Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH:2]=1.[H-].[Na+].[CH2:19]([N:21]1[C:27](=[O:28])[C:26]([CH3:30])([CH3:29])[C:25](=[O:31])[N:24]([CH3:32])[C:23]2[CH:33]=[C:34]([O:37][CH2:38][CH2:39][CH2:40]I)[CH:35]=[CH:36][C:22]1=2)[CH3:20].C(O)C.[ClH:45]>CN(C=O)C.C(O)(C)C>[ClH:45].[CH2:19]([N:21]1[C:27](=[O:28])[C:26]([CH3:29])([CH3:30])[C:25](=[O:31])[N:24]([CH3:32])[C:23]2[CH:33]=[C:34]([O:37][CH2:38][CH2:39][CH2:40][N:9]3[C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:16])[CH:35]=[CH:36][C:22]1=2)[CH3:20]
Reactant: O=c1[nH]c2ccccc2n1-c1cccnc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCI)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCn3c(=O)n(-c4cccnc4)c4ccccc43)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(Pyridin-3-yl)-1,3-dihydrobenzimidazole-2-one(0.2 g) was suspended in DMF(6 ml). Sodium hydride (55% in oil, 48 mg) was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. 1-Ethyl-7-(3-iodopropoxy)-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.45 g) was added to the mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was poured to ice water(100 ml), followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). The purified product was condensed under reduced pressure. A 0.5N-hydrogen chloride ethanol solution(1.9 ml) was added to an isopropyl alcohol solution of the residue. The mixture was condensed under reduced pressure. Ether was added to the residue. The generated insoluble matter was separated by filtration and dried to give the title compound(0.38 g) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:21])[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:21][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CN(C1CCOCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C1CCNCC1)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A mixture of 4-[methyl(tetrahydropyran-4-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (101 mg, 0.34 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methylpiperidin-4-yl(tetrahydropyran-4-yl)amine as a white solid (66 mg, 97%). 1H NMR (CDCl3, 300 MHz): δ 4.05-3.97 (m, 2 H); 3.38 (td, J=10.9, 3.8 Hz, 2 H); 3.19 (d, J=12.1 Hz, 2 H); 2.84-2.57 (m, 5 H); 2.27 (s, 3 H); 1.80-1.49 (m, 8 H).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([C:12]1([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]1=[O:24])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:60]1(=[O:70])[NH:64][C:63](=[O:65])[C:62]2=[CH:66][CH:67]=[CH:68][CH:69]=[C:61]12>C1COCC1>[O:65]=[C:63]1[C:62]2[C:61](=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:60](=[O:70])[N:64]1[CH2:2][CH2:3][CH:4]([C:12]1([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]1=[O:24])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)CC1(C(CCO)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)CC1(C(CCN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of tert-butyl α-(2-hydroxyethyl)-3-(2-methylpropyl)-2-oxo-1-(phenylmethyl)-3-pyrrolidineacetate (435 mg, 1.12 mmol) in dry THF (10 mL) is treated with triphenylphosphine (323 mg, 1.23 mmol), diethylazodicarboxylate (194 μL, 1.23 mmol), and phthalimide (181 mg, 1.23 mmol). The solution is allowed to stir overnight at room temperature under N2. The reaction mixture is concentrated and purified by silica gel chromatography (25 g SG, 20% EtOAc/hexane) to give 518 mg (89%) of the title compound as an off-white, amorphous solid.
