Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1.C(O)C.Cl>O>[Cl:1][C:2]1[C:3]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:6]=2[CH:17]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Cl

Procedure:
A mixture of ethyl {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate (14 g) sodium hydroxide (8 g), ethanol (500 ml) and water (300 ml) is refluxed for five hours, cooled in an ice bath and acidified with concentrated hydrochloric acid. The suspension is extracted with chloroform, the extract dried with saturated sodium chloride and the chloroform removed to give a solid, mp 214°-215° C. Recrystallization from a 3:2 mixture of acetonitrile-toluene gives {[5-chloro-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:24]([N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]([CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(Cc2ccccc2)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 4-[(2-bromophenyl)carbamoyl]piperidine-1-carboxylate (8 mmol), benzylbromide (1.05 ml, 8.8 mmol) and Cs2CO3 (5.2 g, 16 mmol) in DMF (20 ml) is stirred at rt overnight. DMF is removed in vacuo and the residue is partitioned between H2O (40 ml) and EtOAc (40 ml). The layers are separated and the aqueous layer is extracted with EtOAc (20 ml). The combined extracts are washed with brine (20 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:28]([CH3:31])=[N:29][N:30]=2)[N:5]=[C:6]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[C:14]3[C:13]([CH3:23])=[N:12][N:11]([CH:24]4[CH2:26][CH2:25]4)[C:10]=3[C:9]2=[O:27])[CH:7]=1.[CH3:32][C:33](OC(C)=O)=[O:34]>N1C=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH:15]2[C:14]3[C:13]([CH3:23])=[N:12][N:11]([CH:24]4[CH2:26][CH2:25]4)[C:10]=3[C:9](=[O:27])[N:8]2[C:6]2[CH:7]=[C:2]([NH:1][C:33](=[O:34])[CH3:32])[C:3]3[N:4]([C:28]([CH3:31])=[N:29][N:30]=3)[N:5]=2)=[CH:21][CH:20]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(N)c3nnc(C)n3n1)C2=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(N2C(=O)c3c(c(C)nn3C3CC3)C2c2ccc(Cl)cc2)nn2c(C)nnc12
Temperature: 115 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A flask was charged with 5-(8-amino-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 126.3) (40 mg, 0.092 mmol) and Ac2O (0.434 mL, 4.60 mmol) in pyridine (2 mL) under Ar and the resulting mixture was heated up and stirred for 20 hr at 115° C. The reaction was quenched with a saturated aq.NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with a saturated aq. NaHCO3 solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 1-4%) and triturated in Et2O to afford the title product (27 mg, 0.057 mmol, 62% yield) as white solid. tR: 4.73 min (HPLC 1); tR: 1.07 min (LC-MS 2); ESI-MS: 477 [M+H]+ (LC-MS 2); ESI-MS: 475 [M−H]− (LC-MS 2); Rf=0.50 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02-1.11 (m, 2H) 1.17-1.30 (m, 2H) 1.90 (s, 3H) 2.25 (s, 3H) 2.51 (s, 3H) 3.76-3.88 (m, 1H) 6.43 (s, 1H) 7.29-7.37 (m, 2H) 7.38-7.48 (m, 2H) 9.12 (s, 1H) 11.07 (s, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]([CH2:6][O:7][CH2:8]2)[CH2:4]1.[Li][CH2:20]CCC.CN(C=O)C.Cl>C1COCC1>[CH:9]12[NH:11][CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][C:3]1[C:10]2=[CH:20][O:1][N:2]=1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2
Reactant: [Li]CCCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1onc2c1C1COCC(C2)N1
Reaction time: 0.5 h

Procedure:
To a solution of compound 104b (512 mg, 2 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry DMF (740 mg, 10 mmol, 5.0 eq) in THF (2 mL) was added dropwise, the mixture was stirred for another 2 h from −60° C. to room temperature. To it 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (332 mg) as an oil. MS: calc'd (MH+) 167, measured (MH+) 167.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>>[CH3:8][C:6]1[C:5]([O:9][CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C
Temperature: 75 °C
Reaction time: 8 h

