Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.Cl.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34](O)=[O:35])[CH:27]=1.CCN=C=NCCCN(C)C.Cl.N1C=CC=CC=1>O>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:35])[CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: O=C(O)COc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(COc1cccnc1)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.1 mmol) obtained in Example 1, (3), pyridin-3-yloxyacetic acid hydrochloride (23 mg, 0.12 mmol), WSC.HCl (23 mg, 0.12 mmol), and dry pyridine (1 mL) were mixed, and the mixture was stirred at room temperature for 4 hours. This reaction mixture was added with water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and hexane to give 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (41 mg, yield 91%) as yellow crystals.
Reaction SMILES: NCCC1N=CNC=1.[C:9]([N:16]1[CH:20]=[CH:19]N=C1)([N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:10]>CN(C)C=O>[CH:14]1[N:13]=[CH:12][N:11]2[C:15]=1[CH2:19][CH2:20][NH:16][C:9]2=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: NCCc1c[nH]cn1
Solvent: CN(C)C=O
Product: O=C1NCCc2cncn21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
50.00 g (450 mmol) histamine are dissolved in 1500 ml dimethylformamide, 73.87 g (450 mmol) carbonyldiimidazole are added. The reaction mixture is stirred for 5 hours at 70° C. and for 16 hours at ambient temperature. Then the mixture is evaporated down, the residue is extracted hot from acetonitrile.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[C:25]([O:29][C:30]([N:32]([C:40]1[C:45]([CH3:46])=[CH:44][C:43](CO)=[CH:42][N:41]=1)[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:31])([CH3:28])([CH3:27])[CH3:26]>ClCCl>[Br:24][CH2:20][C:43]1[CH:44]=[C:45]([CH3:46])[C:40]([N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[N:41][CH:42]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(CO)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
Triphenylphosphine (7.43 g, 28.3 mmol) and CBr4 (9.49 g, 28.6 mmol) was added to a solution of 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-hydroxymethyl-3-methylpyridin (8.00 g, 23.6 mmol) in dichloromethane (220 mL) at 0° C. The reaction mixture was stirred for 3 h and was then concentrated under reduced pressure. Flash chromatography (hexane/EtOAc, 80:20) gave 5-bromomethyl-2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methylpyridin (8.0 g,77%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1>>[O:15]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][C:9](=[O:11])[C:8]3[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:12]([NH2:14])=[O:13])=[CH:24][C:19]=2[O:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: Nc1ccc2c(c1)OCCO2
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccc2c(c1)OCCO2

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2,3-dihydrobenzo[1,4]dioxin-6-ylamine by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[N:23]=[C:24]([CH:26]2[CH2:30][O:29]C(C)(C)[O:27]2)[O:25][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[N:23]=[C:24]([CH:26]([OH:27])[CH2:30][OH:29])[O:25][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4oc(C5COC(C)(C)O5)nc4c3c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4oc(C(O)CO)nc4c3c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
A solution of 200 mg of 2-(2,2-dimethyl-1,3-dioxolan-4-yl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester in 20 ml of methylene chloride is mixed drop by drop at room temperature with 1 ml of trifluoroacetic acid, and it is stirred at room temperature under protective gas for another 4 hours. The reaction solution is neutralized with the equimolar amount of sodium bicarbonate solution. The precipitated solid product is suctioned off and washed with methylene chloride. After the drying in a vacuum at 50° C., 112 mg of 2-(1,2-dihydroxyethyl)-10-methoxymethyl-oxazolo-[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester with a melting point of 168° C. (decomposition) is obtained.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.II.[I:15](O)(=O)=O>C(O)C.O>[F:1][C:2]1[C:3]([OH:12])=[C:4]([I:15])[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=C1COc2cc(O)c(F)cc21
Reactant: [O-][I+2]([O-])O
Agent: II
Solvent: O
Solvent: CCO
Product: O=C1COc2c1cc(F)c(O)c2I
Reaction time: 2 h
Yield: 385.3 %