Reaction SMILES: ClS(O)(=O)=O.[F:6][C@H:7]1[C:24]2[C@:19]([CH3:26])([CH2:20][CH2:21][C:22](=[O:25])[CH:23]=2)[C@:18]2(O)[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH2:17]2)([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]3)[CH2:8]1>C(Cl)Cl>[F:6][C@H:7]1[C:24]2[C@:19]([CH3:26])([CH2:20][CH2:21][C:22](=[O:25])[CH:23]=2)[C:18]2[C@H:9]([C@H:10]3[C@@:14]([CH2:16][CH:17]=2)([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]3)[CH2:8]1
Reactant: C[C@]12CCC(=O)C=C1[C@H](F)C[C@H]1[C@@H]3CCC(=O)[C@@]3(C)CC[C@@]12O
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Product: C[C@]12CCC(=O)C=C1[C@H](F)C[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 1.25 h

Procedure:
Chlorosulfonic acid (2.0 ml) is added to methylene chloride (50 ml) containing 6β-fluoro-9α-hydroxyandrost-4-ene-3,17-dione (III, Example 2, 5.2 g) previously cooled to -20°. After 1.25 hr, the cold solution is quenched by adding slowly water (2 ml). The organic mixture is then washed with water, aqueous sodium carbonate, dried over sodium sulfate, and the organic solvent removed under reduced pressure to give the title compound. Rf (ethyl acetate/hexane, 1/1)=0.5; NMR (CDCl3) 0.9, 1.5, 5.1, 5.6 and 5.9 δ.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)(C(C)(C)C)(C)C.O[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>C(Cl)Cl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:25]=[CH:24][C:23]([O:19][C:17](=[O:18])[C:16]3[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:21][CH:20]=3)=[CH:28][CH:27]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCOc1ccc(C(=O)O)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(OC(=O)c3ccc(OCCCO)cc3)cc2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2 (10 g, 32.21 mmol), 4′-hydroxy-biphenyl-4-carbonitrile (6.35 g, 32.53 mmol), and toluenesulfonic/4-(dimethylamino)pyridine complex (0.95 g, 3.22 mmol) in anhydrous methylene chloride (100 mL) was added N,N-dicyclohexylcarbodiimide (6.98 g, 33.82 mmol) under argon. The reaction mixture was stirred at 40° C. overnight. Upon filtering off the white residues, the filtrate was diluted with additional methylene chloride. The solution was then washed with water. The silyl ether of the title compound was purified by flash column chromatography on silica gel with gradient elution from 0 to 2% acetone in methylene chloride. The silyl-protected compound was hydrolyzed in tetrahydrofuran: water:acetic acid (80 mL: 80 mL: 240 mL) overnight. The volume of the solution was reduced by 50% via evaporation under reduced pressure. Methylene chloride was added to the slurry for washing sequentially with H2O, a 10% NaHCO3 solution and brine before drying over anhydrous MgSO4. The crude product resulting from evaporation of the solvent was purified by recrystallization from ethanol to yield 3 (10.71 g, 89%). 1H NMR spectral data (400 MHz, CDCl3): δ 2.10 (quintet, 2H, —CH2—), δ 3.95 (t, 2H, —CH2OAr), δ 4.25 (t, 2H, HOCH2—), δ 7.00–8.25 (m, 12H, aromatic rings).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11]([CH2:14]C)[C:9]=2[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:11]([CH3:14])[N:12]=[N:13][N:10]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cn1nnnc1CCl
Product: Cn1nnnc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-tetrazole and isolated as yellow solid. MS(m/e): 415.3 (MH+).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[NH2:2].[C:15](/[N:17]=[C:18](\OC1C=CC=CC=1)/[NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]2)=[C:22]([F:34])[CH:21]=1)#[N:16]>CN1CCCC1=O>[F:34][C:22]1[CH:21]=[C:20]([NH:19][C:18]2[N:17]=[C:15]([NH2:16])[N:1]([C:3]3[N:4]=[CH:5][C:6]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[N:8]=3)[N:2]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH2:32][CH2:31][CH2:30][N:29]([CH3:33])[CH2:28][CH2:27]1
Reactant: NNc1ncc2c(n1)CCCCCC2
Reactant: CN1CCCN(c2ccc(N/C(=N/C#N)Oc3ccccc3)cc2F)CC1
Solvent: CN1CCCC1=O
Product: CN1CCCN(c2ccc(Nc3nc(N)n(-c4ncc5c(n4)CCCCCC5)n3)cc2F)CC1