Procedure:
1-Fluoro-5-methyl-4-methoxy-2-nitrobenzene (D17) (0.79 mmol, 146 mg) was treated under argon at room temperature with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.8 mmol, 160 mg, 1 eq) and diisopropylethylamine (0.8 mmol, 103 mg, 1 eq) then stirred at 75° C. overnight. Completion was not observed, and the mixture was heated at higher temperature, 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.8 mmol, 160 mg, 1 eq) and diisopropylethylamine (0.8 mmol, 103 mg, 1 eq) were added again and allowed to react overnight at 100° C. The mixture was concentrated under reduced pressure, treated with 10% Na2CO3 aqueous solution and extracted twice with ether. Organics were combined, dried on MgSO4, concentrated under reduced pressure and chromatographed (0-50% ethyl acetate/petrol ether) to give the title compound as an orange residue (0.33 mmol, 120 mg, 42% yield). M+H=310.1, main fragment (molecule has lost its tert-butyl group).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[CH2:6]([P:10]([CH2:13][CH:14]([CH3:16])[CH3:15])([SH:12])=[S:11])[CH:7]([CH3:9])[CH3:8]>>[CH2:6]([P:10]([CH2:13][CH:14]([CH3:16])[CH3:15])([S:12][CH2:1][CH2:2][CH2:3][CH3:4])=[S:11])[CH:7]([CH3:9])[CH3:8]
Reactant: CCCCBr
Reactant: CC(C)CP(=S)(S)CC(C)C
Product: CCCCSP(=S)(CC(C)C)CC(C)C

Procedure:
n-Butyl bromide was reacted with the ammonium salt of diisobutylphosphinodithioic acid to obtain n-butyl diisobutylphosphinodithioate, a colorless liquid, b.p. 97°-103° C at 0.05 mm. which on testing lasted 200 hours longer than the control. The total number of hours required to reach failure was 1.4 times that of the control.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14].[I:16]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:16])[C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[NH2:14]
Reactant: II
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1N
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Amino-4-trifluoromethyl-benzoic acid methyl ester, (48 g, 219 mmol) was dissolved in MeOH (750 ml). Silver sulfate (68.3 g, 219 mmol) and iodine (55.6 g, 219 mmol) was added and rinsed in with MeOH (50 ml). The reaction mixture was left for 1 hour at RT. The reaction mixture was filtered under vacuum and the filtrate concentrated in vacuo. The residue was taken up in MeOH (100 ml) and water (10 ml) and the mixture heated at 80° C. The crude solution was hot filtered to remove residual inorganics and the warm filtrate was poured slowly into water (750 ml) with vigorous stirring. The mixture was left to particulate for 10 minutes and filtered to give the title compound as an orange solid. MS m/z 345 [M+H]+.
Reaction SMILES: C([O:8][CH:9]1[CH2:13][N:12]([C:14](=[O:35])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[CH:11]([CH2:36][O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O-:44])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])[CH2:10]1)C1C=CC=CC=1.[CH3:49][C:50](O)=O.CCO>[Pd]>[OH:8][CH:9]1[CH2:13][N:12]([C:14](=[O:35])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[O:24])=[C:18]([O:33][CH3:34])[CH:17]=2)[CH:11]([CH2:36][O:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([O:44][CH2:49][CH3:50])=[O:43])=[CH:40][C:39]=2[O:47][CH3:48])[CH2:10]1
Reactant: CC(=O)O
Reactant: COc1cc(CC(=O)N2CC(OCc3ccccc3)CC2COc2ccc(C(=O)[O-])cc2OC)ccc1NC(=O)Nc1ccccc1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2CC(O)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Reaction time: 5 h
Yield: 24 %

Procedure:
A stirred mixture of 4-[4-benzyloxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate (440 mg, 0.645 mmol) and 5% Pd/C (400 mg) in AcOH:EtOH (1:1, v/v, 100 mL) was hydrogenated at 1 atm for 5 hr. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The residue was chromatographed on silica-gel with CHCl3:EtOH (10:1, v/v) as eluent to give 90 mg (24%) ethyl 4-[4-hydroxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]-3-methoxybenzoate as a pale yellow oil. 1H-NMR (CDCl3) δ1.39 (3 H, t, J=7.3 Hz), 2.04-2.37 (total 5 H, m), 3.44-4.70 (16 H, series of m), 6.63 (1 H, s), 6.70-6.80 (2 H, m), 6.84 (1 H, d, j=8.3 Hz), 7.11 (1 H, t, J=7.8 Hz), 7.20-7.24(3 H, m), 7.45 (1 H, d, J=2.0 Hz), 7.59 (2 H, dd, J=8.3, 2.0 Hz), 8.01 (1 H, d, J=7.8 Hz).
Reaction SMILES: [CH2:1]([C:8]1[CH2:12][CH2:11][CH2:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18](=O)[CH2:19]Br)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CO>[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]2[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:8]3[N:9]([CH2:10][CH2:11][CH2:12]3)[CH:19]=2)=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: c1ccc(CC2=NCCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(-c2cn3c(c2-c2ccccc2)CCC3)cc1
Yield: 56 %