Procedure:
A solution of 5-fluoro-6-hydroxybenzofuran-3(2H)-one (0.190 g, 1.13 mmol) in ethanol (5 mL) was added with iodine (0.115 g, 0.452 mmol) at room temperature. The reaction mixture was added dropwise with a solution of iodic acid (0.0396 g, 0.226 mmol) in water (2 mL), and the mixture was stirred for 2 hours. The reaction mixture was added with water (30 mL), and the precipitated solid was collected by filtration, and dried under reduced pressure to obtain 5-fluoro-6-hydroxy-7-iodobenzofuran-3(2H)-one (0.256 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=[O:18])=[N:9]2)=[CH:4][CH:3]=1.CCO.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:17][OH:18])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
The aldehyde of Step 1 (46.64 g, 156.6 mmol) was dissolved in 300 mL of THF. At 0° C., 800 mL of EtOH was added, followed by NaBH4 (5.93 g, 157 mmol). The mixture was then stirred at r.t. (room temperature) for 1 h and poured into cold 25% aq (aqueous) NH4OAc. The organic solvents were evaporated and the title alcohol was extracted with toluene:THF 1:1, dried over Na2SO4 and filtered through silica to yield 47.9 g of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[CH:32][CH:31]=1)[CH2:3][C@H:4]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:41][O:42][C:43]([NH:45][C@@H:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[C:47](O)=[O:48])=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:16]([O:15][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C@@H:4]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:3][C@@H:2]([NH:1][C:47](=[O:48])[C@H:46]([C:50]([CH3:52])([CH3:51])[CH3:53])[NH:45][C:43]([O:42][CH3:41])=[O:44])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]2[S:37][CH:38]=[CH:39][N:40]=2)=[CH:34][CH:35]=1)=[O:20])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@@H](N)Cc1ccc(-c2nccs2)cc1)O[Si](C)(C)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2nccs2)cc1)C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution containing the product from Example 146A (0.053 g) in tetrahydrofuran (0.70 mL) were added the product from Example 1F (0.015 g, 0.079 mmol), DEPBT (0.033 g, 0.110 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.373 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic was washed with additional 10% Na2CO3 solution and then brine, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with chloroform and ending with 80 % ethyl acetate in chloroform to give the product (0.042 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=O)[CH2:3][CH2:2]1.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[N:23][N:24]([C:26]2[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)[CH:25]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([CH:7]([NH:32][C:29]2[CH:30]=[N:31][C:26]([N:24]3[CH:25]=[C:21]([C:20]([F:34])([F:33])[F:19])[CH:22]=[N:23]3)=[CH:27][CH:28]=2)[C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(=O)C2CCOCC2)cc1
Reactant: Nc1ccc(-n2cc(C(F)(F)F)cn2)nc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: COC(=O)c1ccc(C(Nc2ccc(-n3cc(C(F)(F)F)cn3)nc2)C2CCOCC2)cc1
Yield: 0.1 %

Procedure:
A round bottom flask was charged with methyl 4-(tetrahydro-2H-pyran-4-carbonyl)benzoate (150 mg, 572 mmol), 6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-amine (130 mg, 572 mmol) and MeOH (1.2 mL). Decaborane reagent (26.4 mg, 229 mmol) was added in one portion and the reaction stirred over the week-end. The reaction mixture was quenched with HCl solution (1N, aq.) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) provide (±)-methyl 4-((tetrahydro-2H-pyran-4-yl)((6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)amino)methyl)benzoate (206 mg, 78%) as a colorless gum. MS (M+1): 461.3.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[C:3]1=[O:16].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[CH:26][C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:4]2([CH2:9][CH2:8][N:7]([C:27](=[O:28])/[CH:26]=[CH:25]/[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]([F:30])([F:31])[F:17])[CH2:6][CH2:5]2)[C:3]1=[O:16]
Reactant: O=C(O)C=Cc1ccccc1C(F)(F)F
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
A solution of 1-methylspiro[indoline-3,4′-piperidin]-2-one (100 mg, 0.46 mmol) in CH2Cl2 (5 mL) was added 3-(2-trifluoromethyl-phenyl)-acrylic acid (120 mg, 0.56 mmol), HOBt (124 mg, 0.92 mmol), EDCI (181 mg, 0.92 mmol) and DIEA (297 mg, 2.30 mmol). The reaction mixture was stirred at rt overnight. The above mixture was concentrated and the residue was purified by preparative HPLC to give (E)-1-methyl-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidin]-2-one (50 mg, 26%). 1H NMR (CDCl3): 1.85-2.00 (m, 4H), 3.72 (s, 3H), 3.90-4.00 (m, 2H), 4.15-4.30 (m, 1H), 4.40-4.50 (m, 1H), 6.80-6.90 (m, 2H), 7.10-7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.45-7.60 (m, 2H), 7.68-7.72 (m, 2H), 7.91-8.00 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:12]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 64 %

