Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[F:46][C:47]([F:61])([F:60])[C:48]1[CH:53]=[CH:52][C:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)=[CH:50][CH:49]=1>CN(C)C=O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:57]1[CH2:56][CH2:55][N:54]([C:51]2[CH:50]=[CH:49][C:48]([C:47]([F:60])([F:61])[F:46])=[CH:53][CH:52]=2)[CH2:59][CH2:58]1)=[O:6]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-Iodo-5-methanesulfonyl-benzoic acid (Example C, 3.0 g, 9.2 mmol) in dimethylformamide (20 ml) were successively added TBTU (3.8 g, 11.5 mmol), N-ethyldiisopropylamine (8.0 ml, 46.0 mmol) and 1-(4-trifluromethylphenyl)piperazine (ABCR F07741NB, [30459-17-7], 2.5 g, 11.0 mmol). The reaction was then stirred at room temperature for two hours, then concentrated in vacuo and purified by column chromatography (SiO2, 50 g, CH2Cl2/MeOH/NH3=100/0/0 to 95/4.5/0.5), to give the title compound as a pale brown foam; MS (m/e): 539.1 (M+H+). TBTU=2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][C:18]1[CH:19]=[C:20]([CH2:23][C:24]([O:26]CC)=[O:25])[NH:21][CH:22]=1.N1C=CC=C1.Cl(O)(=O)(=O)=O>CCOCC>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[N:2][CH3:1])[C:22]2[NH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][C:18]=2[CH3:17])=[CH:5][CH:6]=1
Reactant: CCOC(=O)Cc1cc(C)c[nH]1
Reactant: CN=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Solvent: c1cc[nH]c1
Product: CN=C(c1ccc(Cl)cc1)c1[nH]c(CC(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.8 %

Procedure:
N-Methyl 4-chlorobenzimidoyl chloride (2.37 g, 12.6 mmole) was placed in a dry 50 ml round bottom flask and treated with alcohol free chloroform and chlorosulfonic acid (0.15 g, 1.3 mmole). The reaction was placed under a nitrogen atmosphere and stirred at room temperature while ethyl 4-methyl-1H-pyrrole-2-acetate (2.11 g, 12.6 mmole) was added dropwise over a five-minute period. Upon addition of the pyrrole, the reaction mixture turned dark brown and the reaction temperature rose. The reaction was stirred overnight at room temperature, then quenched with saturated aqueous sodium bicarbonate. The phases were separated and the organic phase was extracted with saturated aqueous sodium bicarbonate, washed with water, dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in absolute ethanol, treated with 70% perchloric acid (2.0 g, 14 mmole) cooled and diluted with ether. A brown viscous liquid separated which was suspended in methylene chloride and treated with saturated aqueous sodium bicarbonate. The solution was dried over sodium sulfate, filtered, and concentrated. The residue was placed on a silica gel column and eluted with methylene chloride/methanol (99/1) to remove nonpolar impurities. The silica gel was extracted with methanol to yield 0.47 g (12%) of the title compound as a dark brown solid, m.p. 79°-80° C. (dec).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17](=[O:18])[N:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13]1.CO>C(OCC)C>[O:18]=[C:17]1[NH:16][C:15]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:14]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:13][N:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:31])=[O:2]
Reactant: COC(=O)CCCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)nc1=O
Solvent: CCOCC
Solvent: CO
Product: O=C(O)CCCCCCCCN1NC(c2ccccc2)=C(c2ccccc2)NC1=O
Yield: 81 %

Procedure:
A mixture of methyl-3-oxo-5,6-diphenyl-1,2,4-triazine-2(3H)-nonanoate (1.90g' 4.5mmol), 5N N (2.72mL, 13mmol) and methanol (30mL) was heated on a steam bath for 30 minutes. The volatiles were removed in vacuo and the residue diluted with water and dilute HC1 solution until pH=1 The mixture was extracted with CH2C12, the combined extracts dried over sodium sulfate and concentrated to give an oil. Chromatography on a column of silica gel using diethyl ether as eluent gave 3-oxo-5,6-diphenyl-1,2,4-triazine-2(lH)-nonanoic acid (1.50g, 81%) which crystallized on standing and had mp 97-100° C.
Reaction SMILES: [CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2].[OH-].[Li+].O1CCCC1.CO>O>[CH:1]([N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][C:5]1=[O:14])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccn(C(C)C)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ccc(C(=O)O)cc1=O
Yield: 76.7 %

