 (1H, d, J 16.2Hz), 3.70 (1H, d, J 16.2Hz), 3.86 (1H, d, J 12.5Hz), 4.01 (1H, d, J 12.5Hz), 4.71 (2H, s), 4.98 (1H, d, J 4.8Hz), 5.64 (1H, s), 5.88 (1H, dd, J 4.8 and 9.0Hz), 6.06 (1H, d, J 9.0Hz), 6.95 (1H, s), 7.2-7.4 (15H, m).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:27][CH2:26][C@:5]2([NH:9][C@@H:8]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)[CH:13]=[CH:12][N:11]=3)[CH2:7][CH2:6]2)[C:4]1=[O:28].C=O.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:31][N:9]1[C@:5]2([CH2:26][CH2:27][N:3]([CH3:2])[C:4]2=[O:28])[CH2:6][CH2:7][C@@H:8]1[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CN1CC[C@@]2(CC[C@H](c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)N2)C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CC[C@@]2(CC[C@H](c3cc(-c4ccc(C(F)(F)F)cc4)ccn3)N2C)C1=O
Reaction time: 1 h

Procedure:
To a solution of (2R,5S)-7-methyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one hydrochloride (which may be prepared as described in Example 52) (21 mg, 0.0500 mmol) in methanol (0.5000 mL) was added 3 meq of 3.7% formalin solution and sodium triacetoxyborohydride (16.21 mg, 0.0800 mmol) and the mixture was stirred for 1 h. The mixture was evaporated and partitioned between satd. aq. NaHCO3 (2 ml) and MDC (3×5 ml) and the residue purified on an SCX-2 cartridge (0.5 g) eluting with MeOH to 2% aq NH3 in MeOH to give (2R,5S)-1,7-dimethyl-2-[4-[4-(trifluoromethyl)phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one, a clear oil (16.9 mg);
Reaction SMILES: N1N(C2C=CC(C(F)(F)F)=CC=2C(O)=O)N=CC=1.N1(C2C=CC(C(F)(F)F)=CC=2C(O)=O)C=CN=N1.[N:37]1[NH:38][N:39]=[CH:40][CH:41]=1.[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48](I)[C:44]=1[C:45]([OH:47])=[O:46]>O1CCOCC1.O>[F:42][C:43]1[C:51]([F:52])=[CH:50][CH:49]=[C:48]([N:38]2[N:39]=[CH:40][CH:41]=[N:37]2)[C:44]=1[C:45]([OH:47])=[O:46]
Reactant: c1cn[nH]n1
Reactant: O=C(O)c1c(I)ccc(F)c1F
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1ccnn1
Agent: O=C(O)c1cc(C(F)(F)F)ccc1-n1nccn1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(-n2nccn2)ccc(F)c1F

Procedure:
Prepared according to the procedure for 2-(2H-1,2,3-triazol-2-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37a) and 2-(1H-1,2,3-triazol-1-yl)-5-(trifluoromethyl)benzoic acid (Intermediate 37b) from 2H-1,2,3-triazole (CAS number 288-36-8; 0.75 g, 10.86 mmol) and 2,3-difluoro-6-iodobenzoic acid (CAS number 333780-75-9; 1.54 g, 5.43 mmol) in 1,4-dioxane (10 ml) and water (0.2 ml). The crude solid was purified by column chromatography (silica, 0-3% methanol/DCM) to afford 2,3-difluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 39a). The mixed fractions were further purified by column chromatography (silica, 0-3% methanol/DCM) followed by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% formic acid) to afford 2,3-difluoro-6-(1H-1,2,3-triazol-1-yl)benzoic acid (Intermediate 39b).
Reaction SMILES: [Li].C[Si]([N-:6][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]#[N:17].Cl>C1COCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:16]([NH2:6])=[NH:17]
Reactant: COc1cc(C#N)ccc1[N+](=O)[O-]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(C(=N)N)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 0.17 h

