Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[C:13](=[O:16])[O:12][C:11](=[O:17])[NH:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC(N(C)C)=O>[CH2:24]([N:10]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[S:15][C:14]=2[C:13](=[O:16])[O:12][C:11]1=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2cc(-c3ccccc3)sc2c(=O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1oc(=O)n(Cc2ccccc2)c2cc(-c3ccccc3)sc12
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of 6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione (1 g, 4.1 mmol) and anhydrous sodium carbonate (477 mg, 4.5 mmol) diluted in 15 ml of anhydrous dimethylacetamide was stirred for one hour under nitrogen before adding benzyl bromide (785 mg, 4.5 mmol). The mixture was stirred overnight at room temperature. 912 mg (66.3%) of 1-benzyl-6-phenyl-1H-thieno[3,2-d][1,3]oxazine-2,4-dione were obtained as a pale yellow solid after filtration and washing the precipitate with acetone and pentane. NMR 1H (DMSO D6, 400 MHz) 7.8-7.76 ppm (m, 3H, Haro); 7.51-7.45 ppm (m, 3H, Haro); 7.43-7.41 ppm (m, 2H, Haro); 7.35-7.3 ppm (m, 2H, Haro); 7.28-7.24 ppm (m, 1H, Haro); 5.22 ppm (s, 1H, NCH2).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.[N:25](OCCCC)=[O:26]>C(OCC)C>[CH3:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([N:25]=[O:26])[CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)OCC(c1ccccc1)=N2
Reactant: CCCCON=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1ccc2c(c1)OCC(c1ccccc1)N2N=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 7-methyl-3-phenyl-2H-1,4-benzoxazine (22.5 g, 99.87 mmol) in ethyl ether (300 mL) is added trifluoroacetic acid (7.7 mL, 99.87 mmol). The resulting solution is chilled to 5° C. in an ice bath and n-butyl nitrite (12.26 mL, 99.87 mmol) is added dropwise. The mixture is stirred for 1 h; solids formed during the reaction. The solids are collected by filtration and washed with ether. The filtrates are partitioned between ether and water and the organic layers are washed three times with water (500 mL), dried over magnesium sulfate, and concentrated to dryness. The combined solids gave 23.22 g (97%) of 7-methyl-4-nitroso-3-phenyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [CH:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])([CH3:3])[CH3:2]>[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[NH2:15][C:11]1[CH:10]=[C:9]([S:6]([NH:5][O:4][CH:1]([CH3:3])[CH3:2])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)ONS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Product: CC(C)ONS(=O)(=O)c1cccc(N)c1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a Parr H2 vessel containing 5% Pd/BaSO4 (0.350g) was added a methanolic solution (125 mL) of N1-isopropoxy-3-nitro-1-benzenesulfonamide (3.50 g, 0.0135 mol) at rt under Ar atm. The solution was hydrogenated at 45psi for approx. 1.0 h. The reaction mixtire was filtered (1/2″ celite pad) and evaporated to give the product as yellow crystalline solid 2.90 g (96%). 1H NMR (CDCl3) 1.20(d,25H); 4.27(m,1H) 7.05(s,1H); 7.75(1,1H); 8.22(d,1H); 8.48 (dd,1H); 8.74(t, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=[O:12])[C:4]([CH3:16])=[N:3]1.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COCCOC.O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH2:11][OH:12])[CH:13]=[CH:14][CH:15]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Cc1nn(C)c(C)c1-c1cccc(C=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1nn(C)c(C)c1-c1cccc(CO)c1
Reaction time: 3 h
Yield: 58 %

Procedure:
