Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][C:15](=[O:34])[C@@H:16]1[CH2:20][C@H:19]([OH:21])[CH2:18][N:17]1[C:22](=[O:33])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25]>ClCCl.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:34])[C@@H:16]1[CH2:20][C@H:19]([O:21][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:18][N:17]1[C:22](=[O:33])[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (678 μL) and methanesulfonyl chloride (342 L) were added to a solution of 1-(N-tert-butoxycarbonyl-N-methylglycyl)-cis-4-hydroxy-L-proline methyl ester (A, 699 mg) in dichloromethane (15 mL) at 0° C. After stirring at 0° C. for 45 min and at room temperature for 45 min, the reaction mixture was diluted with chloroform. The organic layer was washed with 10% citric acid, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to afford the title compound (0.82 g) as a pale yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].[Br-:23].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:4]([C:1](=[O:3])[CH2:2][Br:23])=[C:5]2[C:10]=1[NH:9][C:8](=[O:22])[CH:7]=[CH:6]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
To a suspension of 5-acetyl-8-(benzyloxy)quinolin-2(1H)-one (19.4 g, 66.4 mmol) in anhydrous THF (240 mL) and anhydrous methanol (165 mL) was added a solution of tetra-n-butylammonium tribromide (Bu4NBr3) (54.5 g, 113.0 mmol) in anhydrous THF (130 mL) dropwise over 1.5 hours. The resulting solution was stirred at RT overnight before concentrating under reduced pressure without heating. The residue was re-dissolved in methanol (200 mL). Saturated aqueous ammonium chloride solution (390 mL) was added with ice-cooling. The resulting suspension was filtered and the solid washed with water and air-dried under vacuum. The solid was suspended in DCM and methanol (1:1 v/v, 100 mL) for 90 minutes. The solid was collected by filtration, washed with DCM and air-dried to afford the title compound (18.0 g, 73%). 1H NMR (400 MHz, DMSO-d6): δ 11.07 (s, 1H); 8.51 (d, J=10.0 Hz, 1H); 7.94-7.83 (m, 1H); 7.60 (d, J=7.5 Hz, 2H); 7.44-7.27 (m, 4H); 6.79-6.65 (m, 1H); 5.53-5.39 (s, 2H); 4.93 (s, 2H)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:22][CH2:23][CH3:24])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:14]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH2:23]([O:22][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][C:13]=1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:24]
Reactant: CCOC(=O)/C=C/c1cc(OCc2ccccc2)ccc1OCC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1cc(O)ccc1OCC
Yield: 96.3 %

Procedure:
A mixture of ethyl (E)-3-(5-benzyloxy-2-ethoxyphenyl)-2-propenoate (1.85 g), 5% palladium carbon (3.0 g), ethanol (50 mL) and tetrahydrofuran (30 mL) was subjected to catalytic hydrogenation at room temperature and 1 atm. After filtering off the catalyst, the solvents were evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-(2-ethoxy-5-hydroxyphenyl)propionate as a colorless oil (1.30 g, 96%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: O.C([N:9]1[CH2:14][CH2:13][CH:12]([CH3:15])[CH:11]([N:16]([CH3:26])[C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:10]1)C1C=CC=CC=1.C(O)(=O)C>[OH-].[OH-].[Pd+2].C(O)(C)C>[CH3:26][N:16]([C@@H:11]1[C@H:12]([CH3:15])[CH2:13][CH2:14][NH:9][CH2:10]1)[C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: CC1CCN(Cc2ccccc2)CC1N(C)c1ncnc2[nH]ccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: C[C@@H]1CCNC[C@@H]1N(C)c1ncnc2[nH]ccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt % Pd(OH)2/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55° C. and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-30° C. and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-90° C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30° C. and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30° C. and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50° C. for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated.
Reaction SMILES: [CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>O1CCOCC1>[CH2:1]([S:5]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(S(=O)(=O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)CS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 80 °C
Yield: 105.8 %

