Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(N)ncc1Br
Temperature: 17.5 °C

Procedure:
To a solution of 2-amino-4-picoline (20 g, 0.185 mol) in glacial acetic acid (185 mL) was added bromine (12.5 mL, 0.243 mol) dropwise with stirring while maintaining the internal temperature between 15-20° C. by cooling in an ice bath. After the addition was completed, the reaction was stirred for 1 h. The resulting solid was filtered, washed with water, and treated with dilute aqueous sodium hydroxide. The remaining white solid was filtered, washed with water and then hexane. Recrystallization from diethyl ether-cyclohexane afforded the title compound; yield 8.1 g (23%).
Reaction SMILES: C(OC(=O)C)(=O)C.[Br:8][C:9]1[S:13][C:12]2=[C:14](C(O)=O)[N:15]=[CH:16][N:11]2[CH:10]=1>ClC1C=CC(Cl)=CC=1Cl.CCCCCC>[Br:8][C:9]1[S:13][C:12]2=[CH:14][N:15]=[CH:16][N:11]2[CH:10]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CC(=O)OC(C)=O
Solvent: Clc1ccc(Cl)c(Cl)c1
Solvent: CCCCCC
Product: Brc1cn2cncc2s1
Temperature: 130 °C
Reaction time: 24 h
Yield: 78.1 %

Procedure:
Acetic anhydride (0.1 ml, 1.06 mmol) was added to a solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (36 mg, 0.14 mmol) in 1,2,4-trichlorobenzene (1 ml), and the mixture was stirred at 130° C. for 24 hr. The reaction solution was allowed to cool to room temperature, was diluted with hexane, and was extracted with 1 M hydrochloric acid (2 ml×3). The aqueous layer was neutralized with a 2 M aqueous solution of sodium hydroxide and was extracted with ethyl acetate (4 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate =1:1→1:2) to give 2-bromoimidazo[5,1-b]thiazole (22.2 mg, 76%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=2[F:21])=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[CH3:22][O:23][C:24]([C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=2[CH3:38])=[N:28][C:27]=1[CH3:39])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:22][O:23][C:24]([C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]3[C:4]([C:11]4[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][C:12]=4[F:21])=[N:5][O:6][C:7]=3[CH:8]3[CH2:10][CH2:9]3)=[CH:33][C:32]=2[CH3:38])=[N:28][C:27]=1[CH3:39])=[O:25]
Reactant: Fc1cccc(C(F)(F)F)c1-c1noc(C2CC2)c1CBr
Reactant: COC(=O)c1sc(-c2ccc(O)cc2C)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccc(OCc3c(-c4c(F)cccc4C(F)(F)F)noc3C3CC3)cc2C)nc1C
Reaction time: 60 h
Yield: 19.3 %