3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)benzaldehyde (2.05 g, 9.57 mmol) was dissolved in a mixed solution of 1,2-dimethoxyethane (10 mL) and tetrahydrofuran (10 mL), sodium borohydride (0.265 g, 7.00 mmol) was added under ice-cooling, and the mixture was stirred under a nitrogen atmosphere at the same temperature for 3 hr. Dilute aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane-ethyl acetate) to give the title compound (1.20 g, yield 58%) as a colorless oil. MS: m/z 217 (MH+).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7]2.Br.OS([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][CH:12]=[C:4]([Cl:3])[CH:5]=2)[C:9]1=[O:13]
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: BrBr
Agent: Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1Br
Reaction time: 2 h

Procedure:
A solution of 37.9 g (0.237 mole) of bromine in 120 ml of glacial acetic acid is slowly added dropwise, whilst stirring, to a solution of 40.0 g (0.237 mole) of 5-chloro-1-indanone in 590 ml of glacial acetic acid, to which 0.2 ml of 48% strength aqueous hydrobromic acid has been added. The mixture is stirred for a further 2 hours and the reaction solution is poured into 1 l of water, to which 2.5 g of NaHSO3 have been added. The product, which initially precipitates in the viscous form, becomes crystalline after stirring for a relatively long time. The crude product is filtered off (melting point 69°-76° C.), washed with water and recrystallized from petroleum ether. The pure 2-bromo-5-chloro-1-indanone melts at 89°-90° C.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][CH2:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:30][CH3:31])CC)C>ClCCl.C(OCC)(=O)C>[CH:19]1[C:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:2]([NH:1][C:6](=[O:7])[C:5]4[CH:4]=[CH:3][CH:2]=[CH:24][C:30]=4[CH3:31])=[CH:3][CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 130.8 %

Procedure:
A mixture of 0.10 g of 5-(4-aminobenzoyl)-6,7-dihydro-5H-dibenz[b,d]azepine, 0.10 g of triethylamine in 1 ml of dichloromethane is stirred at room temperature for 6 hours. The mixture is diluted with 6 ml of ethyl acetate and the solution washed with 1N HCl, 1N NaOH, brine and dried (Na2SO4). The solvent is removed and the solid purified by chromatography on thick layer silica gel plates with the solvent ethyl acetate-hexane (1:1) to give 90 mg of a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](O)=[O:8].[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:34][CH2:35][NH2:36])=[CH:30][NH:31]2)=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:33]=[C:32]2[C:28]([C:29]([CH2:34][CH2:35][NH:36][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:8])=[CH:30][NH:31]2)=[CH:27][CH:26]=1
Reactant: NCCc1c[nH]c2cc(F)ccc12
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)O
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)NCCc1c[nH]c2cc(F)ccc12

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carboxylic acid 100 and 2-(6-fluoro-1H-indol-3-yl)ethylamine in a similar manner as that described for example 102. 1H NMR (CD3CN) δ 8.48 (1H, d, J=5.6 Hz), 7.91 (1H, d, J=5.6 Hz), 7.63–7.59 (2H, m), 7.54 (1H, d, J=5.6 Hz), 7.38 (1H, d, J=2.3 Hz), 7.17 (1H, d, J=2.3 Hz), 7.14 (1H, t, J=2.3 Hz), 7.11 (1H, d, J=2.3 Hz), 6.85 (1H, m), 6.65 (1H, bm), 6.61 (1H, d, J=5.6 Hz), 3.69 (2H, q, J=7.1 Hz), 3.06 (2H, t, J=7.1 Hz), 2.57 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C1N=CN([C:19](N2C=NC=C2)=[O:20])C=1.O>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]2[CH2:5][NH:6][C:19](=[O:20])[NH:1][CH2:2][C:3]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc([N+](=O)[O-])cc1CN
Solvent: O
Solvent: C1CCOC1
Product: O=C1NCc2ccc([N+](=O)[O-])cc2CN1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
