Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(=[N:4][O:5][C:6]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])C.Cl>C(O)C>[C:16]1([CH2:15][O:14][C:12]2[CH:11]=[CH:10][C:7]3[C:8]([NH2:9])=[N:4][O:5][C:6]=3[CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)=NOc1cc(OCc2ccccc2)ccc1C#N
Agent: Cl
Solvent: CCO
Product: Nc1noc2cc(OCc3ccccc3)ccc12

Procedure:
20.2 g (0.072 mol) of 2-[[(1-methylethylidene) amino]oxy]-4-(phenylmethoxy)benzonitrile are reacted with 340 ml of a 4N solution of hydrochloric acid in ethanol for 20 hours and then the solvent is evaporated. The crystalline product is subsequently triturated in dichloromethane, then the mixture is filtered and the solid is dissolved in the minimum amount of lukewarm methanol. The solution is alkalified with ammonia and then diluted with water. After filtration and washing with water, 16.3 g of product are obtained.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[I:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(O)C>[I:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:1][C@@H:2]([OH:3])[CH2:4][OH:5])=[CH:9][CH:8]=1
Reactant: OC[C@H]1CO1
Reactant: Oc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H](O)COc1ccc(I)cc1
Temperature: 25 °C

Procedure:
(S)-Glycidol (0.36 ml, 5.5 mmol) is added to a solution of 4-iodophenol (1 g, 4.5 mmol) and triethylamine (31 ml, 0.2 mmol) in ethanol (5 ml) and the resulting light brown solution is heated at reflux for 15 hours. The reaction is allowed to cool to room temperature and the solvent removed in vacuo. The residue is purified by chromatography (SiO2, EtOAc/iso-hexane) to afford (S)-3-(4-Iodo-phenoxy)-propane-1,2-diol as a colourless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:36][C:37]4[C:42]([C:43]([NH:45][CH3:46])=[O:44])=[C:41]([F:47])[C:40]([F:48])=[CH:39][CH:38]=4)[C:20]4[CH:25]=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].O.[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[CH3:51][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[CH:25][C:20]4=[C:19]([NH:36][C:37]4[C:42]([C:43]([NH:45][CH3:46])=[O:44])=[C:41]([F:47])[C:40]([F:48])=[CH:39][CH:38]=4)[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCCN4C(=O)CN(C)C)[nH]c3nccc2-3)ccc(F)c1F
Temperature: 120 °C
Yield: 46.6 %

Procedure:
6-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (139 mg, 0.193 mmol) was dissolved in 1,4-dioxane (6 mL) and transferred to a 20 ml microwave vessel. Water (2 mL) and a solution of 6M NaOH (2 ml) and was added and reaction heated in microwave at 120° C. for 10 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid that was purified via chromatography on SiO2 to afford 6-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-2,3-difluoro-N-methylbenzamide (51 mg, 0.090 mmol) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.92 (m, 2 H), 2.11 (br. s., 6H), 2.67 (br. s., 2 H), 2.74 (d, J=4.49 Hz, 3 H), 3.24 (s, 2 H), 3.69 (t, J=6.09 Hz, 2 H), 3.84 (s, 3 H), 5.76 (s, 1 H), 6.34 (d, J=1.10 Hz, 1 H), 6.82 (br. s., 1 H), 6.96 (br. s., 1 H), 7.38-7.51 (m, 2 H), 7.90-8.01 (m, 1 H), 8.38-8.48 (m, 1 H), 8.63 (d, J=4.67 Hz, 1 H), 9.58 (s, 1 H), 11.33 (br.s, 1 H). (ESIMS (M+H)+=565)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:49])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][OH:48])[CH2:15]2)=[CH:10][CH:9]=1>CCOC(C)=O.CCCCCCC>[CH3:1][O:2][CH2:3][C@H:4]([CH3:49])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][O:48][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CO)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](COS(C)(=O)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21

Procedure:
The title compound is prepared according to general procedure F starting from 1.0 mmol of [(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-methanol. Rf=0.45 (EtOAc/heptane 2:1); Rt=5.52 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:18]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:14])[CH3:15])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:23]([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)(=[O:25])=[O:24])[CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccnc2)c1CN(C)C
Temperature: 25 °C
Yield: 3.9 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (30 mg, 0.15 mmol; Intermediate 97) and pyridine-3-sulfonyl chloride hydrochloride (43 mg, 0.20 mmol) in DCM (1 mL) 5 M NaOH (2 mL) was added. The reaction mixture was stirred at rt over night. The organic phase was collected and the solvent was removed under reduced pressure. Purification by preparative HPLC/UV (System B) afforded the title product (2 mg, 4%) as a white solid. MS (ESI+) for C17H19N3O3S m/z 346 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:33].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:33])=[C:10]2[CH:9]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2COc1cccc(C(F)(F)F)c1
Reactant: ClCCl
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1cccc(C(F)(F)F)c1