Procedure:
A mixture of methyl 4-isobutylsulfonylbenzoate (1.0 g, 3.9 mmol), NaOH solution (10 mL of 1 M, 10.00 mmol), and dioxane (10 mL) was heated at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then concentrated in vacuo. The solid residue was dissolved in water and washed with ethyl acetate (1×10 mL). The aqueous layer was acidified with 1N HCl solution and was extracted with ethyl acetate (2×10 mL) and layers were separated. The combined organics were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography using (0-100%) ethyl acetate/hexanes as eluent to give 4-isobutylsulfonylbenzoic acid (1.0 g, 98%). ESI-MS m/z calc. 242.1. Found 243.2 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3 Hz, 2H), 3.03 (d, J=6.5 Hz, 2H), 2.27 (dt, J=13.3, 6.6 Hz, 1H), 1.08 (d, J=6.7 Hz, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47](O)=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].CCCN.O.O[N:56]1[C:60]2[CH:61]=CC=C[C:59]=2N=N1>C1COCC1>[OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([NH:56][CH:60]([CH3:61])[CH3:59])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][CH:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44]
Reactant: On1nnc2ccccc21
Reactant: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)O)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Solvent: CCCN
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](O)[C@@H](OC)C(NC2=CC(=O)c3c(cc4c(c3O)C(=O)[C@]3(OC)[C@H](O)Cc5cc(C)c(C(=O)NC(C)C)c(O)c5[C@]3(O)C4=O)C2=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 15.1 %

Procedure:
To a solution of (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylic acid (50 mg, 0.073 mmol) in THF (5 mL) was added 2-methylethylamine (12 μL, 0.15 mmol), polystyrene carbodiimide (130 mg, 0.147 mmol, 1.12 mmol/g), and 1-hydroxybenzotriazole hydrate (20 mg, 0.15 mmol). The reaction mixture was stirred at room temperature under nitrogen for 12 h. The reaction was quenched by adding 1N HCl solution (5 mL) and brine (25 mL). The aqueous layer was extracted with methylene chloride (2×50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the crude product. The crude material was purified by preparative HPLC (10:90 acetonitrile/water to 60:40 acetonitrile/water with 0.05% TFA over 10 min, then isocratic) and lyophilized to afford (6R,6aS,14aR)-1,6,8,14a-tetrahydroxy-11-((3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-N-isopropyl-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxamide (8 mg, 15%) as a red-brown powder and as a mixture of diastereomers: 1H NMR (500 MHz, CD3OD) δ 8.11 (s, 1H) 6.59 (s, 1H), 6.19 (s, 0.2H), 5.95 (s, 0.8H), 4.97-4.89 (m, 2H), 4.10-4.03 (m, 1H), 3.75 (s, 3H), 3.73-3.69 (m, 1H), 3.64 (s, 2H), 3.59 (s, 3H), 3.57 (d, J=16.0 Hz, 3H), 3.47-3.35 (m, 1H), 3.23 (d, J=18.7 Hz, 1H), 3.09-3.02 (m, 1H), 2.22 (s, 3H), 1.27 (d, J=6.0 Hz, 2.4H), 1.23 (d, J=6.0 Hz, 0.6H), 1.14 (d, J=17.5 Hz, 6H); MS (ESI−) m/z 723 (M−H); HPLC >99% (AUC), tR 12.93 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]=12.[CH:25]12[O:33][CH:29]([CH2:30][NH:31][CH2:32]1)[CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]2.C(N(CC)CC)C>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[N:17]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:19][C:3]3=[C:2]([N:31]3[CH2:32][CH:25]4[O:33][CH:29]([CH2:28][N:27]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:26]4)[CH2:30]3)[N:7]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c3cnn(CC(F)(F)F)c3n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CN(c3nc(-c4ccc([N+](=O)[O-])cc4)nc4c3cnn4CC(F)(F)F)CC(C1)O2
Temperature: 150 °C
Yield: 70.2 %

Procedure:
To a Smith process vial containing a suspension of 4-chloro-6-(4-nitro-phenyl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazolo[3,4-d]pyrimidine (0.50 g, 1.4 mmol) and tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (0.34 g, 1.5 mmol) in ethanol (10 mL) was added triethylamine (0.55 mL, 4.2 mmol). The mixture was heated in the microwave reactor for 12 minutes at 150° C. The precipitate was collected by Buchner filtration, washed with methanol, and dried under house vacuum to provide tert-butyl 7-(6-(4-nitrophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate as a pale yellow solid (0.54 g, 70%). MS (ES+): 550.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16](O)[C:17]4[S:22][CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:16]1[C:17]2[S:22][CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[N:15]=1
Reactant: Oc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(N2CCN(c3nc(Cl)c4c(n3)CCS4)CC2)cc1
Yield: 86.4 %