Procedure:
To a solution of 4-bromomethyl-5-cyclopropyl-3-(2-fluoro-6-trifluoromethyl-phenyl)-isoxazole (0.083 g, 0.256 mmol) and 2-(4-Hydroxy-2-methyl-phenyl)-4-methyl-thiazole-5-carboxylic acid methyl ester (0.067 g, 0.256 mmol) in 1 mL of DMF is added potassium carbonate (0.035 g, 0.256). The reaction is stirred for 60 hours. The reaction is partitioned between ethyl acetate and water. The layers are separated and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue is chromatographed using a gradient of 5% ethyl acetate in hexanes to 40% ethyl acetate in hexanes to yield the title compound (0.027 g, 18%). ES/MS m/e 547.0 (M+1).
Reaction SMILES: O=C1CCC(=O)N1O[C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].[NH2:36][C@H:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39][C:40](=[O:42])[OH:41]>C1COCC1.CN(C=O)C.O>[C:46]([O:45][C:43](=[O:44])[CH:37]([NH:36][C:9](=[O:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:38][CH2:39][C:40]([OH:42])=[O:41])([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(=O)O
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NC(CCC(=O)O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Icosanedioic acid tert-butyl ester 2,5-dioxo-pyrrolidin-1-yl ester (6.01 g, 12.124 mmol) was dissolved in THF (150 mL) and mixed with a slurry of H-Glu-OtBu (2.71 g, 13.33 mmol) in DMF/water (1/1, 40 mL). This resulted in a gel-like solution which was heated to give a clear solution that was stirred at RT for 3 h. Then the solution was evaporated, 100 mL of water was added and the mixture was heated to 60° C. which resulted in a solution which crystallised on cooling. The precipitate was recrystallised from acetonitrile and the crystals were dried in vacuum. Yield 6.82 g (96%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:22](OC)([CH3:24])[CH3:23].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+].[Cl-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C:13](=[O:19])[N:14]2[C@@H:15]1[CH2:16][CH2:17][O:18][C:22]2([CH3:24])[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)OCC[C@@H]2[C@@H](NC(=O)OCc3ccccc3)C(=O)N21
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a suspension of (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (735 mg) in methylene chloride (30 ml) were added 2,2-dimethoxypropane (0.513 ml) and boron trifluoride etherate (0.026 ml) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 5 hours at ambient temperature. The reaction mixture was poured into a mixture of methylene chloride (30 ml) and aqueous sodium bicarbonate and sodium chloride (1:1). The organic layer was separated and the aqueous layer was extracted with methylene chloride (20 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (16 g) eluting with a mixture of methylene chloride and acetone (10:1-5:1) to give (6R,7R)-7-benzyloxycarbonylamino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (753 mg) as an oil.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[C:11]([O:15][C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])([CH3:14])([CH3:13])[CH3:12].[C:26](=[O:28])=[O:27]>O.C1COCC1>[C:11]([O:15][C:16]([NH:17][C:18]1[C:19]([F:24])=[CH:20][CH:21]=[CH:22][C:23]=1[C:26]([OH:28])=[O:27])=[O:25])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1F
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyllithium in pentane (1.7M, 34 ml, 58 mmol) was added with caution to a solution of (2-fluoro-phenyl)-carbamic acid tert-butyl ester whilst cooling to less than −50° C. The mixture was maintained at this temperature, stirred for 3 h then poured onto a slurry of THF and dry ice. The mixture was allowed to warm to room temperature, diluted with water and evaporated in vacuo. The residue was taken up in water and washed with diethyl ether. A solution of 0.3M potassium hydrogen sulphate was added until pH6 and extracted with chloroform. The chloroform extracts were combined, washed with brine, dried and reduced to give a white solid; yield 2.7 g, 37%.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[NH:4][N:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[OH-].[Na+].[H][H]>[Pd].O>[CH:10]1([CH2:9][O:8][C:7]2[CH:6]=[N:5][NH:4][C:3](=[O:15])[CH:2]=2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: O=c1[nH]ncc(OCC2CCCC2)c1Cl
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1cc(OCC2CCCC2)cn[nH]1
Reaction time: 8 h
Yield: 78.7 %

Procedure:
A pressure vial containing a mixture of 4-chloro-5-cyclopentylmethoxy-2H-pyridazin-3-one (Intermediate 60, 0.75 g, 3.27 mmol), water (12 mL), and a 2N aqueous sodium hydroxide solution (2.1 mL) was treated with 10% palladium on carbon (75.1 mg, 10% weight of 4-chloro-5-cyclopentylmethoxy-2H-pyridazin-3-one). The reaction was then pressurized with hydrogen (40 psi), where it shook overnight. The resulting reaction mixture was removed from the hydrogenator and then warmed with a heat gun and quickly filtered through filter paper. The filter cake was rinsed with warm water and methylene chloride. The filtrate was filtered through filter paper to remove some residual catalyst and washed with methylene chloride. The filtrate was concentrated in vacuo to remove organics. Upon concentrating the aqueous layer was acidified with a 1N aqueous hydrochloric acid solution. The resulting precipitate was collected by filtration, rinsed with water and then dried in vacuo to afford 5-cyclopentylmethoxy-2H-pyridazin-3-one (499.6 mg, 78%) as an off-white solid; ES+-HRMS m/e calcd for C10H14N2O2 [M+H+] 195.1128, found 195.1128. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23-1.38 (m, 2H), 1.46-1.67 (m, 4H), 1.68-1.82 (m, 2H), 2.23-2.34 (m, 1H), 3.87 (d, J=7.0 Hz, 2H), 6.17 (s, 1H), 7.65 (d, J=2.6 Hz, 1H), 12.61 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][NH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[C:16](=[O:19])[CH2:17]Br>C(N(CC)CC)C>[Cl:12][C:13]1[CH:14]=[C:15]([C:16](=[O:19])[CH2:17][N:10]([CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:11])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: CNCc1cccc(OC)c1
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: COc1cccc(CN(C)CC(=O)c2ccc(Cl)c(Cl)c2)c1

