Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.Cl[CH2:14][CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[O:18]=[S:17]1(=[O:19])[CH2:16][CH2:15][CH2:14][N:1]1[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(N)nc1
Reactant: O=S(=O)(Cl)CCCCl
Product: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1

Procedure:
Using ethyl 6-aminonicotinate (2.02 g) and 3-chloropropane-1-sulfonyl chloride (1.8 mL) and by the reaction and treatment in the same manner as in Preparation Example 17, the title compound (2.29 g) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:3]=1
Reactant: CCOC(=O)C(=O)NNc1cc(I)ccn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(=O)NNc1cc(I)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.9 %

Procedure:
To a solution of ethyl [2-(4-iodopyridin-2-yl)hydrazino](oxo)acetate (0.15 g, 0.41 mmol) in tetrahydrofuran (3.5 mL) was added dropwise a solution of lithium hydroxide (0.030 g, 1.25 mmol) in water (1.5 mL). The resulting mixture was stirred at room temperature for 1 hour. Water was added and it was acidified using hydrochloric acid 2N until pH=3. The formed precipitate was filtered, rinsed with water and dried under vacuum to yield the title compound (0.20 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[SH:11].[C:12](O)(=O)[CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>CN1CCCC1=O.O>[F:8][C:7]1[C:2]2[N:1]=[C:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[S:11][C:3]=2[C:4]([F:10])=[CH:5][C:6]=1[F:9]
Reactant: O=C(O)CCCC(=O)O
Reactant: Nc1c(F)c(F)cc(F)c1S
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CCCc1nc2c(F)c(F)cc(F)c2s1
Temperature: 100 °C
Reaction time: 6 h
Yield: 43.9 %

Procedure:
2-Amino-3,4,6-trifluorothiophenol (200 mg, 1.1 mmol) was dissolved in N-methylpyrrolidone (NMP, 1 ml) under a nitrogen stream. To the resultant solution was gradually added glutaric acid (127 mg, 1.1 mmol) at room temperature and the mixture was stirred at 100° C. for 6 hours. After naturally cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate. The alkaline phase was acidified with 10% hydrochloric acid and re-extracted with ethyl acetate. The combined organic phases were dried and then evaporated to yield a residue, which was recrystallized from acetonitrile to give 4-(4,5,7-trifluorobenzothiazol-2-yl)butanoic acid (133 mg, 44%).
Reaction SMILES: IC.[F-].[CH2:4]([N+](CCCC)(CCCC)CCCC)CCC.[C:21]([O:25][C:26](=[O:54])[NH:27][C:28]([C:30]1[S:31][C:32]([S:52][CH3:53])=[C:33]([S:35]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:41]=[C:42]([OH:44])[CH:43]=2)(=[O:37])=[O:36])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CCOC(C)=O>[C:21]([O:25][C:26](=[O:54])[NH:27][C:28]([C:30]1[S:31][C:32]([S:52][CH3:53])=[C:33]([S:35]([C:38]2[CH:39]=[C:40]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[Cl:51])[CH:41]=[C:42]([O:44][CH3:4])[CH:43]=2)(=[O:36])=[O:37])[CH:34]=1)=[NH:29])([CH3:24])([CH3:23])[CH3:22]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cc(O)cc(-c2ccccc2Cl)c1
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(-c2ccccc2Cl)cc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Iodomethane (3 μL, 0.045 mmol) and tetrabutylammonium fluoride (1M in THF, 14 μL, 0.014 mmol) was added to a solution of {[4-(2′-chloro-5-hydroxy-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 19: step b) 5 mg, 0.009 mmol) in THF. After stirring for 2 hours, the solution was diluted with EtOAc (20 mL). The organic layer was washed with water (2×4 mL) and brine (5 mL), and was dried over MgSO4. Removal of the solvent in vacuo followed by purification of the residue (preparative TLC; 30% EtOAc in hexanes) afforded the title compound (3.1 mg, 62%). 1H-NMR (CDCl3): δ 7.84 (s, 1H), 7.64 (t, 1H, J=1.6 Hz), 7.53 (dd, 1H, J=1.6, 2.6 Hz), 7.47 (m, 1H), 7.33 (m, 3H), 7.21 (dd, 1H, J=1.6, 2.6 Hz), 3.89 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H). ESI-MS (m/z): Calcd. for C13H13BrN2O3S3: 421.4; found: 421.