Procedure:
12.95 g 2-[4-(4-chloro-phenyl)-piperazin-1-yl]-6,7-dihydro-thieno[3,2-d]pyrimidin-4-ol and 50.89 ml (546 mmol) phosphorus oxychloride are heated for 4 hours to 120° C. Then the reaction mixture is evaporated down, the residue is mixed with water. The precipitate formed is suction filtered, washed with water and dried. The crude product is stirred with methanol and suction filtered. 11.78 g of the product are obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](N(OC)C)=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:14][Mg]Cl>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:9])[CH3:14])[CH:5]=[CH:4][N:3]=1
Reactant: CON(C)C(=O)c1ccnc(Cl)n1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccnc(Cl)n1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 2-chloro-N-methoxy-N-methylpyrimidine-4-carboxamide (75 mg, 0.372 mmol) in THF (3 mL) at −78° C. under a nitrogen atmosphere was added methyl magnesium chloride (3.0 M in THF, 0.124 mL, 0.372 mmol) dropwise. The solution was warmed to room temperature for 1 hr. The solution was diluted with EtOAc, washed with 1 N the organic layer was neutralized with saturated aqueous NaHCO3, dried with MgSO4, filtered, and concentrated to dryness. Purification on silica gel by flash chromatography (0-100% EtOAc/hexanes) afforded 1-(2-chloropyrimidin-4-yl)ethanone (45 mg, 0.29 mmol, 77% yield). 1H NMR (500 MHz, CDCl3) δ 8.86 (d, J=4.9, 1H), 7.83 (d, J=4.9, 1H), 2.71 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15].CCO.O>O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15]
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2o1)OC
Solvent: O
Solvent: CCO
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoate (1.0 g, 3.87 mmol) in EtOH/water 1/1 (80 ml) potassium hydroxide (0.43 g, 7.66 mmol) was added. The solution was refluxed for 1 hour, then it was cooled to RT and poured into water (200 ml). After acidification to pH 2 (1N HCl) the resulting suspension was extracted with EtOAc (3×50 ml). The organic phase was washed with water (2×30 ml), dried (MgSO4) and concentrated to give a yellow solid. This was repeatedly washed with CH2Cl2 and dried to give the pure title compound (0.80 g, 3.28 mmoles, yield 84.6%) as yellow crystals, m.p.=206°.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([C:34]2([CH3:38])[CH2:37][O:36][CH2:35]2)=[CH:30][CH:29]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([CH:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]4([CH3:38])[CH2:35][O:36][CH2:37]4)=[CH:32][CH:33]=3)[OH:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC1(c2ccc(I)cc2)COC1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(I)c1C(O)c1ccc(C3(C)COC3)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 3-(4-iodophenyl)-3-methyloxetane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH3:11][C:12](OC(C)=O)=O>CC(O)=O>[CH3:11][C:12]1[NH:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: CC(=O)O
Product: Cc1nc2cc(C#N)ccc2[nH]1
Temperature: 150 °C