Procedure:
1-(3-Methoxyphenyl)-N-methylmethanamine is reacted with 3,4-dichlorophenacyl bromide in the presence of triethylamine to give 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanone. Reduction of this ketone by sodium borohydride yields 1-(3,4-dichlorophenyl)-2-((3-methoxybenzyl)(methyl)amino)ethanol, which undergoes acid mediated cyclization to give 4-(3,4-dichlorophenyl)-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline. This racemic tetraisoquinoline derivative can be separated via chiral HPLC or supercritical fluid chromatography (SFC) to give the single enantiomers. Alternatively, the chiral separation can be achieved by recrystallization using chiral acids such as di-p-toluoyl-D-tartaric acid or di-p-toluoyl-L-tartaric acid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](/[CH:35]=[CH:34]/[CH2:33][O:32][CH3:31])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC/C=C/c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 80 °C
Yield: 82.2 %

Procedure:
6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 2a, 200 mg, 0.383 mmol), PdCl2(dppf)-CH2Cl2 adduct (47.0 mg, 0.057 mmol), 1-4-dioxane (1 mL), trans-3-methoxy-1-propenylboronic acid pinacol ester (0.15 mL, 0.707 mmol) and Na2CO3 (0.48 mL, 0.960 mmol, 2M) were charged in a vial. The mixture was evacuated and purged with nitrogen six times and heated at 80° C. for 35 min. The mixture was diluted with EtOAc and the organic phase was washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford a residue, which was purified by column chromatography on silica gel (10 g, EtOAc in hexane, 0-10%, 10 CV; 10-20%, 20CV) to afford (E)-6-chloro-3-(3-methoxyprop-1-en-1-yl)-1-trityl-1H-pyrazolo[4,3-c]pyridine (147 mg, 0.315 mmol, 82% yield) as a light yellow solid. MS ESI calc'd. for C29H25ClN3O [M+H]+ 466, found 466.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[C:8](OC)=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][OH:9]
Reactant: COC(=O)c1ccc(-c2ccc(OC)cc2)cc1F
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(CO)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
At 0° C., a solution of 1.36 g (5.23 mmol) of methyl 3-fluoro-4′-methoxy-1,1′-biphenyl-4-carboxylate from Ex. V in 10 ml of anhydrous TMF is added dropwise to 3.14 ml (3.14 mmol) of a 1-molar solution of LiAlH4 in anhydrous THF. The mixture is initially stirred at 0° C. for 2 h. 10 ml of a sat. solution of NH4Cl are then added carefully, the mixture is diluted with ethyl acetate and the organic phase is separated off. The organic phase is washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and, after filtration, freed from the solvent. The resulting crude product is purified by flash chromatography (silica gel, cyclohexane/ethyl acetate 5:1). This gives 914 mg (3.94 mmol, 73% yield) of (3-fluoro-4′-methoxy-1,1′-biphenyl-4-yl) methanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C([O:7][C:8]1[CH:9]=[C:10]2[C:15](=[N:16][C:17]=1[CH:18]=[O:19])[N:14]([CH2:20][CH3:21])[CH:13]=[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]2=[O:27])C>ClCCl>[CH2:20]([N:14]1[C:15]2[C:10](=[CH:9][C:8]([OH:7])=[C:17]([CH:18]=[O:19])[N:16]=2)[C:11](=[O:27])[C:12]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:13]1)[CH3:21]
Reactant: CCOC(=O)c1cn(CC)c2nc(C=O)c(OCC)cc2c1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)c1cn(CC)c2nc(C=O)c(O)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To 500 ml of dichloromethane was added 53 g of pulverized aluminium chloride and stirred at room temperature for 1 hour. To the above mixture, a solution of 25.0 g of ethyl 1,4-dihydro-6-ethoxy-1-ethyl-7-formyl-4-oxo-1,8-naphthyridine-3-carboxylate dissolved in 200 ml of dichloromethane was slowly added dropwise. After the resulting mixture was stirred at room temperature for 3 hours, ice water was added to the reaction mixture and allowed to separate into two layers. The aqueous layer was extracted with chloroform and the chloroform extract and the organic layer were combined, and washed with water, dried and evaporated in vacuo to obtain 21.8 g of ethyl 1,4-dihydro-1-ethyl-7-formyl-6-hydroxy-4-oxo-1,8-naphthyridine-3-carboxylate (Compound IX where R1 =R3 =C2H5), m.p. 243°-245° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14]CC(C)C)=O.[F:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.CCOCC.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1)=[O:14]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC(C)COC(=O)c1cccc2c(Br)cccc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(F)cc1)c1cccc2c(Br)cccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83 %