Procedure:
According to the general procedure (GP12), chlorination of 3-ethyl-1-iodo-8-(3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (1.272 g; 2.307 mmol), and purification by FC (DCM/MeOH=60/1) gave the expected product 1-chloro-3-ethyl-8-(3-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow oil (0.403 g; 38%). LC-MS: tR=1.03 min.; [M+H]+=460.37 g/mol.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6](=[O:19])[NH:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][C@@H:33]1[C@@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:44])([CH3:43])[CH3:42])[C@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[C@@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[O:35][C@H:34]1Br)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>C(#N)C>[C:1]([N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:6]([O:19][C@@H:34]2[O:35][C@H:36]([CH2:53][O:54][C:55](=[O:60])[C:56]([CH3:59])([CH3:58])[CH3:57])[C@@H:37]([O:46][C:47](=[O:52])[C:48]([CH3:49])([CH3:50])[CH3:51])[C@H:38]([O:39][C:40](=[O:45])[C:41]([CH3:42])([CH3:43])[CH3:44])[C@H:33]2[O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:28])[CH3:29])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Br)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)n1nc(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.26 g) in acetonitrile (20 mL) were added potassium carbonate (1.01 g) and 2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl bromide (2.96 g) under stirring at room temperature. In addition, the mixture was heated to 50° C. and stirred for 3 hours. After the completion of the reaction, the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-acetyl-4-benzyl-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyl-oxy)-1H-pyrazole (2.68 g).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(N2CCN(C3CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ccc(N2CCN(C3CC3)CC2)cc1
Yield: 99.4 %

Procedure:
To a solution of 1-cyclopropyl-4-(4-nitro-phenyl)-piperazine (1.24 g, 5.00 mmol) in methanol (25 mL) was added Pd/C (10%, 100 mg) and trifluoroacetic acid (1.0 mL). The mixture was stirred under 1 atm of hydrogen (balloon) overnight, filtered and concentrated. To the residue was added water and 1N aq. NaOH to adjust the PH>11. The mixture was extracted ethyl acetate, and the organic layer was dried over Na2SO4, concentrated to give the title compound (1.08 g, 100%) as a brown oil. MS (ES+): m/z=218.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][CH:9]=1)=[O:4]>CCOC(C)=O.CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C#CCNS(C)(=O)=O)s1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(CCCNS(C)(=O)=O)s1
Yield: 97.6 %

Procedure:
A solution of 5-(3-methanesulfonylamino-prop-1-ynyl)-thiophene-2-carboxylic acid methyl ester (3.0 g, 10.9 mmol) in EtOAc (100 mL) and MeOH (50 mL) was hydrogenated with 10% Pd/C (680 mg) at 50 psi for 7 h. The solution was filtered through a pad of Celite with the aid of MeOH and was concentrated in vacuo to provide the title compound as an off-white solid (2.95 g). 1H NMR (300 MHz, CDCl3) δ7.62 (d, 1H), 7.23 (d, 1H), 4.29 (m, 1H), 3.85 (s, 3H), 3.18 (q, 2H), 2.93 (m, 5H), 1.96 (m, 2H).
Reaction SMILES: [I-].BrC1C=CC=C[N+]=1C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].[C:15]1([CH2:21][C:22](O)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[C:15]1([CH2:21][C:22]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccccc1
Agent: C[n+]1ccccc1Br
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cc1ccccc1
Yield: 82 %