Procedure:
(according to Laufer et al. J. Med. Chem. 1994, 37, 1894-1897) 2-Benzyl-1-pyrroline (Example 1 a, 19.8 g, 80% strength, 0.1 mol), dissolved in MeOH (300 ml) is treated with 4-chlorophenacyl bromide (23,4 g, 0.1 mol) and then with NaHCO3 (10 g, 0.12 mol) and stirred at RT for 16 h with exclusion of light. Precipitated crystallizate is filtered off with suction and washed with MeOH. 16.4 g (56%) of product are obtained after drying.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.C(=O)([O-])[O-].[K+].[K+].[OH:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][CH:23]([CH2:29][CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1.CC(N(C)C)=O>CC(=O)CC>[O:31]([CH2:30][CH2:29][CH:23]([CH2:22][C:21]1[CH:38]=[CH:39][C:18]([O:17][CH2:2][CH2:3][O:4][CH:5]2[CH2:10][CH2:9][CH2:8][CH2:7][O:6]2)=[CH:19][CH:20]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: BrCCOC1CCCCO1
Reactant: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCC(C)=O
Product: CCOC(=O)C(CCOc1ccccc1)Cc1ccc(OCCOC2CCCCO2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
2-(2-bromoethoxy)tetrahydropyran (1.24 g) and potassium carbonate (1.09 g) were added to a solution of ethyl 2-(4-hydroxybenzyl)-4-phenoxybutyrate (620 mg), which is the product of Reference example 3(d), in 2-butanone (8 ml). The mixture was stirred at 100° C. for 5 hours. To the reaction mixture dimethylacetamide (10 ml) was added and the mixture was stirred at 100° C. for 1.5 hours. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluant to afford the desired compound (738 mg) as a syrup.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3.O.[CH2:19](Br)[CH2:20][CH2:21][CH3:22]>C(O)(C)C>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([OH:16])=[CH:9][CH:8]=3)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCBr
Reactant: O=c1c2ccc(O)cc2oc2cc(O)ccc12
Solvent: CC(C)O
Solvent: O
Product: CCCCOc1ccc2c(=O)c3ccc(O)cc3oc2c1
Reaction time: 72 h

Procedure:
3,6-Dihydroxy xanthone (1,60.7 mmol) was dissolved into hot basic water (Na2CO3 240 mmol in 600 ml water). After the 3,6-dihydroxy xanthone was completely dissolved, the temperature was controlled to 70° C. Isopropyl alcohol (10 ml) was added to the reaction mixture and butyl bromide (180 mmol) was added dropwise. The reaction mixture was stirred rigorously for 72 hours. A white precipitate appeared which was then filtered and washed with water. There was almost no disubstituted compound in the product. This precipitate was dissolved in 3% NaOH, filtered and finally reprecipitated with HCl yielding 90% of 3-butoxy-6-hydroxy xanthone.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3]1=[O:24].[CH3:25][C:26]([CH3:44])([CH3:43])/[CH:27]=[CH:28]/[C@H:29]1[O:34][C:33]([CH3:36])([CH3:35])[O:32][CH:31]2[CH:37]([O:41][CH3:42])[C:38](=[O:40])[O:39][C@H:30]12.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@H:6]1[CH2:5][N:4]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:3](=[O:24])[C@@H:2]([NH:1][C:38](=[O:40])[C@@H:37]([C@H:31]2[C@H:30]([OH:39])[C@@H:29](/[CH:28]=[CH:27]/[C:26]([CH3:43])([CH3:25])[CH3:44])[O:34][C:33]([CH3:36])([CH3:35])[O:32]2)[O:41][CH3:42])[CH2:8][CH2:7]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC1C(=O)O[C@H]2C1OC(C)(C)O[C@@H]2/C=C/C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](N)C(=O)N(Cc2cccnc2)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CN(Cc2cccnc2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@H]1O
Yield: 57.2 %