Procedure:
Step 1 A solution of 5-bromo-1-naphthoic acid (prepared according to the procedure of Hausamann, Chem. Ber., 1876, 9, 1519; 2.00 g, 7.97 mmol) in THF (50 mL) was treated with TEA (2.22 mL, 15.93 mmol), then with isobutyl chloroformate (1.088 g, 7.97 mmol) and the resulting suspension was stirred at rt. After 25 min, the mixture was treated with additional TEA (2.22 mL, 15.93 mmol), then with a solution of N,O-dimethylhydroxylamine hydrochloric acid salt (0.777 g, 7.97 mmol) in water (5 mL), and the mixture was stirred at rt. After 2.5 h, the mixture was concentrated and the residue was taken up in EtOAc and water. The mixture was filtered, the layers were separated, and the organic phase was washed with NaHCO3 (aq), dried and concentrated to provide 5-bromo-N-methoxy-N-methyl-1-naphthamide as a pasty solid (1.03 g, 30%) contaminated with ca. 30% isobutyl 5-bromo-1-naphthoate. Mass spectrum m/z 294, 296 (M+H)+. Without further purification, a solution of this material (1.01 g, 2.404 mmol) in THF (15 mL) was stirred on ice and treated with (4-fluorophenyl)magnesium bromide, 2M in ether (7.21 mL, 14.42 mmol). The solution was stirred on ice and allowed to slowly warm to rt. After 16 h, the mixture was treated with 1 M hydrochloric acid and extracted twice with EtOAc. The combined organic layers were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide (5-bromonaphthalen-1-yl)(4-fluorophenyl)methanone as a pale yellow viscous oil (658 mg, 83%). 1H NMR (400 MHz, methanol-d4) δ 8.49 (1 H, d, J=8.6 Hz), 7.95 (1 H, d, J=8.6 Hz), 7.86-7.93 (3 H, m), 7.74 (1 H, dd, J=8.5, 7.2 Hz), 7.64-7.68 (1 H, m), 7.40 (1 H, dd, J=8.5, 7.6 Hz), 7.25 (2 H, t, J=8.8 Hz). Mass spectrum m/z 329, 331 (M+H)+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[CH:19]=[CH:18][CH:17]=[CH:16][C:8]=1[O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:9][C:8]1[CH:16]=[CH:17][C:18]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:19][C:7]=1[CH3:6])[CH3:15]
Reactant: CCOC(=O)COc1ccccc1C
Reactant: O=S(=O)(O)Cl
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Temperature: 4 °C
Reaction time: 2 h