Procedure:
99 ml (99 mmol) lithium-bis-trimethylsilylamide solution (1 mol/l in THF) are diluted with 640 ml THF, cooled to 10° C. and combined with 8.3 g (46.591 mmol) 3-methoxy-4-nitro-benzonitrile. The reaction mixture is stirred for 10 min at 20° C. The mixture is cooled to 0° C. and combined with 80 ml 3 N hydrochloric acid. The reaction mixture is evaporated down in vacuo and extracted with water and ethyl acetate. The aqueous phase is adjusted to pH 14 with 3 N sodium hydroxide solution. The product is then suction filtered.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:17]([CH3:21])[C:18]([OH:20])=[O:19].[N+](=[CH2:24])=[N-]>O1CCOCC1>[CH3:24][O:19][C:18](=[O:20])[CH:17]([C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9]=[CH:10][C:11]=2[CH:1]=1)[CH3:21]
Reactant: C=[N+]=[N-]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: C1COCCO1
Product: COC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5.0 G. of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid (preparation described infra) is suspended in 50 ml. of dioxane, added to excess ethereal diazomethane and stirred until dissolution is complete and evaporated to dryness. Purification as in part A on silica gel affords a nearly quantitative yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid methyl ester as in part A.
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11](=[O:18])[CH2:12][NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.O>C1COCC1.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([CH2:12][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)=[O:18])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)CNCC(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N(CC(=O)Nc2ccc(Cl)c(Cl)c2)CC(C)C)cc1
Yield: 75.4 %

Procedure:
To a solution of N-(3,4-dichloro-phenyl)-2-isobutylamino-acetamide hydrobromide (0.090 g) in THF were slowly added a solution of triethylamine (0.064 mg) in THF (5 mL) and a solution of 4-methoxybenzoyl chloride (47 mg) in THF (5 mL) and the reaction mixture was stirred at room temperature for 24 hours. Then water was added to the reaction mixture and the precipitate was isolated by filtration and then purified by column chromatography to yield the title compound (78 mg). MS (m/e): 409.2 (M−H, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)cc1
Reactant: Clc1ccc(I)cc1
Product: COC(=O)c1ccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodobenzene (commercially available) and 4-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 7.97 (d, 1H), 7.25-7.43 (m, 12H), 7.07 (dt, 1H), 6.71 (dt, 1H), 6.61 (d, 1H), 6.54 (d, 1H), 4.97 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]=[O:15].[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([Mg]Cl)[CH2:25][CH2:24]1.CN1CCC(Cl)CC1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:16][CH:17]([O:19][CH2:20][CH3:21])[CH3:18])[C:9]1[S:10][CH:11]=[CH:12][C:13]=1[CH:14]([CH:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[OH:15]
Reactant: CN1CCC([Mg]Cl)CC1
Reactant: CCOC(C)OC(c1ccccc1F)c1sccc1C=O
Agent: CN1CCC(Cl)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(C)OC(c1ccccc1F)c1sccc1C(O)C1CCN(C)CC1
Temperature: -20 °C
Yield: 20 %

Procedure:
To a stirred solution of the 2-[(2-fluorophenyl)(1-(ethoxy)ethoxy)methyl]-3-thiophenecarboxaldehyde and tetrahydrofuran (400 ml), cooled to -78° C. under nitrogen, was added, via syringe, N-methyl-4-piperidinylmagnesium chloride over 1.5 hrs. (the Grignard reagent was prepared from N-methyl-4-chloropiperidine (29.4 g) according to the procedure of J. T. Strupczewski, et al., et al., J. Med. Chem., 28, 761 (1985), followed by dilution with tetrahydrofuran (45 ml)). The solution was allowed to warm slowly to -20° C. over 2.5 hrs, and dilute aqueous ammonium chloride solution and ether were added. The layers were separated and the organic layer washed with water. The combined aqueous layers were back-extracted with ether, and the combined organic layers washed with brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-45% methanol/dichloromethane) to afford 6.4 g (20% overall) of α-[2-[2-fluorophenyl-(1-(ethoxy)ethoxy)methyl]-3-thienyl]-1-methyl-4-piperidinemethanol.
Reaction SMILES: CN(C)C=O.[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([OH:20])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:11][CH3:12])[O:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(OCC)(=O)C>[OH:6][CH:7]([C:13]1[C:18]([CH3:19])=[CH:17][C:16]([O:20][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:15]([CH3:21])[CH:14]=1)[CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: CCOC(=O)CCl
Reactant: COC(OC)C(O)c1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(C)c(C(O)C(OC)OC)cc1C
Yield: 77.1 %

