Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1ccccc1Cl
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3Cl)nc2n(CCC)c1=O
Yield: 75 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.00 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.67 g (14.6 mmol) of 2-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.72 g (yield 82%) of Compound 40 as white needles.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[C:10]2[CH2:9][CH:8]([C:11]([OH:13])=[O:12])[O:7][C:6]=2[C:5]([Cl:14])=[CH:4][C:3]=1[C:15](=[N:25][OH:26])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3ccc(F)cc3)cc(Cl)c2O1
Yield: 99 %

Procedure:
A mixture of 4,7-dichloro-2,3-dihydro-5-(4-fluorobenzoyl)benzo[b]furan-2-carboxylic acid (12.4 g), hydroxylamine hydrochloride (20.6 g) and pyridine (120 ml) was refluxed for 5.5 hours. Aftre distilling off the solvent, water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. By distilling off the solvent, 12.8 g of 4,7-dichloro-2,3-dihydro-5-(4-fluoro-α-hydroxyiminobenzyl)benzo[b]furan-2-carboxylic acid was obtained. This compound (12.8 g) was dissolved in 150 ml of anhydrous dimethylformamide, and to the ice-cooled solution, 4.8 g of 60% sodium hydride was added in small portions under agitation. After continuing the agitation for 5 hours at room temperature, the mixture was left to stand overnight. Water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 4.4 g of 5-chloro-7,8-dihydro-3-(4-fluorophenyl)furo[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 215°-218° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 333.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:6]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])[CH:7]=1.[NH2:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]=1>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])=[C:6]([S:8]([NH:11][C:12]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([C:29]([F:32])([F:31])[F:30])[N:22]=2)=[O:13])(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1nc(N)nc(C(F)(F)F)n1
Reactant: CC(C)OC(=O)c1ccc(Cl)cc1S(=O)(=O)N=C=O
Solvent: ClCCCl
Product: COc1nc(NC(=O)NS(=O)(=O)c2cc(Cl)ccc2C(=O)OC(C)C)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
19.6 g of a solution of 6.1 g of 5-chloro-2-(i-propoxycarbonyl)benzenesulfonyl isocyanate (20 mmol) in 1,2-dichloroethane are added dropwise to a solution of 3.9 g of 2-amino-4-methoxy-6-trifluoromethyl-1, 3,5-triazine (20 mmol) in 150 ml of 1,2-dichloroethane at 25° C. The mixture is stirred at 25° C. for 16 h and then at 50° C. for 3 h. After removal of volatiles under waterpump vacuum at 60° C., the residue is extracted with 200 ml of a mixture of tert-butyl methyl ether and diethyl ether. The solvents are removed under waterpump vacuum at 50° C. and the residue is stirred in a little i-propanol. The solid product is filtered off with suction and dried under waterpump vacuum at 40° C. This results in 7.2 g of the title compound (14 mmol; 70% of theory) of melting point 160°-163° C.
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3].CC(C)([O-])C.[K+].[CH2:41]([O:45][C:46]1[CH:51]=[CH:50][C:49]([C@H:52]2[CH2:57][CH2:56][C@H:55]([CH:58]=O)[CH2:54][CH2:53]2)=[C:48]([F:60])[C:47]=1[F:61])[CH2:42]CC.O>C1COCC1>[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12]/[CH:13]=[CH:58]/[C@H:55]2[CH2:54][CH2:53][C@H:52]([C:49]3[CH:50]=[CH:51][C:46]([O:45][CH2:41][CH3:42])=[C:47]([F:61])[C:48]=3[F:60])[CH2:57][CH2:56]2)=[C:7]([F:33])[C:6]=1[F:34])[CH3:3]
Reactant: CCOc1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c1F
Reactant: CCCCOc1ccc([C@H]2CC[C@H](C=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(CC/C=C/[C@H]2CC[C@H](c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Well-dried 3-(4-ethoxy-2,3-difluorophenyl)propyl triphenylphosphonium bromide (s23) (6.6 g) was mixed with THF (100 ml) under an atmosphere of nitrogen, and the solution was cooled to −10° C. Potassium t-butoxide (t-BuOK; 1.4 g) was added in two portions in the temperature range of −10° C. to −5° C. After 60 minutes of stirring at −10° C., the compound (s25) (3.0 g) dissolved in THF (30 ml) was added dropwise in the temperature range of −10 to −5° C. After 30 minutes of stirring at 0° C., the reaction mixture was treated with water, and the aqueous layer was extracted with toluene. The combined organic layers were washed with water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder. The purified product was mixed with sodium benzenesulfonate dihydrate (6.1 g) and Solmix A-11 (100 ml). Then, 6N-hydrochloric acid (20 ml) was added, and the mixture was heated to reflux for 2 hours. The reaction mixture was treated with water, and the aqueous layer was extracted with toluene (100 ml). The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography with toluene as an eluent and silica gel as a stationary phase powder, and then by recrystallization from a mixed solvent of ethyl acetate and Solmix A-11 (ethyl acetate:Solmix=1:4 by volume) to give (E)-1-ethoxy-2,3-difluoro-4-(4-(trans-4-(4-ethoxy-2,3-difluorophenyl)cyclohexyl)but-3-en-1-yl)benzene (No. 82) (4.6 g). The yield based on the compound (s13) was 41.9%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:4]=1[CH:5]=[O:6].[Br:12]Br.O>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:12][C:8]1[C:7]([CH3:11])=[C:4]([C:3]([O:2][CH3:1])=[CH:10][CH:9]=1)[CH:5]=[O:6]
Reactant: BrBr
Reactant: COc1cccc(C)c1C=O
Agent: [Fe]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C)c1C=O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
2-Methoxy-6-methylbenzaldehyde (7.32 g, 0.049 mol) in carbon tetrachloride (183 ml) was cooled to −10° C., and iron powder (150 mg, 0.002 mol) was added to it. Bromine (3.0 ml, 0.058 mol) was added over a period of 10 minutes. The mixture was stirred for 1 hour and then poured into water (225 ml). The organic layer was washed with sodium thiosulfate solution (2×50 ml), water (50 ml) and brine solution (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 3-Bromo-6-methoxy-2-methyl-benzaldehyde (10.32 g, 92.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[C:22](Cl)(Cl)=[O:23]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:22](=[O:23])[NH:13][N:12]=[C:10]3[CH2:9][CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(Cl)Cl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2