2-aminomethyl-4-nitrobenzylamine (3.10 g, 17.1 mmol) was dissolved in tetrahydrofuran (300 mL) and a solution of N,N-carbonyldiimidazole (2.78 g, 17.1 mmol) in THF (40 mL) was added dropwise at room temperature over 30 minutes. The reaction was allowed to stir at room temperature for 72 hours. The solution was then poured over water (150 mL) and organics were extracted with ethyl acetate (3×100 mL). Combined organic extracts were dried over Na2SO4, filtered and reduced to afford 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one as a crude brown solid. Purification by flash column chromatography (0% MeOH/DCM-10% MeOH/DCM) afforded 2.5 grams of 7-nitro-1,2,4,5-tetrahydro-benzo(e)(1,3)diazepin-3-one as a yellow solid. LC/MS (ESI)=208.42 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9](N(CC=C)CC=C)=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3].[Cl:26]C1C([N+]([O-])=O)=CC(C(O)=O)=CC=1[N+]([O-])=O.C(O)CC>S(=O)(=O)(O)O.O>[CH2:1]([O:4][C:5](=[O:25])[C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Cl:26])=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[CH2:2][CH3:3]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: C=CCN(CC=C)c1c([N+](=O)[O-])cc(C(=O)OCCC)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1

Procedure:
According to a preferred form of realization of the process of the present invention n-propyl-4-diallylamino-3,5-dinitro-benzoate may be prepared by reacting 1 mole of 4-chloro-3,5-dinitro-benzoic acid with 1.25 moles of n-propanol at a temperature between 85° C. and 90° C., in the presence of a sulfuric acid catalyst, whereby the water formed is removed by azeotropic distillation with benzene. The distillation of water having been completed (5-7 hours) the reaction mixture, is cooled and the n-propyl-4-chloro-3,5-dinitro-benzoate is isolated. This compound is reacted with a 1.1 molar amount of diallyl amine at a temperature between 70° C. and 80° C., in an aqueous melt in the presence of 0.1 mole of 75% phosphoric acid and 1.05 moles of a 10% sodium hydroxide solution as acid binding agent. The reaction mixture is allowed to sedimentate, the organic phase is poured into water and the crystalline n-propyl-4-diallylamino-3,5-dinitro-benzoate is isolated.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][CH2:17][CH2:18]Br>C(O)C>[Br:16][CH2:17][CH2:18][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 70 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (3 g, 0.024 mol) in ethanol (30 mL) was added potassium carbonate (6.6 g, 0.047 mol) and 1,2-dibromoethane (21 mL, 0.24 mol). The reaction mixture was stirred at 70° C. for 20 hours. The salts were filtrated and the filtrate was concentrated. The crude was dissolved in ethyl acetate and the organic layer was washed with water, sodium hydroxide 2N and brine, dried, and filtered. The organic solvent was removed under reduced pressure to give the title compound as a yellow-orange solid (88%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:11]=[C:10]([CH2:12][CH3:13])[C:9]([C:14]2[NH:18][C:17]([CH2:19][CH2:20][O:21][CH3:22])=[N:16][N:15]=2)=[CH:8][C:4]=1[C:5]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:7])[CH3:2]
Reactant: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)O
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc(CC)c(-c2nnc(CCOC)[nH]2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
To a round-bottom flask was added a solution of 2,4-diethyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)benzoic acid (compound 209.1, 300 mg, 0.940 mmol, 1.00 equiv, 95%) in N,N-dimethylformamide (20 mL). 4-(Piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 243 mg, 1.09 mmol, 1.10 equiv), EDC.HCl (380 mg, 1.98 mmol, 2.00 equiv), and 4-dimethylaminopyridine (240 mg, 1.96 mmol, 2.09 equiv) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature, then diluted with 100 mL of ethyl acetate. The organic layer was washed with 3×15 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate as eluent. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001 (SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (35% CH3CN up to 60% in 8 min, up to 100% in 1 min, down to 35% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 188 mg (42%) of the title compound as a white solid. m/z (ES+) 472 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)CCC1CCCC1