Procedure:
To a flask containing chlorosulfonic acid (15.0 mL, 226 mmol) at 4° C. was added ethyl (2-methylphenoxy)acetate A1a (10.0 g, 51.6 mmol) slowly. The mixture was stirred at 4° C. for 30 min and room temperature for 2 h, and then poured into ice water. The precipitated white solid was filtered, washed with water, and dried under vacuum overnight to provide 14.0 g (93%) of A1b as a white solid; 1H NMR (300 MHz, CDCl3) δ 7.87–7.84 (m, 2 H), 6.80 (d, J=9.5 Hz, 1 H), 4.76 (s, 2 H), 4.29 (q, J=7.1 Hz, 2 H), 2.37 (s, 3 H), 1.31 (t, J=7.1 Hz, 3 H); MS (ES) m/z: 315 (M+Na+).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[CH:16]=[CH:15][C:14](=[CH:17][C:18]#[N:19])[CH2:13][C:7]32[CH2:11][N:10]([CH3:12])[CH2:9][C:8]=13.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN(C)C=O>[C:18]([CH:17]=[C:14]1[CH2:13][C:7]23[CH2:11][N:10]([CH3:12])[CH2:9][C:8]2=[C:2]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH:3]=[CH:4][N:5]=[C:6]3[CH:16]=[CH:15]1)#[N:19]
Reactant: CN1CC2=C(Cl)C=CN=C3C=CC(=CC#N)CC32C1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(C2=C3CN(C)CC34CC(=CC#N)C=CC4=NC=C2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
5.8 g (22 mmol) of 4-chloro-10-cyanomethylene-2-methylpyrrolo[4,3-e]benzazepine were dissolved in 50 ml of dimethylformamide, 6.6 ml (60 mmol) of N-methylpiperazine were added (strongly exothermic reaction) and the mixture was stirred at 80° C. under nitrogen for 1 h. After removal of the solvent under reduced pressure the residue was taken up in about 200 ml of ice/water, the mixture was make alkaline with a little 10% strength sodium hydroxide solution and then stirred while cooling for 1 h and the pale brown crude product was filtered off with suction, washing copiously with water. The crude product was purified by column chromatography (silica gel, mobile phase 95/5 methylene chloride/methanol). 5.3 g (73%) of yellowish 10-cyanomethylene-2-methyl-4-(4-methyl-1-piperazinyl)pyrrolo-[4,3-e]benzazepine were obtained in the form of a mixture of the (E) and (Z) isomers, which was recrystallized from isopropanol: melting point 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[N:14]1.[N+:27]([O-])([OH:29])=[O:28]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][C:18]([N+:27]([O-:29])=[O:28])=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:20]=2)[CH:15]=[N:14]1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2c(cnn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 63 %

Procedure:
To a solution of ethyl 1-(2,6-dichloro-4-trifluoromethylphenyl)indazol-6-yl carboxylate [Compound No. 62] (3 g) in conc. sulfuric acid (20 g), fuming nitric acid (0.7 g) was added dropwise while cooling with ice, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed and dried. The crystals were purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give ethyl 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-nitroindazol-6-yl carboxylate (2.1 g).
Reaction SMILES: [Cl-].[Na+].[F:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13]([OH:15])=O)=[N:6][CH:7]=[CH:8][CH:9]=1.Cl.[F:27][C:28]1[CH:29]=[CH:30][C:31]([C@H:34]([NH2:36])[CH3:35])=[N:32][CH:33]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[F:3][C:4]1[C:5]([C:10]2[CH:11]=[C:12]([CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:18]=2)[C:13]([NH:36][C@@H:34]([C:31]2[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=2)[CH3:35])=[O:15])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](N)c1ccc(F)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3ncccc3F)c2)nc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3ccc(F)cn3)cc(-c3ncccc3F)c2)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the sodium chloride salt of 3-(3-fluoropyridin-2-yl)-5-(5-methylpyridin-2-yl)benzoic acid (25.0 mg, 0.05 mmol) in N,N-dimethylformamide (0.35 mL) were added (1R)-1-(5-fluoropyridin-2-yl)ethanamine hydrochloride salt (16.5 mg, 0.08 mmol), EDC (14.9 mg, 0.08 mmol), HOBT (7.92 mg, 0.05 mmol) and triethylamine (21.6 μL, 0.16 mmol). The reaction mixture was stirred at ambient temperature. After 18 h, the mixture was cooled to ambient temperature. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→50% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. HRMS 431.1706 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.73 (q, J=1.6 Hz, 1H); 8.57-8.54 (m, 2H); 8.52 (t, J=1.7 Hz, 1H); 8.45 (q, J=1.5 Hz, 1H); 8.44 (d, J=2.8 Hz, 1H); 7.78 (d, J=8.1 Hz, 1H); 7.62-7.52 (m, 3H); 7.43-7.31 (m, 3H); 5.43 (p, J=7.0 Hz, 1H); 2.40 (s, 3H); 1.61 (d, J=6.8 Hz, 3H).