Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CCOCC>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21]
Reactant: CCOC(=O)CBr
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 49.9 %

Procedure:
To a solution of benzyl mercaptan (1.18 mL, 10.0 mmol) in DMF (20 mL) is added potassium carbonate (1.51 g, 10.9 mmol) and ethyl bromoacetate (1.17 mL, 10.6 mmol), and the mixture is stirred at RT for 25 min. Et2O is added, and the mixture is washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue is vacuum distilled (130-140° C.) to give 1.05 g of the product 402.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[C:11]1([P:17](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][P:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NP(=O)(c2ccccc2)c2ccccc2)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)diphenyl phosphinic amide was prepared by the method of Example 3 with 4-bromo-3-methyl-5-amino isoxazole (0.18 g, 1.0 mmol), THF (5 ml), NaH (60% oil dispersion, 88 mg, 2.2 mmol), and diphenyl phosphinic chloride (0.23 ml, 1.2 mmol). Recrystallization three times from chloroform and hexanes provided 0.17 g (45%) of faint pink crystals, m.p. 178.5-181° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[CH:24][N:23]=1.O>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1)[O:19][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:35])[F:37])=[CH:30][CH:29]=2)=[CH:24][N:23]=1
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)nc2)cc1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cn2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
8.0 mg (0.31 mmol) of 95% sodium hydride were added at 0° C. to a solution of 65 mg (0.28 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 3.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 76 mg (0.28 mmol) 2-chloromethyl-5-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at r.t overnight. After addition of 6 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1. The residue was purified by chromatography on silica (eluent: ethyl acetate) to give 91 mg (70%) of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH3:18]>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[N:9]2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)NC(=O)C2(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−5°-0° C.) of 6-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (600 mg, 3.14 mmol) in THF (10.5 mL) is added 60% NaH (132 mg, 3.30 mmol) and the mixture stirred for 15 min. Add dropwise to the reaction mixture iodomethane (215 μL, 3.45 mmol), the cold bath is removed and stirred for 2 hrs. The reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:31]([OH:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (55 mg, 0.13 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (71.1 mg, 0.52 mmol), 2-methyl-2-butene (0.087 mL, 0.77 mmol) and sodium chlorite (69.9 mg, 0.77 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in methanol to afford 6-Benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (35 mg, 62% yield) as a light yellow solid. HR-MS m/e calcd for C26H21N1O6 (M−H+) 444.1442, found 444.1442; 1H NMR (300 MHz) compatible.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:5]=1[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]>C(O)C.[Fe]>[NH2:15][C:13]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[C:4]([Cl:3])[CH:14]=1
Reactant: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1ccc(N)cc1Cl
Reaction time: 5 h
Yield: 80 %

Procedure:
Iron powder (pre-reduced with hydrogen, 10.0 g) was suspended in ethanol (80 ml) and water (10 ml) and concentrated hydrochloric acid (4 ml) were added with vigorous stirring. 2-Chloro-4-nitro-N,N-dimethylbenzamide (7.50 g) was added in small portions over 15 minutes and the mixture then heated to 50°-60° C. and stirred for 5 hours. The mixture was filtered through Celite and the ethanol evaporated. Water (200 ml) and concentrated hydrochloric acid (20 ml) were added and the reaction washed with ethyl acetate and then basified to pH8 with sodium bicarbonate and extracted with methylene chloride. The organic extract was dried and evaporated to give 4-amino-2-chloro-N,N-dimethylbenzamide as a grey crystalline solid (5.21 g) which was recrystallised from chloroform/ethyl acetate to give off-white crystals (3.46 g, m.p. 170°-173° C.).
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:21][C@H:22]([C:28]([OH:30])=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][NH2:27].O>C1(C)C(C)=CC=CC=1>[C:1]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]([C:28]([OH:30])=[O:29])[NH2:21])(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](N)C(=O)O
Yield: 85.9 %