Procedure:
To N,N-dimethylformamide (81 g) were added 4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethylphenol (20.0 g), potassium carbonate (15.8 g) and ethyl chloroacetate (12.4 g) at room temperature with stirring. The mixture was stirred at room temperature for an hour, and then stirred at 71° C. for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and a mixture of ethyl acetate and hexane was added to the residue. The precipitated crystals were collected by filtration to give ethyl 2-[4-(1-hydroxy-2,2-dimethoxyethyl)-2,5-dimethyl-phenoxy]acetate (21.3 g).
Reaction SMILES: C([O:3][C:4]([C@@:6]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][C@H:15](NC(OC(C)(C)C)=O)[C:14](=[O:32])[N:13]1[C@@H:9]([CH2:10][C@@H:11]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:35]=3)[CH2:12]1)[C:8](=[O:52])[NH:7]2)=[O:5])C.[Li+].[OH-:54]>C1COCC1.O.CO>[C:6]([O:54][C@@H:15]1[C:14](=[O:32])[N:13]2[C@:9]([N:7]=[C:8]=[O:52])([CH2:10][C@@H:11]([O:33][C:34]3[C:43]4[C:38](=[CH:39][C:40]([O:44][CH3:45])=[CH:41][CH:42]=4)[N:37]=[C:36]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:35]=3)[CH2:12]2)[C:8](=[O:52])[NH:7][C@@:6]2([C:4]([OH:3])=[O:5])[C@@H:22]([CH2:23]2)[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:23])([CH3:22])[CH3:4]
Reactant: [OH-]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)C[C@H]1C(=O)N2
Agent: COc1ccc2c(O[C@H]3CN4C(=O)[C@@H](OC(C)(C)C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@]4(N=C=O)C3)cc(-c3ccccc3)nc2c1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(O[C@H]3CN4C(=O)[C@@H](OC(C)(C)C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@]4(N=C=O)C3)cc(-c3ccccc3)nc2c1

Procedure:
Following the experimental and purification procedure of Step 1i, (1S,4R,6S,13S,17R)-7-cis-13-tert-butoxycarbonylamino-17-(7-methoxy-2-phenyl-quinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo [13.3.0.04,6]octadec-7-ene-4-carboxylic acid ethyl ester (290 mg, 0.406 mmol) was reacted with 100 mg (2.5 mmol) of LiOH in 23.9 mL of 14.4:7.7:1.8 of THF/H2O/MeOH to afford (1S,4R,6S,13S,17R)-7-cis-13-tert-butoxy-carbonylamino-17-(7-methoxy-2-phenylquin-olin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (279 mg, 100%): 1H NMR (300 MHz, CD3OD) δ 0.97-1.05 (m, 2H), 1.14 (s, 9H), 1.20-1.55 (m, 5H), 1.60-1.73 (m, 2H), 1.85 (brs, 1H), 2.06-2.22 (m, 1H), 2.29 (brs, 1H), 2.52-2.73 (m, 2H), 3.93 (s, 3H), 4.14-4.19 (m, 1H), 4.26 (d, J=9.5 Hz, 1H), 4.56-4.67 (m, 2H), 5.47-5.53 (m, 2H), 5.71-5.78 (m, 1H), 7.08 (dd, J=9.1, 2.2 Hz, 1H), 7.22 (s, 1H), 7.37 (d, J=2.2 Hz, 1H), 7.45-7.56 (m, 3H), 8.02, 8.04 (2s, 2H), 8.09 (d, J=9.1 Hz, 1H). LC-MS (Method E-retention time: 1.60), MS m/z 685 (M++1). Step 7j: Preparation of Compound 7, Example 7 (1S,4R,65,13S,17R)-7-cis-[4-Cyclopropanesulfonylamino-carbonyl-17-(7-methoxy-2-phenylquinolin-4-yloxy)-2,14-dioxo-3,15-diazatricyclo[13.3.0.04,6]octadec-7-en-13-yl]carbamic acid tert-butyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A cooled (0° C.) solution of 4-fluorobenzenesulfonyl chloride (2.00 g; 10.3 mmol) in THF (40 ml) is treated with a 2 M solution of dimethylamine in THF (11.3 ml; 22.6 mmol) and stirred at 0° C. for 30 minutes. The solvents were removed under reduced pressure, the residue taken up in EtOAc, the organic phase was washed with a saturated solution of NH4Cl twice and with water. The organic phase was dried on MgSO4, filtered and the solvent removed under reduced pressure to afford the title compound (1.80 g, 86%).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11]1[CH:20]=[C:19]2[C:21]([O:23][C:24](=O)[C:17]3=[C:18]2[C:13](=[C:14]([Br:26])[CH:15]=[CH:16]3)[CH:12]=1)=[O:22]>N1C=CC=CC=1>[CH2:2]([O:9][N:10]1[C:24](=[O:23])[C:17]2[CH:16]=[CH:15][C:14]([Br:26])=[C:13]3[C:18]=2[C:19](=[CH:20][CH:11]=[CH:12]3)[C:21]1=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C1c2cccc3c(Br)ccc(c23)C(=O)N1OCc1ccccc1
Yield: 87.2 %