Procedure:
To a suspended toluene (2 ml) solution of 2-bromo-1-methylpyridinium iodide (720 mg, 2.4 mmol) was added a mixture of tert-butyl alcohol (148 mg, 2.0 mmol), phenylacetic acid (272 mg, 2.0 mmol) and tri-n-butylamine (888 mg, 4.8 mmol) in toluene (2 ml), and the resulting mixture was refluxed for 3 hours. After evaporation of the solvent, the residue was separated by silica gel column chromatography, and tert-butyl phenylacetate was isolated in 82% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:14]=[C:13]2[C:15]([O:17][C:18](=[O:19])[C:11]3=[C:12]2[C:7](=[C:8]([Cl:20])[CH:9]=[CH:10]3)[CH:6]=1)=[O:16]>S(=O)(=O)(O)O>[CH:5]1[CH:14]=[C:13]2[C:15]([O:17][C:18]([C:11]3=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([Cl:20])[C:7](=[C:12]23)[CH:6]=1)=[O:19])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C1OC(=O)c2ccc(Cl)c3cccc1c23
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc([N+](=O)[O-])c(Cl)c3cccc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Mixture of concentrated sulfuric acid (2.7 mL) and concentrated nitric acid (2.0 mL) was added to a solution of 4-chloro-1,8-naphthalic anhydride (3.0 g, 12.8 mmol) in concentrated sulfuric acid (10.5 mL) at 0° C. The mixture was stirred at room temperature for 2 hours and poured into ice water (50 mL). The separated solid was filtered, washed with water, and dried to give 2.1 g of the title compound (Reference: Tet., 1995;51(33):9127-9138).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.[N+:20]([C:23]1[CH:24]=[C:25]([S:29]([CH2:32][CH2:33]O)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>O>[N+:20]([C:23]1[CH:24]=[C:25]([S:29]([CH2:32][CH2:33][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C(OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cccc(S(=O)(=O)Cl)c1
Temperature: 70 °C

Procedure:
To solid 3-chlorosulfonylbenzoic acid (3.2 g, 14.4 mmol) was added solid PCl5 (3.0 g, 14.4 mmol) at room temperature with mixing. The mixture was heated to 70° C. forming a brown liquid that was heated for an additional 2 h. POCl3 side product was removed by vacuum distillation and the residual brown oil was dissolved in 15 mL of CH3CN, and then 2-(3-nitrobenzenesulfonyl)ethanol (2.8 g, 12.0 mmol) was added. The mixture was heated to reflux temperature for 36 h. Thereafter water was added and the mixture was extracted with CH2Cl2. The resulting oil was purified by short column chromatography (eluent: CH2Cl2 to 1% MeOH in CH2Cl2) to give a brown semisolid, which became a white solid by treatment with ether-EtOAc (yield 2.75 g (53%)).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].CS(C)=O.Cl[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>O>[CH2:36]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccccc1-c1ccccc1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 96 %

Procedure:
A 100 mL 3-neck flask was equipped with a magnetic stirrer, a reflux condenser, a nitrogen blanket, and a heating mantle with a temperature controller and a thermocouple. The flask was charged with o-phenylphenol (3.42 grams, 0.02 moles), with KOH pellets (1.37 grams, 0.02 moles, 85%), and with 15 mL of DMSO. The mixture was stirred at 100° C. under nitrogen until all of the KOH had dissolved (about 2 hours). The dark solution was cooled to 70° C., then the 1-chlorohexadecane (5.22 grams, 0.02 moles) was then added all at once. An exotherm to about 80° C. was observed. The reaction mixture was then stirred at 75° C. for about 7.5 hours, then it was poured into about 500 mL of water; solids separated. After stirring at room temperature for about 2 hours, the mixture was filtered. The solids were washed on the filter with a little water, then they were air dried to give 7.58 grams of waxy white solid. The yield was 96%; mp=35-37° C. Structure was confirmed by IR, GC/MS, and 1H- and 13C-NMR analyses.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>[OH-].[Na+]>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:2][CH2:3]1)([OH:9])=[O:8]
Reactant: O=C(O)C1CCNCC1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)N1CCC(C(=O)O)CC1