Procedure:
0.15 g of 7-chloro-5-(2-fluorophenyl)-2-hydrazino-3H-1-benzazepine is dissolved in 10 ml of pyridine and treated with 1.44 ml of a 14.3% solution of phosgene in toluene. The mixture is heated to 60° for 5 minutes and then evaporated in vacuo. The residue is partitioned between benzene and water. The benzene phase is washed successively with water, with sodium hydrogen carbonate solution and with water. The solvent is evaporated in vacuo. The residue is chromatographed on 15 g of silica gel while eluting with benzene/ethyl acetate (19:1 and 9:1). After recrystallization from ether/hexane, there is obtained pure 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 223°-225°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C([Br:16])(=O)C.C(=O)([O-])[O-].[NH4+].[NH4+]>>[Br:16][C:6]1[CH:5]=[CH:4][N+:3]([O-:12])=[C:2]([CH3:1])[C:7]=1[CH3:8]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: CC(=O)Br
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: Cc1c(Br)cc[n+]([O-])c1C
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
To 2,3-Dimethyl-4-nitropyridine N-oxide (3.00 g) which had been cooled to 0° C., added was acetyl bromide (18.0 ml), followed by stirring at 50° C. for 20 minutes and then at 75° C. for 15 minutes. The reaction mixture was charged in ice water and neutralized with an aqueous solution of ammonium carbonate. The neutralized solution was separated using methylene chloride. The organic layer was dried over anhydrous sodium sulfate and the filtrate was concentrated, whereby a crudely purified product of 4-bromo-2,3-dimethylpyridine N-oxide was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 4-fluorobenzotrifluoride (105 μL, 0.822 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (68 mg, 43%) as an off white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:10])[CH3:9]>>[C:8]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1
Product: CC(=O)Nc1ccccc1
Yield: 79 %

Procedure:
Acetanilide is prepared by the method of Example 5 using 5.0 mls (0.055 mole) of aniline, 7.5 grams of Type 3A molecular sieves, and 4.58 mls (0.064 mole) of acetyl chloride. The crude product is recrystallized from toluene to obtain 5.87 grams (81% of theoretical) of pure acetanilide, m.p. 112°-114° C. (literature m.p. 114° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C([Sn](CCCC)(CCCC)[C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)CCC>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Cc2cc(-c3ccco3)ccc2N1