Procedure:
Methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate (70 mg, 0.36 mmol), lithium hydroxide (57.1 mg, 1.36 mmol), tetrahydrofuran (50 mL), methanol (10 mL) and water (10 mL) was stirred at 20° C. for 4 hours. The mixture was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 72%) as a white solid. LRMS (M+H+) m/z: calcd 181.07. found 181.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:17]CCC.CI>C1COCC1>[C:1]([Si:5]([CH3:14])([CH3:15])[O:6][C@H:7]([CH:12]=[CH2:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:17])([CH3:3])([CH3:4])[CH3:2]
Reactant: [Li]CCCC
Reactant: C#CCC[C@@H](C=C)O[Si](C)(C)C(C)(C)C
Solvent: CI
Solvent: C1CCOC1
Product: C=C[C@H](CCC#CC)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
Compound (4a) (481.6 mg, 2.146 mmol) was dissolved in THF (21.5 mL) and cooled to −78° C. before treated with 1.6 M n-BuLi (2.7 mL, 4.32 mmol) dropwise. The resulting solution was stirred 15 minutes at the same temperature and then methyl iodide (0.67 mL, 1.528 g, 10.765 mmol) was added. During the night the mixture was slowly warmed to room temperature. After 13 hours the reaction was quenched with water. The solution was extracted with ether (3×), the combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by chromatography (pentane/ether 200/1) provided 395.5 mg of compound (5a) as clear colourless oil with 77% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:2]12.Br[CH2:18][CH2:19][CH2:20][Cl:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:9][CH:2]12
Reactant: ClCCCBr
Reactant: CC(C)(C)OC(=O)N1CC2CCCNC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CCCN(CCCCl)C2C1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of tert-butyl hexahydro-1H-pyrrolo[3,4-b]pyridine-6(2H)-carboxylate (1.60 g), 1-bromo-3-chloropropane (1.50 mL) and K2CO3 (3.00 g) in acetone was heated to reflux for 9 h. The reaction mixture was cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 1:1 (v/v) PE/EA) to give the title compound as yellow oil (0.53 g, 65.00%), HPLC: 89.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 303.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19]Br)=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1ccc(CCBr)cc1
Product: CCOC(=O)C1CCCN(CCc2ccc(OC)cc2)C1

Procedure:
This compound was prepared as described in Preparation 3 using ethyl piperidine-3-carboxylate and 4-methoxyphenethyl bromide as reagents. The title compound was obtained as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=2)[N:5]2[N:16]=[C:17]([CH3:19])[CH:18]=[C:4]2[N:3]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=2)[N:5]2[N:16]=[C:17]([CH3:19])[C:18]([I:20])=[C:4]2[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1cc2nc(Cl)cc(-c3cc(F)cc(F)c3)n2n1
Solvent: ClCCl
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(Cl)nc2c1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.5 %

Procedure:
5-Chloro-7-(3,5-difluorophenyl)-2-methylpyrazolo[1,5-a]pyrimidine (327 mg) is dissolved in CH2Cl2 (50 mL). N-Iodosuccinimide (NIS, 304 mg) is added to the reaction solution. The reaction mixture is stirred at room temperature for about 16 hours. The reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (301 mg).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[Cl:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 31b (0.4 g, 0.85 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-isobutyl-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 89%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1COCC1>[CH3:13][S:14]([O:5][CH2:4][CH2:3][O:2][CH3:1])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOS(C)(=O)=O