Procedure:
A solution containing 4-amino-3-nitro phenol (1.09 g, 7.07 mmole), benzylbromide (1.28 g, 7.5 mmole and cesium carbonate (2.43 g, 7.5 mmole) were stirred for 4 days at room temperature. After the reaction was complete, the reaction mixture was poured into ice water (500 ml), stirred 1 hour, and the resultant solid was filtered and dried under vacuum to provide the title compound (1.1 g, 64%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:47])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:47])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 50.9 %

Procedure:
Starting with 0.144 g (0.70 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.35 g (0.69 mmol) of 2-(4-bromobutoxy)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.202 g; 63.4% overall yield) was obtained as a white solid, mp 177°-180° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12.[S:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[S:52](Cl)(=[O:54])=[O:53]>>[CH3:1][O:2][C:3]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:4]=1[CH2:5][N:6]([CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:15]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=4)[N:19]([CH3:30])[CH:18]=3)=[CH:16][C:9]=12)[S:52]([C:48]1[S:47][CH:51]=[CH:50][CH:49]=1)(=[O:54])=[O:53]
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2cccs2)c(OC)c1
Yield: 30.5 %

Procedure:
Thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is prepared as described in Example 211b starting with 0.80 g of (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine and 0.114 g of 2-thiophenesulfonyl chloride instead of the 4-(trifluoromethoxy)benzenesulfonyl chloride used in Example 211b. 0.150 g of thiophene-2-sulfonic acid (2,4-dimethoxybenzyl) [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amide is obtained, the characteristics of which are as follows:
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(N[C@H](C(N)=O)C)=O)CC1C=CC=CC=1.[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([OH:42])=O)[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1.[CH2:53]([NH2:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[NH:28]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:29]([C:40]([NH:60][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:42])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: NCc1ccccc1
Agent: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1)OCc1ccccc1
Yield: 89 %