Procedure:
Lysine stearate (35.0 g) was suspended in 300 ml of xylene using a 600-milliliter reaction vessel. The suspension was boiled through heating, and water formed through azeotropic distillation was removed outside the system. After it was identified that a stoichiometric amount of water was removed (reaction time 3 hours), the residue was cooled. Crystals precipitated were separated through filtration, and washed with 100 ml of a 50% ethanol solution. The crystals were recrystallized from a sulfuric acid aqueous solution to obtain 28.8 g of Nε -stearoyl lysine (yield 85.9%). This is designated Derivative A.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22](O)=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3].C(Cl)(=O)C([Cl:29])=O>CN(C=O)C.C(Cl)Cl>[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:14]=1)[O:11][C:10]([C:22]([Cl:29])=[O:23])=[CH:9][C:8]2=[O:25])[CH3:3]
Reactant: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(N2CCN(C)CC2)c2oc(C(=O)Cl)cc(=O)c2c1
Reaction time: 2 h

Procedure:
Into a 100 mL round bottom flask equipped with a reflux condenser, nitrogen inlet and magnetic stirrer is placed 250 mg (0.68 mmol, 1.0 equiv.) of 6-Ethoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride salt (Reference Example 23d) and 20 mL of methylene chloride. To the stirring suspension is then added 129.5 mg, 164 L(1.02 mmol, 1.5 equiv.) of oxalyl chloride followed by addition of one drop of DMF from a 50 microliter syringe to act as catalyst. The mixture is stirred for 2 hours, then concentrated to dryness on a rotary evaporator under a nitrogen atmosphere, followed by drying under high vacuum. The completeness of the reaction was ascertained by analysis of an aliquot, which was quenched with a THF solution of methylamine, by LC/MS. The crude material was used as obtained in the subsequent amidation reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl) piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.50 (s, 3H), 3.18-3.28 (m, 4H), 3.73-3.78 (m, 4H), 4.14 (s, 3H), 6.86 (dd, J=12.2 Hz, 2H), 7.00-7.60 (m, 5H), 7.71 (d, J=8.2 Hz, 1H).
Reaction SMILES: [CH:1]1([CH:4](O)[CH:5]2[C:9](=[O:10])[C:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:7]([O:20][CH3:21])[CH2:6]2)[CH2:3][CH2:2]1.CCN(CC)CC.CS(Cl)(=O)=O.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH:1]1([CH:4]=[C:5]2[C:9](=[O:10])[C:8]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:7]([O:20][CH3:21])[CH2:6]2)[CH2:2][CH2:3]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CC2)C1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(=CC2CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14 %

Procedure:
To a solution of 5-(Cyclopropyl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (622 mg, 2.1 mmol) in CH2Cl2 (10 ml) at 0 C were added dropwise Et3N (0.59 ml, 4.2 mmol) followed my methane sulfonyl chloride (0.33 ml, 4.2 mmol). The reaction was allowed to warm to room temperature over 10 minutes and then quenched by addition of 1M HCl (10 ml). The layers were separated and the organic phase was evaporated to dryness under reduced pressure. The crude mesylate was dissolved in MeOH (10 ml) and K2CO3 (580 mg, 4.2 mmol) was added in a single portion. The reaction was stirred at room temperature for 2 hours and then the solvent was removed under reduced pressure. The crude material was partitioned between EtOAc (20 ml) and H2O (20 ml), the organic phase was washed with brine (20 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure. The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product as a colourless oil (83 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16]>C1(C)C=CC=CC=1>[CH2:15]([O:17][C:18](=[O:19])/[CH:20]=[CH:8]/[C:7]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=1)[CH3:16]
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1ccc(OC)c(OC(C)C)c1
Temperature: 25 °C