Procedure:
The 2-methoxyethanol (Aldrich, 94 mg, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH2:25][CH2:24][C:5]2=[C:6]([S:13][C:14]3[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=3)[C:7]3[C:12]([N:4]2[CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[NH2:26][OH:27].Cl.C[O-].[Na+]>CO>[OH:27][NH:26][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([S:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]3[CH2:3][N:2]([CH3:1])[CH2:25][CH2:24][C:5]=23)=[CH:15][CH:16]=1
Reactant: NO
Reactant: COC(=O)c1ccc(Sc2c3n(c4ccccc24)CN(C)CC3)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCc2c(Sc3ccc(C(=O)NO)cc3)c3ccccc3n2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
To a solution of methyl 4-((2-methyl-1,2,3,4-tetrahydropyrimido[1,6-a]indol-5-yl)thio)benzoate (0.4 g) and NH2OH.HCl (0.63 g) in 4 mL of dry MeOH was added 2.5 mL of 25% NaOMe solution in methanol. The reaction mixture was stirred for 4 h at r.t. and then quenched with 10 mL of potassium phosphate buffer solution. The mixture was extracted 40 mL of EtOAc. The extract was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluted with up to 10% MeOH/CH2Cl2 to give 0.12 g of the title product as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>C1(C)C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:10]([C:27]3[N:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)n[nH]2)CC1
Reactant: Brc1ncccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc(Cl)cc3)nn2-c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of INTERMEDIATE 1 (3.0 g, 8.29 mol), 2-bromopyrimidine (2.9 g, 18.24 mol) and Cs2CO3 (10.8 g, 33.2 mol) in toluene (90 mL) in a pressure vessel was degassed with a stream of nitrogen. CuI (1.58 g, 8.29 mol) and 1,10-phenanthroline (2.99 g, 16.58 mol) were added. The mixture was degassed again with nitrogen, capped and heaed at 120° C. for 1.5 h. The mixture was allowed to cool to room temperature, filtered through a plug of Celite™, and washed with EtOAc. The EtOAc was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using gradient elution (10% to 50% ACN-DCM) to give the title compound as an off-white solid. LC-MS m/z 440.14 [M+H]+.
Reaction SMILES: [C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10](Cl)=[O:11].[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])=[C:17]([N+:26]([O-:28])=[O:27])[CH:16]=1>CN(C1C=CN=CC=1)C.ClCCl>[C@:1]12([CH3:13])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:25][C@@H:21]([C:18]1[CH:19]=[CH:20][C:15]([I:14])=[CH:16][C:17]=1[N+:26]([O-:28])=[O:27])[CH:22]([CH3:24])[CH3:23])=[O:11]
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Reactant: CC(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 28.1 %

Procedure:
Under a nitrogen atmosphere (1S)-camphanic acid chloride (0.89 g, 4.09 mmol) was added to a solution of (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propanol (1.10 g, 3.41 mmol) and DMAP (0.50 g, 4.09 mmol) in anhydrous dichloromethane (30 mL). The mixture was stirred for 1.5 hours at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to (RS)-1-(4-Iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanates (1.44 g, 84%, 1:1 mixture of diastereomers) as a solid, which was dissolved in boiling methanol (70 mL) and left at room temperature overnight. Crystals formed were filtered to yield pure (R)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.465 g, 65%). The mother liquor was evaporated, and the residue was dissolved in boiling isopropanol (40 mL) and left at room temperature overnight. Crystals formed were filtered and recrystallized from boiling isopropanol (20 mL) to yield pure (S)-1-(4-iodo-2-nitrophenyl)-2-methyl-1-propyl (1S)-camphanate (0.288 g, 40%). 1H NMR (400 MHz, CDCl3) for (R,S)-camphanate: δ 8.30 (d, 1 H, J=1.8 Hz, Ph-H), 7.92 (dd, 1 H, J=1.8 and 8.3 Hz, Ph-H), 7.56 (d, 1 H, J=8.3 Hz, Ph-H), 6.27 (d, 1 H, J=6.8 Hz, Ph-CH), 2.40 (m, 1 H), 2.23 (m, 1 H), 2.06 (m, 1 H), 1.92 (m, 1 H), 1.72 (m, 1 H), 1.11 (s, 3 H, CH3), 1.03 (d, J=6.8 Hz, 3 H, CH3), 1.02 (s, 1 H, CH3), 0.98 (d, J=6.8 Hz, 3 H, CH3), 0.82 (s, 3 H, CH3); 13C NMR (100 MHz, CDCl3) for (R,S)-camphanate: δ 178.21 (C), 166.92 (C), 148.67 (C), 142.07 (CH), 134.80 (C), 133.34 (CH), 129.73 (CH), 92.59 (C), 90.75 (C), 76.07 (CH), 54.79 (C), 54.34 (C), 33.27 (CH), 31.03 (CH2), 28.88 (CH2), 19.07 (CH3), 17.40 (CH3), 16.70 (CH3), 16.66 (CH3), 9.61 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[N:10][C:9]([C:26]1[NH:30][C:29](=[O:31])[NH:28][N:27]=1)=[CH:8]2.[ClH:32].CCOC(C)=O>>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:26]1[NH:30][C:29](=[O:31])[NH:28][N:27]=1)=[CH:8]2
Reactant: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCN(C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc2cc(-c3n[nH]c(=O)[nH]3)nc(N[C@H]3CCNC3)c12