Procedure:
2-Hydrazinyl-5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidine (58 mg, 0.30 mmol) and (Z)-phenyl N′-cyano-N-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)carbamimidate (111 mg, 0.30 mmol) were dissolved in anhydrous N-methylpyrrolidone (0.5 mL) and subjected to microwave irradiation (220° C., 10 min). The crude reaction mixture was directly purified by C-18 reversed phase chromatography, eluting with acetonitrile and water containing 0.05% formic acid to give N3-(3-fluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-1-(5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidin-2-yl)-1H-1,2,4-triazole-3,5-diamine, compound #4, as a beige solid, 30 mg; 1H NMR (CDCl3/MeOD4, 300 MHz) 8.22 (s, 1H), 8.19 (s, 1H), 7.26 (d, 1H), 6.93 (d, 1H), 6.71 (t, 1H), 3.23 (m, 6H), 3.16 (m, 2H), 2.81 (m, 2H), 2.69 (s, 3H), 2.61 (m, 2H), 2.12 (m, 2H), 1.69 (m, 2H), 1.56 (m, 2H), 1.27 (m, 4H) ppm; MS (ES) 466.27 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][NH2:4].C(N(CC)CC)C.[I:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[I:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:4][CH2:3][CH:2]([CH3:5])[CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: CC(C)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNS(=O)(=O)c1ccc(I)cc1
Yield: 92.4 %

Procedure:
A solution of (2-methylpropyl)amine (121 mg, 1.65 mmol) and triethylamine (0.35 ml, 2.47 mmol) in DCM (10 ml) was treated with 4-iodobenzenesulfonyl chloride (500 mg, 1.65 mmol) by dropwise addition over 10 minutes with stirring under argon. The reaction mixture was stirred at room temperature for 16 hr. Then the reaction mixture was washed with water (10 ml), separated the organic layer, dried with sodium sulphate. Solvent was removed by rotary evaporation to give the title compound as a white solid (517 mg, 92%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:44])[CH3:43])[CH:29]([O:34][Si](C(C)(C)C)(C)C)[C:30]([F:33])([F:32])[F:31])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:45])[N:14]([CH2:24][C:25]([NH:27][CH:28]([CH:42]([CH3:43])[CH3:44])[CH:29]([OH:34])[C:30]([F:32])([F:31])[F:33])=[O:26])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O[Si](C)(C)C(C)(C)C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)F
Reaction time: 4.5 h
Yield: 100.4 %

Procedure:
A solution 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(2-tert-butyldimethylsilyloxy-3,3,3-trifluoro-1-isopropylpropyl)acetamide (0.96 g) in dry tetrahydrofuran (8 mL) was treated with tetrabutylammonium fluoride (1M in tetrahydrofuran; 1.62 mL) and the mixture was stirred for 4.5 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with water (twice) and brine, dried and evaporated to yield a yellow foam. Purification by flash chromatography, eluting with ethyl acetate:chloroform (first 5:95, then 10:90), and overnight drying under vacuum gave 2-(3-benzyloxycarbonylamino-2-oxo-6-phenyl-1,2-dihydro-1-pyridyl)-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide as a white solid (0.793 g); TLC: Rf =0.19, chloroform:ethyl acetate (20:1); 300 MHz NMR: 0.81 (d,3, J=6.7), 0.88 (d,3, J=6.7), 1.67-1.84 (m,1), 3.82 (t,1, J=8.8), 4.0-4.17 (m,1), 4.34 (d,1, J= 15), 4.50 (m,1), 5.18 (s,2), 6.20 (d,1, J=7.7), 6.49 (d,1, J=7), 7.31-7.47 (m,10), 7.86 (d,1, J=9.7), 7.91 (d,1 J=7.7), 8.53 (s,1); MS: m/z=532(M+1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1
Reactant: BrBr
Reactant: Oc1cccc2c1CCCC2
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 37 grams (0.25 mole) of 5,6,7,8-tetrahydronaphthol in 150 ml of carbon tetrachloride was added dropwise with stirring a solution of 44 grams (0.25 mole) of bromine in 50 ml of carbon tetrachloride. When the addition was complete the mixture was stirred for 30 minutes at room temperature and then evaporated in vacuo to a residue which after two recrystallizations from hexane provided 13 grams (22.9 percent) of product, m.p. 83°-85°C.