Procedure:
A mixture of 3-isopropoxy-4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (6.96 g. 20 mmol) in toluene (100 ml) is heated at reflux for 2 hours, cooled to ambient temperature and evaporated. The crude product is taken in to dichloromethane and eluted through a pad of silica to afford (E)-3-(3-isopropoxy-4-methoxy-phenyl)-acrylic acid ethyl ester, TLC Rf 0.70 (1:1 hexane-ethyl acetate). This intermediate is dissolved in nitromethane (10 ml), 1,1,3,3-tetramethylguanidine (0.5 ml) is added and the reaction heated at 70° C. for 36 hours. The solvent is evaporated, the residue is taken into ethyl acetate and washed with 2N aqueous HCl, water and brine. After drying over sodium sulfate and evaporation, the crude product is purified by flash column chromatography (4:1 hexane-ethyl acetate elution) to afford 3-(3-isopropoxy-4-methoxy-phenyl)-4-nitro-butyric acid ethyl ester, 1H NMR (400 MHz, CDCl3) δ 1.20 (t J 7 3H), 1.38 (d J 7 6H), 2.75 (d J 6 2H), 3.90 (m 1H), 4.10 (m 2H), 4.48-4.78 (m 3H), 6.75-6.86 (m 3H). This intermediate is converted into [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-isoquinolin-4-yl]-acetic acid using the general procedure for Intermediate 20. Characterised as the ethyl ester, [MH]+ 496.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C1CCCCC1)CC(O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].B.[CH2:20]1[CH2:24][O:23][CH2:22][CH2:21]1>>[CH:20]1([CH:21]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:22][OH:23])[CH2:24][CH2:22][CH2:21][CH2:20][CH2:24]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C1CCCCC1
Reactant: C1CCOC1
Agent: B
Product: CC(C)(C)OC(=O)NC(CO)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
A solution of N-(t-butyloxycarbonyl)cyclohexylglycine (2.0 g, 7.77 mmol) in anhydrous THF (10 mL) was cooled to 0° C. Borane solution (1 M in THF, 15.5 mL, 15.5 mmol) was added slowly and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with MeOH (5 mL), volatiles were evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with saturated NaHCO3/water, brine, dried (sodium sulfate), and evaporated to give tert-butyl 1-cyclohexyl-2-hydroxyethylcarbamate 2a (1.26 g, 66.7%), MS (CI) m/z 144.20 (MH+-Boc).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[C:25](=[O:27])[CH3:26]>>[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:29]1)[C:25](=[O:27])[CH3:26]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CC(=O)N(C)[C@@H]1CCNC1
Product: CC(=O)N(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N-methyl-N-(pyrrolidin-3-yl)acetamide (1.2 equiv) to give 180 (24.3 mg, M+1 438.1)
Reaction SMILES: Cl.[NH2:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C([O-])(O)=O.[Na+].O>CN(C=O)C>[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:2][C:3]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:5][CH2:4]1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)C1(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.0 g, 7.74 mmol), 2-bromoacetophenone (3.08 g, 15.5 mmol), and NaHCO3 (1.30 g, 15.5 mmol) in DMF (20 mL) was stirred at ambient temperature for 18 h. H2O (20 mL) was added and the mixture was extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The product-containing fractions were combined, adjusted to pH 10 by addition of saturated aqueous Na2CO3 and extracted with EtOAc (2×75 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=248 (M+1).
Reaction SMILES: CN(C)[CH:3]=[N:4][C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:7][N:6]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:31]([O:30][C:28]([C:27]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:5]2=[N:4][CH:3]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)CBr
Reactant: CN(C)C=Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 120 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
A mixture of the above N,N-dimethyl-N′-[3-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-formamidine (3.61 g, 10.0 mmol) and ethyl bromoacetate (3.32 mL, 30.0 mmol) in DMF (10 mL) was stirred at 120° C. for 4 h. Cooled down to 100° C., added DIPEA (0.5 mL, 3.0 mmol) and stirred at 23° C. for 2 h. Poured into sat. NaHCO3-sol., extracted with EtOAc, washed the organic layers with brine, dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (5.01 g) which was purified by silica gel column chromatography with heptane/EtOAc 9:1 to 4:1 to give the title compound as a light yellow solid (2.89 g, 72%). MS (ISP) 403 [(M+H)+]; mp 132° C.
Reaction SMILES: [I:1]I.[CH2:3]([N:10]([CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:11][C:12]([CH3:15])([OH:14])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>COC(C)(C)C.C([O-])(O)=O.[Na+]>[CH2:3]([N:10]1[CH2:11][C:12]([CH3:13])([CH3:15])[O:14][C:17]([CH2:19][I:1])([CH3:18])[CH2:16]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: II
Reactant: C=C(C)CN(Cc1ccccc1)CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC1(C)CN(Cc2ccccc2)CC(C)(CI)O1
Reaction time: 18 h
Yield: 93 %