Procedure:
The title compound was prepared as described for Example 37 using 5-bromooxindole and tri-n-butyl(2-furyl)tin: MS (ES) m/z 200 (M++1).
Reaction SMILES: [C:1]([C:9]1[C:18]([CH2:19]Br)=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+].CN(C)C=O.[I-].[K+]>CCOCC>[C:1]([C:9]1[C:18]([CH2:19][O:26][C:23](=[O:25])[CH3:24])=[N+:17]([O-:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)[O-]
Reactant: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a solution of 3.0 g. (8.4 mmol.) of 2-benzoyl-3-bromomethylquinoxaline 1,4-dioxide and 0.90 g (9.2 mmol.) of potassium acetate in 40 ml. of N,N-dimethylformamide, was added 0.22 g. (1.3 mmol.) of finely ground potassium iodide. The reaction mixture was stirred for 1.5 hours at ambient temperature, and then it was poured into 1,000 ml. of ether. The solid which precipitated was removed by filtration and discarded. Evaporation of the filtrate in vacuo left a yellow solid which was washed with methanol and dried, to give 2.7 g (94% yield) of 2-benzoyl-3-acetoxymethylquinoxaline 1,4-dioxide, m.p. 164°-167° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Br:12]Br>C(O)(=O)C.C(OCC)C>[Br:12][C:8]1[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: BrBr
Reactant: CCc1cccc(CC)c1N
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1cc(Br)cc(CC)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of 2,6-diethylaniline (10.0 g, 67.0 mmol) in acetic acid (50 mL) at ambient temperature was added bromine (10.4 mL, 201 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was diluted with diethyl ether (200 mL) and washed with 5% sodium bisulfite (4×50 mL) and brine. The organic phase was dried with sodium sulfate and the solvents were removed in vacuo. The residue was chromatographed on silica gel, eluting with 9:1 hexane-ethyl acetate to give the title compound (3.28 g, 21 % yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[NH2:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:60])[CH3:59])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42]>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:39][CH2:40][C:41]([NH:43][C@H:44]([B:49]1[O:53][C@@H:52]2[CH2:54][C@@H:55]3[CH2:58][C@H:57]([C@:51]2([CH3:61])[O:50]1)[C:56]3([CH3:59])[CH3:60])[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:42])=[O:6]
Reactant: O=C(O)c1ccccc1Br
Reactant: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)CNC(=O)c1ccccc1Br)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reaction time: 2 h
Yield: 77.8 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][N:11]=[C:10](F)[CH:9]=2)=[CH:6][N:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>CS(C)=O>[Cl:14][C:13]1[C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:4]=2)=[CH:9][C:10]([NH:24][C@H:25]2[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]2)=[N:11][CH:12]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Fc1cc(-c2cnc(Cl)c(NCC3CCOCC3)n2)c(Cl)cn1
Solvent: CS(C)=O
Product: O[C@H]1CC[C@H](Nc2cc(-c3cnc(Cl)c(NCC4CCOCC4)n3)c(Cl)cn2)CC1
Temperature: 120 °C

Procedure:
To a scintillation vial containing 3-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (20 mg, 0.056 mmol) was added DMSO (1 ml) and trans-4-aminocyclohexanol (32.2 mg, 0.280 mmol). The reaction mixture was capped and heated to 120° C. in an oil bath for 3 hr. The reaction product was purified by reverse phase preparative HPLC to yield trans-4-(5-chloro-4-(5-chloro-6-((tetrahydro-2H-pyran-4-yl)methyl)aminopyrazin-2-yl)pyridin-2-yl-amino)cyclohexanol (2.2 mg, 4.86 μmol, 8.69% yield), LCMS (m/z): 452.1 (MH+), retention time=0.76 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.17-1.26 (m, 4H) 1.27-1.39 (m, 2H) 1.58 (dd, J=13.11, 1.76 Hz, 2H) 1.84-2.02 (m, 5H) 3.30 (d, J=7.04 Hz, 4H) 3.43-3.61 (m, 2H) 3.84 (dd, J=11.35, 3.13 Hz, 2H) 6.58 (s, 1H) 7.66 (s, 1H) 7.90 (s, 1H).
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:27][NH2:28]>C(O)C>[CH3:27][NH:28][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([O:22][CH:23]([CH3:25])[CH3:24])[CH:21]=1)[CH3:12]
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cncc(OC(C)C)c2)cc1
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cncc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
A mixture of (2R)-(4E)-5-(5-isopropoxy-3-pyridyl)-4-penten-2-ol p-toluenesulfonate (11.00 g, 29.33 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 2.10 g (31.0%) of a colorless oil, bp 90-100° C. at 0.5 mm Hg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:13]=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[C:14]([CH:16]=[O:17])[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: O=Cc1cn2nccc(N3CCOCC3)c2n1
Reactant: Ic1ccccc1
Product: O=Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccccc1