Reaction SMILES: C([S:4][CH2:5][CH:6]([C:24]([F:27])([F:26])[F:25])[C:7]([NH:9][C@H:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])(=O)C.S([O-])(O)(=O)=O.[K+].C(OCC)(=O)C.C(O)(=O)C>[OH-].[NH4+].O.CO>[F:27][C:24]([F:25])([F:26])[CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:21]([OH:23])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8]
Reactant: CC(=O)SCC(C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)C(CS)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.23 h

Procedure:
A suspension of the product of Example 7 (2.6 g., 6.5 mmol.) in 4.25 mL of concentrated ammonium hydroxide and 9.3 mL of water was stirred at room temperature under argon for 12-15 minutes. The resulting solution was acidified with 200 mL of 5% potassium hydrogen sulfate and extracted with ethyl acetate (5×50 mL). The combined ethyl acetate extract was washed with brine, dried (MgSO4) and evaporated to give 2.4 g. of a light yellow solid. This material was combined with an additional 80 mg. of compound and flash chromatographed on 300 g. of silica gel eluting with methylene chloride:methanol:acetic acid, 40:1:1 to give 2.3 g. of white solid. This solid was triturated with toluene containing approximately 5% ethyl acetate, and 1.25 g. of white crystalline solid was collected by filtration. The filtrate was evaporated to dryness and the residue was triturated in a similar fashion to produce an additional 560 mg. of material which was combined with the initial 1.25 g. crop to yield 1.81 g. of title isomer A compound as a white crystalline solid; m.p. 148.5°-150.5° C., TLC Rf =0.48 (300:100:1 ethyl acetate:hexanes:acetic acid), [α]D =-10.3° (c=1.00, methanol).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[C:14]([CH3:24])[S:13][C:4]=2[NH:5][C:6](=[O:12])[C:7]=1C(OC)=O.[OH-].[Na+].C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[NH2:1][C:2]1[C:3]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)=[C:14]([CH3:24])[S:13][C:4]=2[NH:5][C:6](=[O:12])[CH:7]=1
Reactant: COC(=O)c1c(N)c2c(-c3cccc(OC)c3)c(C)sc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(N)c23)c1
Temperature: 25 °C
Yield: 43.7 %

Procedure:
To a stirred suspension of methyl 4-amino-2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (Description 35) (1.617 g, 4.70 mmol) in ethanol (20 mL) was added aqueous NaOH (5M) (4.70 mL, 23.48 mmol). The suspension was then refluxed under nitrogen for ca. 2 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The residue was partitioned between DCM and water (ca. 50 mL each) and acidified to ca. pH 7 using aqueous HCl (5M). The aqueous layer was separated and re-extracted with DCM (ca. 50 mL×2) and the combined organic layer passed through a phase separator and concentrated in vacuo. The residue was dissolved in diphenyl ether (20 mL, 126 mmol) and heated to 200° C. under nitrogen atmosphere for ca. 2 h. The mixture was then cooled to RT, passed through SCX cartridge (eluting with MeOH followed by 2M NH3 MeOH) and the basic fractions combined and concentrated in vacuo. The residue was purified by normal phase chromatography, eluting with a gradient of 0-20% MeOH in DCM, to afford the title compound (588 mg). LCMS (A) m/z: 285 [M−1]−, Rt 1.10 min (acidic).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:12]([O:19]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
To a stirring solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.27 g, 34.2 mmol) in dichloromethane (35 mL) cooled down to 0° C. was added dropwise a solution of m-chloroperoxybenzoic acid (8.65 g, 1.1 eq) in dichloromethane (50 mL). The mixture stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane and 5% potassium carbonate solution. The combined organic layers were washed with brine, separated and dried (MgSO4). The crude product was purified by column chromatography to yield a (±)-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (4.43 g) as a pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:77][NH:78][CH3:79]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:77][N:78]([CH3:79])[C:2]1[CH:3]=[C:4]([F:24])[C:5]2[N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][C:10]([Br:16])=[CH:9][CH:8]=3