Solvent: c1ccncc1
Product: CC(C)(C)c1c(NC(=O)CCC2CCCC2)nn2cccnc12
Yield: 77.6 %

Procedure:
A mixture from Example 105B (71.2 mg, 0.37 mmol) and 3-cyclopentylpropionyl chloride (94.4 mg, 0.59 mmol) in pyridine (2 mL) was stirred at ambient temperature for 5 h. The mixture was concentrated. Purification by reverse phase HPLC afforded 90.3 mg (77%) of the title compound. 1H NMR (300 MHz, DMSO-d6): δ ppm 1.04-1.15 (m, 2H), 1.44-1.81 (m, 18H), 2.27-2.31 (m, 2H), 6.99 (dd, J=7.0, 3.9 Hz, 1H), 8.48 (dd, J=3.9, 1.9 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.67 (br s, 1H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:19]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]4[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=4)(=[O:37])=[O:36])[CH:29]=3)[NH:24][N:23]=2)(=[O:21])=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CC(C)=O>[CH2:1]([N:24]1[C:25]2[C:30](=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:27][CH:26]=2)[C:22]([S:19]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)(=[O:20])=[O:21])=[N:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzyl bromide (0.46 mL, 3.9 mmol) was added to a stirring suspension of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (1.85 g, 3.54 mmol) and cesium carbonate (1.28 g, 3.93 mmol) in acetone (60 mL). The reaction mixture was stirred under nitrogen at ambient temperature for 1.5 hours. It was then poured into excess water and extracted with chloroform. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography with 40-50% ethyl acetate in hexane. Drying at 80° C. in vacuo for 30 minutes yielded toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester as a light buff foam (1.39 g, 64.1%); Mass Spectrum (+EI, [M+H]+) m/z 613. 1HNMR (500 MHz, DMSO-d6): δ8.74-8.77 (m, 1H), 8.55-8.57 (m, 1H), 8.25-8.27 (m, 1H), 8.01-8.05 (m, 1H), 7.64-7.76 (m, 4H), 7.58-7.64 (m, 2H), 7.25 (d, 2H, J=7.93 Hz), 7.10-7.19 (m, 5H), 7.07 (d, 1H, J=2.19 Hz), 6.94-6.97 (m, 1H), 5.69 (s, 2H), 4.30-4.32 (m, 2H), 4.14-4.16 (m, 2H), 2.18 ppm (s, 3H). Elemental Analysis for C33H28N2O6S2.0.60 mol H2O: Calcd: C, 63.57; H, 4.72; N, 4.49; Found: C, 63.17; H, 4.63; N, 4.30.
Reaction SMILES: C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:40]=[C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)[CH:38]=[CH:37][C:21]=1[CH2:22][NH:23][C:24](=[O:36])[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([CH3:33])=[C:27]([O:34][CH3:35])[CH:26]=1.[C:47]1([CH2:53][CH:54]=O)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCCl>[CH3:35][O:34][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([O:31][CH3:32])[C:28]=1[CH3:33])[C:24]([NH:23][CH2:22][C:21]1[CH:37]=[CH:38][C:39]([C:41]2[N:45]=[C:44]([CH3:46])[O:43][N:42]=2)=[CH:40][C:20]=1[NH:19][CH2:54][CH2:53][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:36]
Reactant: O=CCc1ccccc1
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2N)cc(OC)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCc2ccccc2)cc(OC)c1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic acid (0.040 mL, 5 eq) and sodium triacetoxyborohydride (42 mg, 0.20 mmol) were added to a suspension of compound 1g (50 mg, 0.13 mmol) and phenylacetaldehyde (0.020 mg, 2 eq) in DCE (1.5 mL). The reaction was stirred at rt for 16 h and concentrated on a rotary evaporator. The residue was purified by preparative tlc (silica gel, 1:1 ethyl acetate/hexane) to afford compound 9a. ESI-MS m/e 487.3 (M+1).