Procedure:
The coupling procedure described above for the preparation of Cbz-Phe-Ala-NH2 was employed using 10.0 g of Cbz-Trp-OH (Sigma Chemical Company) and 4.84 mL of freshly distilled BnNH2 in dry THF to give 11.3 g (89% yield) of crystalline Cbz-Trp-NHBn. Characteristic analytical data are as follows: mp 104°-105° C.; 1H NMR (300 MHz, CDCl3) δ8.00-6.88 (m, 16H, Ar), 5.85 (br, 1H, H-α), 5.45 (br, 1H, H-N), 5.10 (s, 2H, CH2--O), 4.57-4.45 (br, H-), 4.27 (t, 6H, CH2 --N), 3.38 (dd, J=4, 14 Hz, 1H, H-β), 3.16 (dd, J=8, 14 Hz, 1H, H-β); mass spectrum (EI), m/e 427 (M+), 336 (M+ -Bn), 277 (M+ -Cbz-NH), 130 (M+ -Cbz-NH-CH-CONH-Bn), 91 (Bn+); [α]25D +7.0° (c=0.20, EtOAC).
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(O)(=O)C.[K+].[Br-]>CO.[Hg](Br)Br>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Br[Hg]Br
Agent: [Br-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1C(=O)CC=C4[C@@H](C2)N(C)CC[C@]431
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of thebaine (1.00 g., 3.22 mmol) in methanol (40 ml.) was added to a stirred suspension of mercuric acetate (1.54 g., 4.82 mmol, 150 mol%) in methanol (30 ml.) at reflux for 50 min. under N2. After reflux, the mixture was filtered and the solvent evaporated in vacuo to give 2.67 g. of residue. This residue was taken up in 100 ml. of 3N acetic acid (17 ml. glacial HOAc diluted to 100 ml. H2O) and stirred at room temperature under N2 for 100 min. at which time 70 ml. of sat. aq. KBr was added to ppt. HgBr2. The precipitated mercury salts were filtered off through filter-aid after stirring for about 1 hour. The filtrate was cooled to 0° C. and 50 ml. of chloroform was added. The aqueous phase was basified to pH 12 with concentrated aq. NaOH. The chloroform layer was separated and the aqueous layer extracted with several portions of chloroform. All of the chloroform extracts were combined, washed with water, dried over Na2SO4, filtered and evaporated in vacuo to give crystalline neopinone; 0.995 g. (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]([C:15](=[NH:19])OCC)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][CH2:34][NH2:35]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([C:15](=[NH:19])[NH:35][CH2:34][CH2:33][CH:29]3[CH2:30][CH2:31][CH2:32][NH:28]3)=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: CCOC(=N)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: NCCC1CCCN1
Solvent: CO
Product: N=C(NCCC1CCCN1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-(pyrrolidin-2-yl)ethanamine (28 μl, 0.23 mmol) via procedure W to afford 90 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(pyrrolidin-2-yl)ethyl)carbamimidoyl)benzamide. MS (Q1) 448 (M)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.B1(C2C=CC(N)=CC=2)OC(C)(C)C(C)(C)O1>>[CH:15]([N:11]1[CH2:12][CH2:13][CH2:14][N:8]([C:5]2[N:6]=[N:7][C:2]([C:22]3[CH:23]=[CH:24][C:19]([NH2:18])=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)([CH3:17])[CH3:16]
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CC(C)N1CCCN(c2ccc(Cl)nn2)CC1
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CC(C)N1CCCN(c2ccc(-c3ccc(N)cc3)nn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 1-(6-chloro-pyridazin-3-yl)-4-isopropyl-perhydro-1,4-diazepine and 4-aminophenylboronic acid, pinacol cyclic ester. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 2H), 7.53 (d, 1H), 6.76 (m, 3H), 3.86 (t, 2H), 3.77 (m, 4H), 2.93 (heptet, 1H), 2.81 (m, 2H), 2.58 (m, 2H), 1.95 (m, 2H), 1.00 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([O:32]CC)=O)[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:36][NH2:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:35])=[C:14]([C:30]([NH:37][CH3:36])=[O:32])[C:15](=[O:29])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:28])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O
Reactant: CN
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxo-1-piperidinyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methylamine using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.65-1.81 (m, 6 H), 2.19 (t, J=6.21 Hz, 2 H), 2.91 (d, J=4.84 Hz, 3 H), 3.20 (t, J=5.79 Hz, 2 H), 3.38 (q, J=7.09 Hz, 2 H), 4.16-4.25 (m, 4 H), 7.11-7.18 (m, 2 H), 7.37-7.44 (m, 2 H), 8.01 (s, 1 H), 8.55 (d, J=1.68 Hz, 1 H), 10.14 (d, J=4.63 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 467 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:5][C@@:4]1([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[C:6]#N.C([OH:20])C.[OH-].[Na+].Cl>ClCCl>[C:8]1([C@@:4]23[CH2:5][C@@H:3]2[CH2:2][O:1][C:6]3=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: CCO
Reactant: N#C[C@]1(c2cccc3ccccc23)CC1CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C1OC[C@H]2C[C@@]12c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
(1R)-2-Hydroxymethyl-1(1-naphthyl)-cyclopropanecarbonitrile (1a 10 g, 44.6 mmol), ethanol (20 mL) and 25N sodium hydroxide solution (10 mL) were heated under reflux for 18 hours. The reaction is monitored by TLC (dichloromethane (100%)). The reaction mixture was cooled to room temperature and ice cold water (12 mL) was added to the reaction mixture followed by concentrated hydrochloric acid drop wise to adjust the pH of the reaction mass to 1-2 and stirred for overnight. The aqueous layer was extracted with dichloromethane (200 mL). The organic layer was washed with 3% sodium bicarbonate solution, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to yield 5 g (50%) of product. 1H NMR δ(300 MHz,CDCl3): 0.78-0.81 (1H,m), 1.45-1.48 (1H,m,), 1.68-1.72 (1H,m,) 2.45-2.51 (1H,m), 4.37-4.40 (1H,d, J=9 Hz), 4.65-4.69 (1H,dd, J=9,3 Hz), 7.34-7.52 (4H,m), 7.76-7.91 (3H,m).