Procedure:
A solution of (3S,6R)-3-amino-6-(tert-butyl-dimethyl-silanyloxy)-1-pyridin-3-ylmethyl-azepan-2-one (1.84 g, 5.3 mmol), (4R,4aR)-4-((E)-3,3-Dimethyl-but-1-enyl)-7-methoxy-2,2-dimethyl-tetrahydro-furo[3,2-d][1,3]dioxin-6-one (1.0 g, 3.5 mmol) and diisopropylethylamine (1.37 g, 11.0 mmol) in isopropanol (10 mL) is refluxed for 16 h. The solution is evaporated and chromatographed on silica (95% CH2Cl2/5% CH3OH) to give 1.27 g (57.0%) of (R)-N-[(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)2-oxo-1-pyridin-3-ylmethyl-azepan-3-yl]-2-[(4R,5R,6R)-6-((E)-3,3-dimethyl-but-1-enyl)-5-hydroxy-2,2-dimethyl-[1,3]dioxan-4-yl]-2-methoxy-acetamide as a white solid. MS (ESI) 634.3 (M+H)+
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]2[C:22]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[S:29](=[O:32])(=[O:31])[CH2:30][C:21]=3[C:20]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])=[N:19]2)[CH2:13]1.[Na+].[I-]>C(#N)C.C(Cl)Cl>[N:35]1([C:33]([C:20]2[C:21]3[CH2:30][S:29](=[O:32])(=[O:31])[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]=3[N:18]([CH:14]3[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][CH2:10][N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])[CH2:13]3)[N:19]=2)=[O:34])[CH2:36][CH2:37][O:38][CH2:39][CH2:40]1
Reactant: O=C1CCCN1
Reactant: O=C(c1nn(C2CCCN(CCCl)C2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C1CCCN1CCN1CCCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)C1
Yield: 9.9 %

Procedure:
A solution of 2-pyrrolidone (35 mg; 0.42 mmol; 2 eq.) with NaH (10 mg; 0.42 mmol; 2 eq.) in ACN at 0° C. is added to a solution of enantiomer B of 1-[1-(2-chloroethyl)piperidin-3-yl]-3-(morpholin-4-ylcarbonyl)-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg; 0.21 mmol; 1 eq.) and NaI (31 mg; 0.21 mmol; 1 eq.) in ACN (2 mL). Reaction mixture is heated to 60° C. for 18 h after which DCM is added and organic phase is washed with water and brine. It is dried over MgSO4 then purified by MD-Autoprep to give 11 mg (9%) of the title compound as a white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.05 (d, J=7.7 Hz, 1H), 8.00-7.82 (m, 2H), 7.81-7.67 (m, 1H), 4.89-4.64 (m, 3H), 4.00-3.83 (m, 2H), 3.83-3.56 (m, 8H), 3.22-3.12 (m, 1H), 2.99-2.82 (m, 1H), 2.67-2.34 (m, 4H), 2.29-2.15 (m, 2H), 2.15-1.54 (m, 8H). MS (ESI+): 528.5. HPLC (max plot) 97.6%; Rt 1.86 min.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([OH:18])[CH2:13][NH:14]CC=C)=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(#N)C.O>[CH3:1][C:2]1[O:3][C:4]2[C:11]([CH:12]([OH:18])[CH2:13][NH2:14])=[CH:10][CH:9]=[CH:8][C:5]=2[C:6]=1[CH3:7]
Reactant: C=CCNCC(O)c1cccc2c(C)c(C)oc12
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Cc1oc2c(C(O)CN)cccc2c1C
Yield: 43.1 %

Procedure:
1 g (4 mmol) of 2,3-dimethyl-7-(2-allylamino-1-hydroxyethyl)benzofuran, 85 mg (0.092 mmol) of Wilkinson's catalyst (tris(triphenylphosphine)rhodium(I)) and 25 ml of an acetonitrile/water (84/16) mixture are introduced into a 100 ml three-necked flask equipped with a distillation system and a 50 ml dropping funnel. 30 ml of the same acetonitrile/water (84/16) mixture are placed in the dropping funnel. The solution is stirred at reflux, under a nitrogen stream, for 1 h 30, small amounts of acetonitrile/water (84/16) mixture being added regularly in order to replace the solvent distilled off. The mixture is subsequently concentrated under vacuum and the residue is purified by column chromatography (elution solvent: 90/10 dichloromethane/methanol) and then dried in a desiccator under vacuum over phosphorus pentoxide. 354 mg of 2,3-dimethyl-7-(2-amino-1-hydroxyethyl)benzofuran are obtained--M.p.: 73° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])(O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:4]([Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH2:20][CH2:19][C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][C:23]=3[O:32][CH2:33][O:34][CH3:35])=[CH:17][CH2:16]2)=[CH:13][CH:14]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COCOc1ccc(C2(O)CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1ccc(C2=CCC(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)CC2)c(OCOC)c1
Temperature: 25 °C