Reaction SMILES: [Li]CCCC.[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[CH3:7].[CH2:15]([Sn:19](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1>[CH2:6]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Sn:19]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:16][CH2:17][CH3:18])[CH3:7]
Reactant: CCOCn1ccnc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
1.6 M n-BuLi (12.0 mL, 19.2 mmol) is slowly added to a solution of 1-ethoxymethyl-1H-imidazole (2.20 g, 17.4 mmol; prepared essentially as described by Tang, et al. (1978) J. Am. Chem. Soc. 100:3918) in THF (30 mL) at −78° C. under N2. The reaction mixture is stirred at −78° C. for 20 minutes, whereupon tributyltin chloride (5.7 mL, 20.9 mmol) is slowly added. The reaction mixture is stirred at −78° C. for 10 minutes, and then warmed to room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture is concentrated in vacuo. The residue is triturated with hexanes and filtered, and the filtrate is concentrated in vacuo. The residue is again triturated with hexanes and filtered, and the filtrate concentrated in vacuo. The 1H NMR of the resulting oil indicates a 2:1 mixture of 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole: 1-ethoxymethyl-1H-imidazole. This material is used in the next reaction without further purification. Selected 1H NMR resonances (400 MHz, CDCl3) δ 7.21 (s, 1H), 7.14 (s, 1H), 5.24 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[S:4][C:3]=1[C:11]([O-:13])=O.C[Al](C)C.[CH3:18][NH2:19]>C(Cl)Cl>[CH3:18][NH:19][C:11]([C:3]1[S:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=1[NH2:1])=[O:13]
Reactant: CN
Reactant: CC(C)(C)c1cc(N)c(C(=O)[O-])s1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CNC(=O)c1sc(C(C)(C)C)cc1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14 %

Procedure:
Under argon, 3-amino-5-tert-butyl-thiophene-2-carboxylate (2.13 g, 10 mmol) was added to a premixed (15 minutes) methylene chloride (50 mL) solution of trimethylaluminum (5.0 mL, 2.0 M in hexanes) and methylamine (5.0 mL, 2.0 M in THF). The mixture solution was stirred at room temperature for 10 minutes and heated at 41° C. for 3 days. The mixture was cooled and carefully quenched with dilute HCl followed by extraction with methylene chloride. The organic phase was dried over sodium sulfate and concentrated. Column chromatography (hexanes/ethyl acetate) gave 0.3 g of 3-amino-5-tert-butyl-thiophene-2-carboxylic acid methylamide in 14% yield: 1H NMR (300 MHz, CDCl3) δ 6.44 (s, 1H), 5.6 (br, 2H), 5.4 (br, 1H), 3.02 (d, 3H), 1.44 (s, 9H); MS (m/e): 212.9 (M+1).
Reaction SMILES: C(N(CC)CC)C.[SH:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1.[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[CH3:15]>C1COCC1>[CH2:14]([O:16][C:17](=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:8][C:9]1[S:10][CH2:11][CH2:12][N:13]=1)[CH3:15]
Reactant: CCOC(=O)CCc1ccccc1Br
Reactant: SC1=NCCS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccccc1SC1=NCCS1

Procedure:
1.4 ml of triethylamine are added dropwise to a solution of 1.8 g of 2-mercapto-1,3-thiazoline and 2.6 g of 2-bromo-hydrocinnamic acid ethyl ester in 15 ml of THF and the whole is stirred under reflux for 6 hours. The reaction mixture is filtered, the filtrate is concentrated by evaporation and the residue is partitioned between ethyl acetate and water. The organic phase is washed with water, dried, concentrated by evaporation and purified by chromatography on silica gel with eluant R. Rf (W)=0.67.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH2:19][CH2:18][C@@:17]34[C:20]5[C:26]6[CH2:27][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][C:11]2([C@@H:16]4[O:22][C:21]=5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=6)OCC[O:12]2)[CH2:4][CH2:3][CH2:2]1>Cl>[CH:1]1([CH2:5][N:6]2[CH2:19][CH2:18][C@@:17]34[C:20]5[C:26]6[CH2:27][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][C:11](=[O:12])[C@@H:16]4[O:22][C:21]=5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=6)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc2c3c1O[C@H]1C4(CC[C@H]5[C@@H](C2)N(CC2CCC2)CC[C@@]351)OCCO4
Agent: Cl
Product: N#Cc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(CC2CCC2)CC[C@]314
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A suspension of (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-1,2,3,4,4a,5,6,7a-octahydrospiro[4,12-methanobenzofuro[3,2-e]isoquinoline-7,2′-[1,3]dioxolane]-9-carbonitrile (31.1 g, 79.2 mmol) in 6M HCl(aq) (250 mL) was stirred at room temperature at room temperature for 24 hours. Further 6M HCl was added (25 mL) and stirred for an additional 24 hours. The reaction was poured onto ice/NH3(aq) and stirred for 30 minutes and the solid collected by suction filtration and washed with water. The solid was dissolved in dichloromethane and washed with brine, dried over MgSO4 and concentrated under reduced pressure to give (4R,4aR,7aR,12bS)-3-(cyclobutylmethyl)-7-oxo-2,3,4,4a,5,6,7,7a-octahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-9-carbonitrile (26.1 g, 96% pure LCMS, 95% yield); [M+H]+ 367.2.