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16]([C:18]1[C:19]2[CH:26]=[N:25][N:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:20]=2[CH:21]=[N:22][CH:23]=1)=[O:17])[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:6]=1.C(N(CC)C(C)C)(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([N:24]2[C:20]3[CH:21]=[N:22][CH:23]=[C:18]([C:16]([NH:15][C@H:4]([C:5]4[CH:10]=[CH:9][N:8]=[C:7]([S:11]([CH3:14])(=[O:12])=[O:13])[CH:6]=4)[CH2:3][CH2:2][O:1][S:44]([CH3:43])(=[O:46])=[O:45])=[O:17])[C:19]=3[CH:26]=[N:25]2)=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1cc([C@H](CCO)NC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(S(C)(=O)=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-3-hydroxy-1-(2-methanesulfonyl-pyridin-4-yl)-propyl]-amide (0.10 g, 0.21 mmol) and N,N-diisopropylethylamine (167 μL, 0.957 mmol) in dichloromethane (20 mL) was cooled in an ice water-brine bath. After 5 minutes, methanesulfonyl chloride (25 μL, 0.32 mmol) was added and the cold bath was removed until the mixture became homogeneous. The mixture was again cooled in an ice bath. After 30 minutes, the mixture was quenched with saturated aqueous ammonium chloride (10 mL), washed with brine (10 mL), dried over magnesium sulfate and concentrated to afford methanesulfonic acid (S)-3-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-3-(2-methanesulfonyl-pyridin-4-yl)-propyl ester which was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[OH:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[OH:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)=[O:16]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)C(C)(C)CO)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
tert-Butyl 4-aminocyclohexylcarbamate (4:1 cis:trans mix of isomers, 1.00 g, 4.67 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (0.60 g, 5.13 mmol) and triethylamine (1.30 ml, 9.33 mmol) were dissolved in dimethylformamide (20 ml) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (984 mg, 5.13 mmol) and 1-hydroxybenzotriazole (694 mg, 5.13 mmol) were added. The reaction was stirred under nitrogen at room temperature for 18 h then partitioned between water and ethyl acetate. The organic phase was washed with water, dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting using dichloromethane:methanol:0.880ammonia (95:5:0.5) as eluant to give tert-butyl 4-[(3-hydroxy-2,2-dimethylpropanoyl)amino]cyclohexylcarbamate (840 mg) as a white foam as a ca. 4:1 mixture of diastereoisomers.
Reaction SMILES: S([O:11][C:12]1[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[C:14]([O:15]S(C2C=CC(C)=CC=2)(=O)=O)[C:13]=1[NH:32]C(=O)C)(C1C=CC(C)=CC=1)(=O)=O.S(=O)(=O)(O)O.[OH-].[Na+].C(=O)(O)[O-].[Na+]>>[NH2:32][C:13]1[C:14]([OH:15])=[CH:26][C:27]([N+:29]([O-:31])=[O:30])=[CH:28][C:12]=1[OH:11]
Reactant: CC(=O)Nc1c(OS(=O)(=O)c2ccc(C)cc2)cc([N+](=O)[O-])cc1OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Nc1c(O)cc([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
2-Acetamido-5-nitroresorcinol ditosylate (9.0 g, 0.017 mole) was added to cold sulfuric acid (25 ml, at or below 10° C.). The mixture was stirred cold an additional fifteen minutes and then at ambient temperature for 1.5 hours. The mixture was then poured into 250 ml ice water and sodium hydroxide (30 g, 0.75 mole) was slowly added. The mixture was then treated with sodium bicarbonate until it was no longer acidic, and aqueous solution was extracted twice with ethyl acetate (150 ml). The extracts were combined, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield a light yellow solid (2.5 g, 86.2 percent). TLC showed the product was pure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)=[CH:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[NH:21][C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH:14]=2)[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C=C(c1cccc(F)c1)c1cc2cccnc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(c1cccc(F)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