Procedure:
4-Carboxy-1-ethoxycarbonylpiperidine is prepared from piperidine-4-carboxylic acid (Aldrich, Steinheim, FRG), for example by reacting piperidine-4-carboxylic acid with ethyl chloroformate in aqueous sodium hydroxide solution for 2 h at from 0° to 5° C. The title compound is extracted from the aqueous phase by shaking with toluene. The toluene phase containing the dissolved title compound is dried over Na2SO4 and directly subjected to further use.
Reaction SMILES: [CH2:1]([C:4]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:5]=1[CH2:6][O:7][CH2:8][C:9]1[CH:40]=[C:12]2[N:13]=[C:14]([CH3:39])[C:15]([C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([N:17]3[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]3)[N:11]2[N:10]=1)C=C.[BH4-].[Na+]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl.O>[C:35]([O:34][C@@H:28]([C:15]1[C:14]([CH3:39])=[N:13][C:12]2=[CH:40][C:9]3=[N:10][N:11]2[C:16]=1[N:17]1[CH2:18][CH2:19][C:20]([CH3:23])([O:24][CH2:25][CH2:26][CH2:27][CH2:1][C:4]2[CH:44]=[C:43]([CH3:42])[CH:45]=[CH:41][C:5]=2[CH2:6][O:7][CH2:8]3)[CH2:21][CH2:22]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:36])([CH3:38])[CH3:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C)cc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(C)ccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of (S)-ethyl 2-(2-(((2-allyl-4-methylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol) and Grubbs II catalyst (68.6 mg, 0.081 mmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (3.06 mg, 0.081 mmol) was then added and the reaction was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{4,16,24-trimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (30 mg, 0.051 mmol, 62.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m, 1H), 7.08-6.97 (m, 2H), 6.50 (s, 1H), 6.16 (s, 1H), 4.88 (s, 2H), 4.76-4.59 (m, 3H), 4.24-4.08 (m, 2H), 3.96 (t, J=11.0 Hz, 1H), 3.57-3.40 (m, 2H), 2.92 (d, J=11.0 Hz, 1H), 2.80-2.72 (m, 2H), 2.69-2.59 (m, 4H), 2.34 (s, 3H), 2.11-2.01 (m, 1H), 1.98-1.86 (m, 3H), 1.86-1.74 (m, 2H), 1.76-1.60 (m, 2H), 1.29-1.22 (m, 12H), 1.19 (t, J=7.2 Hz, 3H). LCMS (M+1)=593.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:26])[C@H:10]([CH:11]([OH:25])[C:12]3[CH:17]=[CH:16][C:15]([O:18]C4CCCCO4)=[CH:14][CH:13]=3)[C@H:4]2[S:3]1>CC(C)=O.P(=O)(O)(O)O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:27])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:26])[C@H:10]([CH:11]([OH:25])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@@H](C(O)c3ccc(OC4CCCCO4)cc3)C(=O)N2[C@H]1C#N
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC1(C)S[C@@H]2[C@@H](C(O)c3ccc(O)cc3)C(=O)N2[C@H]1C#N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2,2-Dimethyl-3α-cyano-6α-[p-(2-tetrahydropyranyloxy)-α-hydroxybenzyl]penam (45 mg, 0.12 mmol) is dissolved in 3 ml of acetone and 0.5 ml of 10% phosphoric acid. After stirring 18 hours at room temperature, the solution is diluted with a 10 fold excess of ethyl acetate and washed with saturated sodium chloride. Purification of the crude phenol (42 mg) by PLC (35% acetone/toluene) provides 2,2-dimethyl-3α-cyano-6α-(p-hydroxy-α-hydroxybenzyl)penam.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21]O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:20])[O:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][O:11]1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])O.[Na+].[SH:40][C:41]1[NH:42][C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[N:45]=1.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]1[C:3]([CH2:21][S:40][C:41]2[NH:45][C:44]3[CH:46]=[CH:47][CH:48]=[CH:49][C:43]=3[N:42]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1([CH3:20])[O:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][O:11]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CO
Reactant: Sc1nc2ccccc2[nH]1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CSc1nc2ccccc2[nH]1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a THF (7 ml) solution of the (3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)methoxy)pyridin-2-yl)methanol (312 mg, 1.00 mmol) obtained in the step (5e), triethylamine (0.30 ml, 2.15 mmol) was added at room temperature, and then methanesulfonyl chloride (0.12 ml, 1.55 mmol) was added under cooling in an ice-salt bath and stirred for 30 minutes in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with water and a saline solution, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was dissolved in ethanol (6 ml). To the resultant solution, 2-mercaptobenzimidazole (150 mg, 1.00 mmol) and sodium hydroxide (160 mg, 4.00 mmol) were added and stirred at room temperature for 16.5 hours. After the reaction mixture was concentrated, NH silica gel was added to the residue and the mixture was dried. The obtained crude product was purified by silica gel column chromatography (elution solvent: heptane/ethyl acetate=1/0, 1/1-0/1 gradient) and desired fractions were concentrated to obtain the title compound (377 mg, 85.0% yield) as a white foam.