Procedure:
A round bottomed flask equipped with magnetic stirrer was charged with 4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-[2,4-bis(methoxymethoxy)phenyl]cyclohexanol (125 mg, 0.25 mmol), toluene (10 ml) and p-toluene sulfonic acid monohydrate (3 crystals). The reaction mixture was heated to reflux temperature for 30 min, then cooled to room temperature before adding saturated aqueous sodium bicarbonate (5 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The title compound was isolated without further purification as an oil (118 mg, 98%) and a mixture of diastereoisomers. δH(CDCl3) 0.19 (6H, s), 0.98 (9H, s), 1.84 (1H, m), 2.00 (1H, m), 2.27 (1H, m), 2.44 (2H, m), 2.56 (1H, m), 3.48 (3H, s), 3.49 (3H, s), 5.15 (2×2H, s), 5.79 (1H, m), 6.67 (1H, dd), 6.77 (2H, d), 6.78 (1H, d), 7.07 (2H, d), 7.11 (1H, d).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:13][C:14]1([CH3:28])[C:18]([CH3:20])([CH3:19])[O:17][B:16]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:15]1>>[CH3:19][C:18]1([CH3:20])[C:14]([CH3:13])([CH3:28])[O:15][B:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=3)=[CH:23][CH:22]=2)[O:17]1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: ClCc1ccc2ccccc2n1
Product: CC1(C)OB(c2ccc(OCc3ccc4ccccc4n3)cc2)OC1(C)C
Yield: 90 %

Procedure:
Alkylation of 2-Chloromethyl-quinoline with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol was carried out according to procedures in Step 5A for Example 2A to give 2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-quinoline in 90% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.2 (s, 12 H) 5.3 (s, 2 H) 7.0 (d, J=8.6 Hz, 2 H) 7.5 (m, 1 H) 7.6 (dd, J=11.4, 8.6Hz, 3 H) 7.7 (m, 1 H) 7.8 (dd, J=8.1, 1.5 Hz, 1 H) 7.9 (d, J=8.6 Hz, 1 H) 8.3 (d, J=8.6 Hz, 1 H).
Reaction SMILES: C([C:4]1[CH:8]=[C:7](Cl)[S:6][C:5]=1[S:10]([NH:13][C:14]1[CH:19]=CC(CCO)=C[CH:15]=1)(=[O:12])=[O:11])(=O)C.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C>[CH3:25][O:26][CH2:27][CH2:28][CH2:29][N:13]1[CH:14]([CH3:15])[CH2:19][C:4]2[CH:8]=[CH:7][S:6][C:5]=2[S:10]1(=[O:11])=[O:12]
Reactant: COCCCBr
Reactant: CC(=O)c1cc(Cl)sc1S(=O)(=O)Nc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCN1C(C)Cc2ccsc2S1(=O)=O
Temperature: -20 °C
Reaction time: 4 h
Yield: 81.8 %

Procedure:
The product from Step B (800 mg, 3.95 mmol) was dissolved in DMF (10 mL) and the solution was cooled to -20° C. Sodium hydride (236 mg of an oil dispersion, 5.91 mmol) was added followed by 3-methoxypropyl bromide (1.8 mL, 11.82 mmol) and this mixture was warmed to 0° C. and stirred for 4 hr. The reaction mixture was poured into ice/water (50 mL) and extracted with ethyl acetate (2×100 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL), dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 10% methanol/methylene chloride) to give the desired product (890 mg, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10](Cl)=O.[CH3:13][C:14]1([CH3:27])[C:23]2[C:18](=[CH:19][C:20]([NH2:25])=[C:21]([NH2:24])[CH:22]=2)[NH:17][C:16](=[O:26])[CH2:15]1>>[CH3:13][C:14]1([CH3:27])[C:23]2[CH:22]=[C:21]3[NH:24][C:10]([C:2]4[NH:1][C:9]5[C:4]([CH:3]=4)=[CH:5][CH:6]=[CH:7][CH:8]=5)=[N:25][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:26])[CH2:15]1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CC1(C)CC(=O)Nc2cc(N)c(N)cc21
Product: CC1(C)CC(=O)Nc2cc3nc(-c4cc5ccccc5[nH]4)[nH]c3cc21
Yield: 45 %

Procedure:
In a manner analogous to that described in Example 2, from indole-2-carboxylic acid chloride and 4,4-dimethyl-6,7-diamino-1,2,3,4-tetrahydroquinolin-2-one (see Example 13 a)), after column chromatography, there was obtained a yield of 45% of theory of the title compound; m.p. 264°-267° C.