Procedure:
A solution of (S)-tert-butyl 3-((8-methoxy-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (80 mg, 0.187 mmol) in HCl/EtOAc (5 mL) was stirred at RT for 1 hour. The reaction mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound, which was used without further purification (120 mg). ESI-MS m/z [M+H]+ 327.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH-].[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[C:7]([OH:13])=[O:8]
Reactant: COc1ccc(F)cc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(F)cc1C(=O)O
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of 5-fluoro-2-methoxybenzaldehyde (1 g) in acetone (4 mL) was added a solution of potassium permanganate (1.54 g) in water (16 mL), and the mixture was heated for reflux for 4 hours. The reaction mixture was cooled to room temperature. To the mixture was added 2 mol/L aqueous sodium hydroxide solution (5.2 mL), and the insoluble material was removed by filtration. The filtrate was washed with ethyl acetate. The aqueous layer was acidified by addition of 2 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate twice. The extracts were combined and washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate) to give 5-fluoro-2-methoxybenzoic acid (0.66 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added potassium carbonate (0.63 g) and iodomethane (0.26 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give methyl 5-fluoro-2-methoxybenzoate (0.7 g). This material was dissolved in tetrahydrofuran (10 mL). To the solution was added methylmagnesium iodide (3.0 mol/L diethyl ether solution, 3.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.65 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CC[N+](CCCN(C)C)=C=N>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Reactant: CNCc1c(C)oc2ccccc12
Agent: CC[N+](=C=N)CCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)OCC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
To a solution of methyl-(2-methyl-benzofuran-3-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (125 mg, 42%) as a light brown solid and as a mixture of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.50-7.59 (m, 3H), 7.19-7.26 (m, 3H), 4.74 (s, 2H), 4.70 (s, 2H), 3.06 (s, 3H), 2.52 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.
Reaction SMILES: C([Li])CCC.[N:6]1[C:11]2[NH:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[NH:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH3:22][CH:23]([CH2:27][C:28]#[CH:29])[C:24](Cl)=[O:25]>CCCCCC.O1CCCC1.C(OCC)(=O)C>[O:25]=[C:24]([N:12]1[C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](=[O:17])[NH:16][C:10]2[CH:9]=[CH:8][CH:7]=[N:6][C:11]1=2)[CH:23]([CH3:22])[CH2:27][C:28]#[CH:29]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: C#CCC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C#CCC(C)C(=O)N1c2ccccc2C(=O)Nc2cccnc21

Procedure:
At 0° to 10° C., with stirring, 416 ml (0.65 mol) of an n-butyl-lithium solution in n-hexane are added dropwise to a suspension of 63 g (0.3 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 1500 ml of absolute tetrahydrofuran. THe mixture is stirred for a further hour at ambient temperature, then cooled to 5° to 10° C. and this temperature 46.8 g (0.36 mol) of 2-methyl-4-pentynoic acid chloride (not purified) dissolved in 100 ml of absolute tetrahydrofuran are added dropwise to the reaction solution. The mixture is stirred for a further 3 hours at ambient temperature, then added to 2000 ml of a saturated saline solution and diluted with about 2000 ml of ethyl acetate. The organic phase is separated off, extracted twice with 500 ml of saturated saline solution, dried over magnesium sulphate and evaporated to dryness in vacuo. The desired compound is obtained as a brownish-yellow product which is used without further purification in the next step.