Procedure:
Add solid I2 (21.1 g, 83.1 mmol) to a biphasic mixture of 1-[benzyl-(2-methyl-allyl)-amino]-2-methyl-propan-2-ol (17.6 g, 75.4 mmol) in tert-butyl methyl ether (250 mL) and 1 M NaHCO3 (100 mL). Stir for 18 h and then add 1 M Na2S2O3 (100 mL). Dilute the mixture with additional tert-butyl methyl ether (200 mL) and separate the organic solution. Wash the organic solution with a mixture of 1 M Na2S2O3 (100 mL) and 1M NaHCO3 (100 mL). Dry, filter, and concentrate the organic solution. Dry the residue at 60° C. under vacuum to give the title compound (25.2 g, 93%) as a golden oil. 1H NMR (400 MHz, DMSO-d6): δ 7.2-7.4 (5H, m), 3.49 (1H, d), 3.47 (2H, s), 3.41 (1H, s), 2.49 (1H, d), 2.23 (1H, s), 2.20 (1H, s), 2.10 (1H, d), 1.24 (3H, s), 1.22 (3H, s), 1.15 (3H, s).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li:31])(C)(C)C>O1CCCC1.CCCCC>[C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[CH:12]=[C:11]2[Li:31])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Reactant: [Li]C(C)(C)C
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: [Li]c1cc2cnccc2n1S(=O)(=O)c1ccccc1

Procedure:
A solution of 0.645 g (2.5 mmols) of 1-benzenesulphonyl-1H-pyrrolo[3,2-c]pyridine and 0.755 ml (5 mmols) of tetramethylethylenediamine in 5 ml of tetrahydrofuran was cooled to -70° C. and 5 mmols of tert-butyl lithium in pentane were added, care being taken that the temperature did not exceed -60° C. The reaction medium was then stirred to obtain a solution of 1-benzenesulphonyl-2-lithio-1H-pyrrolo[3,2-c]pyridine which was used as such.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](Cl)=[O:14].Cl>N1C=CC=CC=1>[Cl:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)[C@H](Cl)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)[C@H](Cl)C(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 4 h

Procedure:
4-Hydroxybenzoic acid (8.9 g, 0.065 moles) is dissolved in 20 mL of absolute pyridine and 10 g (0.065 moles) of (S)-(+)-2-chloro-3-methylbutyryl chloride are added dropwise with stirring at 0° to 5° C. The mixture is allowed to stand for 4 hours at room temperature and then poured onto ice/conc. HCl (200 g/30 mL). The precipitate is filtered off with suction and washed several times with dilute HCl and water. The residue is recrystallized from methanol/water.
Reaction SMILES: [ClH:1].C(OC([NH:9][C:10]1[CH:15]=[C:14]([CH2:16][S:17][C:18]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(O)C>O1CCOCC1>[ClH:1].[NH2:9][C:10]1[CH:15]=[C:14]([CH2:16][S:17][C:18]2[C:23]([C:24]([NH:26][C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=3)=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cc(C)cc(NC(=O)c2cccnc2SCc2ccnc(N)c2)c1
Yield: 88 %

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (5.0 mL) was added to a solution of 2-(2-tert-butoxycarbonylaminopyridin-4-ylmethylthio)-N-(3,5-dimethylphenyl)pyridine-3-carboxamide (Compound No. 2-1, 420 mg, 0.90 mmol) in 1,4-dioxane (5.0 mL) at room temperature, and the mixture was stirred for 12 hours. Ethanol (6.0 mL) was added to the reaction mixture, and the precipitated solid was filtered off. The solid was dried under reduced pressure at 60° C. to give 320 mg of the target compound as a colorless crystal. (Yield 88%)