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1c2ccc(Br)cc2Sc2cc(Br)cc(F)c21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)c1cc(F)c2c(c1)Sc1cc(Br)ccc1N2C(=O)OC(C)(C)C

Procedure:
To a stirred solution of 3,7-dibromo-1-fluoro-10-Boc-phenothiazine (1.43 g, 3.0 mmol) in toluene (60 mL) in 75 mL pressure vessel Pd(dba)2 (86.3 mg, 0.15 mmol), BINAP (67.3 mg, 0.11 mmol), Cs2CO3 (978 mg, 3.0 mmol) and dimethylamine (1.5 mL, 2 M solution in THF) were added. The mixture was refluxed for 24 h. After that reaction mixture was filtered, solvent was removed under vacuum. Product was used without additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[CH3:13][N:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](Cl)=[O:16]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:15](=[O:16])[N:14]([CH3:13])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[CH:9][CH:8]=2)[C:4](=[O:12])[O:5]1
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc2c1C(=O)OC2=O)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxy-isobenzofuran-1,3-dione and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (50%, white solid). HPLC-MS: m/z=298.1 (M+1); Rt: 2.58 min, purity: 85%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:11][PH:12](=[O:14])[CH3:13].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:11][P:12]([C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:8]=1)[NH2:7])([CH3:13])=[O:14]
Reactant: C[PH](C)=O
Reactant: COc1ccc(Br)cc1N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: COc1ccc(P(C)(C)=O)cc1N
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of 5-bromo-2-methoxyaniline (0.404 g, 2.00 mmol) in 8 mL DMF was added dimethylphosphine oxide (0.171 g, 2.20 mmol), palladium acetate (22.4 mg, 0.0100 mmol), XANTPHOS (69.4 mg, 0.120 mmol), and potassium phosphate (0.467 g, 2.20 mmol). The mixture was purged with nitrogen, and subjected to microwaves at 150° C. for 20 minutes. The reaction mixture was concentrated and purified by silica gel chromatography (0-20% 7N ammonia in methanol:dichloromethane) to afford the desired product (0.365 g, 85% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:17][C:18]1[C:25]([F:26])=[CH:24][C:21]([C:22]#[N:23])=[C:20](F)[CH:19]=1>CN(C)C=O>[Cl:17][C:18]1[C:25]([F:26])=[CH:24][C:21]([C:22]#[N:23])=[C:20]([CH:19]=1)[O:1][CH:2]([CH2:14][CH2:15][CH3:16])[CH2:3][CH2:4][N:5]([CH3:13])[C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:11])[CH3:9]
Reactant: N#Cc1cc(F)c(Cl)cc1F
Reactant: CCCC(O)CCN(C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)c(F)cc1C#N

Procedure:
The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester and 4-chloro-2,5-difluorobenzonitrile in N,N-dimethylformamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[CH:27]([Mg]Br)=[CH2:28]>C(OCC)C>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([CH:27]=[CH2:28])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Reactant: C=C[Mg]Br
Agent: [Cl-]
Solvent: CCOCC
Product: C=CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added vinylmagnesium bromide solution (1.0 M in tetrahydrofuran, 13 mL, 13 mmol) dropwise. After stirring at 0° C. for 2 h, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8-vinyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (480 mg, 98%). LC/MS m/e calcd for C22H21NO4 (M+H)+: 364.32, observed: 364.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.74-2.84 (m, 2 H) 3.16-3.24 (m, 2 H) 3.75 (s, 3 H) 3.77 (s, 3 H) 4.97 (d, J=10.11 Hz, 1 H) 5.06 (dd, J=4.55, 2.53 Hz, 2 H) 5.85-5.93 (m, 1 H) 5.95 (s, 1 H) 6.00 (d, J=5.31 Hz, 2 H) 6.72 (d, J=8.34 Hz, 1 H) 6.77 (s, 1 H) 6.86 (d, J=8.34 Hz, 1 H) 7.25 (s, 1 H).