Procedure:
O-Benzyl hydroxylamine hydrochloride (2.0 g, 12.5 mmol) and 4-bromo-1,8-naphthalic anhydride (2.9 g, 10.5 mmol) were reacted in pyridine (50 mL) following the procedure of Example D to give 3.5 g of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([O:23]C)=[O:22])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2]>[OH-].[NH4+]>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([OH:23])=[O:22])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12
Agent: [NH4+]
Agent: [OH-]
Product: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)O)c(C)c12
Temperature: 150 °C
Yield: 31.3 %

Procedure:
A suspension of methyl 4-(4-carbamoyl-2-ethoxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.025 g, 0.06 mmol) in ammonium hydroxide (1.5 mL) was heated at 150° C. in a sealed-tube for 16 hours. The ammonium hydroxide was concentrated in vacuo and the residue redissolved in dimethyl sulfoxide. The sample was purified by reverse phase preparative HPLC to yield white solid (0.007 g, 29%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][C:7]1[C:12]2[CH:13]([CH3:23])[CH:14]([CH2:19][CH2:20][CH2:21][OH:22])[C:15]([CH3:18])([CH3:17])[O:16][C:11]=2[CH:10]=[C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=1)([CH3:4])[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:42].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.CN(C=O)C>O>[CH3:1][C:2]([Si:5]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[O:6][C:7]1[C:12]2[CH:13]([CH3:23])[CH:14]([CH2:19][CH2:20][C:21]([OH:42])=[O:22])[C:15]([CH3:17])([CH3:18])[O:16][C:11]=2[CH:10]=[C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:8]=1)([CH3:4])[CH3:3]
Reactant: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCCO)C(C)(C)O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCc1cc2c(c(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c1)C(C)C(CCC(=O)O)C(C)(C)O2
Yield: 48.4 %

Procedure:
A mixture of 2.2 g (3.97 mmol) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanol and 7.47 g (19.86 mmol) of pyridinium dichromate (Aldrich) in anhy. DMF (Aldrich) was stirred at RT under argon for 20 hr. The reaction was diluted with water and extracted with EtOAc. The organic phase was dried and solvent removed under reduced pressure. The residue was then purified by repeated chromatography on silica gel to give 1.1 g (48%) of 5-[[(1,1-Dimethylethyl)diphenylsilyl]oxy]-3,4-dihydro-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid as a pale yellow foam. HR EI MS: Calc M+, 572.3322; Observed, 572.3315. Ratio of 8:1 diastereoisomers as shown by 1H-NMR.