Procedure:
Compound 5e (300 mg, 1.3 mmol) was coupled with iodobenzene (0.21 mL, 1.9 mmol) according to the procedures described in Example 20, Step A to afford compound 74a. 1H NMR (400 MHz, CDCl3) δ (ppm): 10.11 (s, 1H), 8.09 (d, J=5.6 Hz, 1H), 7.73 (d, J=8.1 Hz, 2H), 7.44-7.63 (m, 3H), 6.13 (d, J=5.6 Hz, 1H), 4.04-4.16 (m, 4H), 3.80-4.02 (m, 4H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([O:9][CH3:10])=[O:8])[CH:2]=1.C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:19][CH2:11][C:1]1[CH:2]=[C:3]([CH:4]=[CH:5][CH:6]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: COC(=O)c1cccc(CBr)c1

Procedure:
Methyl m-toluate was brominated with NBS and AIBN as described in Example 21 to give methyl m-bromomethylbenzoate, and this was further reacted with triethyl phosphite as described in Example 2 without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:29])[C@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:8]C(OCC1C=CC=CC=1)=O)([CH3:4])[CH3:3]>CCO.C(Cl)(Cl)Cl>[CH3:4][C:2]([O:5][C:6](=[O:29])[C@H:7]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH2:8])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Yield: 71.2 %

Procedure:
To a solution of N-[(phenylmethoxy)carbonyl]-L-tryptophan 1,1-dimethylethyl ester (36 g; 98 mmol) in EtOH (150 mL) Pd/C 10% (5 g) was added. A H2 atmosphere was set and hydrogenation was performed with the aid of a Venturi type stirrer. Reaction conversion was estimated by HPLC (Chromatographic method L/46). After 6 h at r.t. the suspension was filtered through paper, then through Millipore® HA 0.45 μm and the filtrate was concentrated under reduced pressure to give a crude oil. The crude was dissolved in CHCl3 (200 mL) and washed with 5% aq. Na2CO3 (200 mL) and brine (150 mL). The organic layer was dried over Na2SO4 and concentrated to give L-tryptophan-1,1-dimethylethyl ester (18.16 g), which was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[CH2:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][N:21]1[C:30](N1C=C[N+](C)=C1)=[O:31]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:30]([N:21]3[CH2:22][CH2:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20]3)=[O:31])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: C[n+]1ccn(C(=O)N2CCc3ccccc3C2)c1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: [I-]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCc2ccccc2C1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3-(3,4-dihydro-1H-isoquinoline-2-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. The crude product was recrystallized (ethanol) (53%). HPLC-MS m/z=415.2 (M+1), Rt: 5.3 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH2:12])[CH3:11].Cl[C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:41][C:24]2=[CH:25][C:26]3[C:27](=[O:40])[N:28]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:29](=[O:32])[C:30]=3[CH:31]=[C:23]2[N:22]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH:10]([NH:12][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[C:15]=1[C:21]1[NH:22][C:23]2=[CH:31][C:30]3[C:29](=[O:32])[N:28]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:27](=[O:40])[C:26]=3[CH:25]=[C:24]2[N:41]=1)[CH3:11]
Reactant: CC(N)Cc1cc(F)ccc1F
Reactant: CN1CCC(N2C(=O)c3cc4nc(-c5c(Cl)cc[nH]c5=O)[nH]c4cc3C2=O)CC1
Product: CC(Cc1cc(F)ccc1F)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3=O

Procedure:
Racemic 1-(2,5-difluorophenyl)propan-2-amine and 2-(4-chloro-2-oxo-1,2-dihydropyridin-3-yl)-6-(1-methylpiperidin-4-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione were submitted to general procedure A. The isolated solid was triturated with water once and MeOH four times to give the title compound as an off-white solid, which was used directly in the next step.