Procedure:
To a solution of 3,4-diaminobenzonitrile (500 mg) in AcOH (10 ml) was added Ac2O (372 μl) at room temperature. The reaction mixture was refluxed for 15 hours (oil bath at 150° C.). It was cooled to room temperature, and concentrated until the amount of AcOH was reduced to a half. It was neutralized with an aqueous Na2CO3 solution, and extracted with EtOAc. The organic layer was washed with a saturated aqueous NaHCO3 solution and saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 2-methyl-1H-benzimidazole-5-carbonitrile (390 mg) as a pale red one.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)#[CH:21].C(N(CC)CC)C.O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[O:23]1[CH:24]=[CH:25][CH:26]=[C:22]1[C:20]1[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[C:11]2=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]2[CH:21]=1
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: C#Cc1ccco1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1cnc2c(c1)cc(-c1ccco1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a solution of 2-benzenesulfonylamino-3-iodo-5-methylthiopyridine (1.60 g) in dioxane (40 ml), 2-ethynylfuran (725 mg), bis(triphenylphosphine) palladium chloride (138 mg), copper(I) iodide (75 mg) and triethylamine (598 mg) were added successively and the mixture was stirred in a sealed tube at 60° C. for 1 hour. After cooling, the reaction solution was poured into water, extracted with dichloromethane, dried over, anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 1.24 g (85%) of the desired product as a brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.C([Li])CCC.CCCCCC.[CH2:21]([O:24][CH2:25][C:26](N(OC)C)=[O:27])[CH:22]=[CH2:23]>O1CCCC1>[CH2:21]([O:24][CH2:25][C:26]([C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[F:8])=[O:27])[CH:22]=[CH2:23]
Reactant: Fc1ccc(Br)cc1I
Reactant: C=CCOCC(=O)N(C)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOCC(=O)c1cc(Br)ccc1F
Temperature: -72 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a stirred −72° C. solution of 4-bromo-1-fluoro-2-iodobenzene (130.4 g, 433.5 mmol) in tetrahydrofuran (722 mL) is added 2.5 M butyl lithium in hexane (173.4 mL, 433.5 mmol) under a nitrogen atmosphere over 40 min. The reaction is stirred for 30 minutes at −72° C. and 2-(allyloxy)-N-methoxy-N-methylacetamide (57.5 g, 361.2 mmol) in tetrahydrofuran (115 mL) is added dropwise for 35 minutes. After 45 min at −72° C., the cooling bath is removed and mixture is warmed to 25° C. The reaction is quenched with saturated aqueous NH4Cl (500 mL), diluted with water (300 mL) and extracted three times with ethyl acetate. Organics are combined, dried over magnesium sulfate, filtered, and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a linear gradient of 5% to 10% ethyl acetate in hexanes to give the title compound (63 g, 64%). ES/MS m/e (79Br/81Br) 273/275 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.CC(N(C)C)=O.CC(C)([O-])C.[K+].[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1)([O-:27])=[O:26]>C(OCC)(=O)C>[OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=C(O)C(O)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C(O)c1ccc(O)cc1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 16.8 g. (0.1 mole) of 4-hydroxymandelic acid in 300 ml. of dimethylacetamide were added 11.2 g. of potassium t-butoxide with an additional 100 ml. of dimethylacetamide. The mixture was stirred at room temperature until a solution was obtained. p-Nitrobenzyl bromide (21.6 g., 0.1 mole) was added to the solution followed by 100 ml. of additional dimethylacetamide. The reaction mixture was stirred for 24 hours and was diluted with one liter of ethyl acetate. The mixture was washed repeatedly with water and dried over magnesium sulfate. The dried solution was evaporated to yield 25 g. (84 percent yield) of p-nitrobenzyl 4-hydroxymandelate.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([NH2:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:30]C1C=CC(S(O)(=O)=O)=CC=1.O.C(OC)(OC)OC>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([F:29])=[CH:23][C:24]4[N:28]=[CH:30][NH:27][C:25]=4[CH:26]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(N)c(N)cc3F)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc4[nH]cnc4cc3F)CC2)CC1
Reaction time: 16 h

Procedure:
The crude 60b was combined with TsOH.H2O (50 mg) in 2 mL of DMF and treated with HC(OMe)3 (1 mL). The mixture was stirred for 16 h then concentrated and purified on preparative HPLC to afford 60-1: LC-MS 418.4 (MH+), tR=4.64 (Method 4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([C:14](=[O:15])NC(=O)[NH:11]1)[CH2:6][CH2:5]2.O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(=O)=[O:30]>O>[NH2:11][C:7]1([C:14]([OH:15])=[O:30])[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C1NC(=O)C2(CCc3cc(Cl)ccc32)N1
Reactant: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Product: NC1(C(=O)O)CCc2cc(Cl)ccc21
Temperature: 120 °C

Procedure:
A mixture of (+/−)-5′-chloro-spiro[imidazolidine-4,1′indan]-2,5-dione (473 mg, 2 mmol) in water (55 mL) containing barium hydroxide nonahydrate (3.06 gm, 10 mmol) was sealed in a screw-top vessel and heated at 120° C. for 22 hours. The reaction suspension was cooled, the vessel opened and the mixture diluted to ˜200 mL with water. This suspension was brought to boil and small pieces of solid carbon dioxide were added over a 1-2 hour period. The heat was removed and the suspension was filtered while still very warm. The aqueous filtrate was concentrated under vacuum and the residue redissolved in water (30 mL). A few drops of sulfuric acid were added and any suspended material removed by filtration before concentrating the aqueous solution to dryness. This residue was triturated with methanol and several crops of the crude title compound were obtained. This material was used as is.