A solution of 2-(1-(3-fluoro-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.2 g, 4.28 mmol) in methanol (35 mL) was treated with 10% palladium on carbon (180 mg). The reaction was stirred at 25° C. under hydrogen atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford 2-(1-(3-fluoro-phenyl)-3-methyl-butyl)-1H-pyrrolo[2,3-b]pyridine (1.2 g, 99%) as an off-white solid: 1H NMR (300 MHz, d6-DMSO): 6 ppm 11.59 (s, 1H), 8.08 (dd, 1H, J1=4.8 Hz, J2=1.5 Hz), 7.82-7.79 (m, 1H), 7.37-7.21 (m, 3H), 7.04-6.95 (m, 2H), 6.30 (s, 1H), 4.23 (t, 1H, J=8.1 Hz), 2.11-2.04 (m, 1H), 1.92-1.85 (m, 1H), 1.40-1.35 (m, 1H), 0.91 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[S:23][C:22]([C:24](OCC)=[O:25])=[CH:21][CH:20]=1>CCCCCC.C1COCC1>[Cl:18][C:19]1[S:23][C:22]([C:24](=[O:25])[CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(Cl)s1
Reactant: Cc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Cc1ccncc1)c1ccc(Cl)s1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
At 0° C., 64.5 ml of a 1M solution of lithium bis(trimethylsilyl)amide in hexane are added dropwise to a solution of 3.00 g (32.3 mmol) of 4-methylpyridine and 6.77 g (35.5 mmol) of ethyl 5-chlorothiophene-2-carboxylate in 58 ml THF, and the reaction mixture is stirred at 5° C. for 3 h. The resulting precipitate was filtered off, acidified with 6M HCl, filtered again and dried. This gives 2.9 g (35%) of the desired product; 1H-NMR (DMSO-d6): δ=8.53 (d, 2H), 8.09 (d, 1H), 7.40 (d, 1H), 7.34 (d, 2H), 4.39 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)CC)C.[CH3:33][O:34][CH2:35][CH2:36][C:37](Cl)=O.C>C(Cl)Cl.CCO.CO>[CH3:33][O:34][CH2:35][CH2:36][C:37]1[N:12]([CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCCC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A solution of tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate (10.2 g, 29.5 mmol) in 250 mL of anhydrous CH2Cl2 was cooled to 0° C. and treated with triethylamine (4.18 mL, 30.0 mmol). Methoxypropionyl chloride (3.30 mL, 30.3 mmol) was then added dropwise over 5 min. The reaction was then warmed to room temperature and stirring was continued for 1 h. The reaction mixture was then concentrated under reduced pressure to give an orange solid. This was dissolved in 250 mL of EtOH and 12.5 mL of triethylamine was added. The mixture was heated to reflux and stirred under N2 overnight. The reaction was then concentrated to dryness under reduced pressure and treated with 300 mL of Et2O. The mixture was then filtered and the filtrate was concentrated under reduced pressure to give a brown solid. The solid was dissolved in 200 mL of hot MeOH and treated with activated charcoal. The hot solution was filtered and concentrated to give 11.1 g of tert-butyl 2-{2-[2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow syrup.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=1.[Na+].Br[C:17]1[CH:25]=[C:24]([CH3:26])[C:23]2[N:22]([CH3:27])[C:21]3[CH2:28][CH:29]4[NH:33][CH:32]([C:20]=3[C:19]=2[C:18]=1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30]4>>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:5]=[C:6]([S:10]([C:17]2[CH:25]=[C:24]([CH3:26])[C:23]3[N:22]([CH3:27])[C:21]4[CH2:28][CH:29]5[NH:33][CH:32]([C:20]=4[C:19]=3[C:18]=2[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31][CH2:30]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S([O-])c1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(Br)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Agent: [Na+]
Product: Cc1cc(S(=O)(=O)c2cccc(OC(F)(F)F)c2)c(C(=O)OC(C)(C)C)c2c3c(n(C)c12)CC1CCC3N1
Yield: 26 %

Procedure:
Intermediate 3 was coupled to the product of Example 71, step C following the procedure of Example 71, step D. The crude product was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(3-trifluoromethoxy-phenyl)sulfonyl-4,5-dimethyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (58 mg, 26%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.02 (br s, 1H), 7.85-7.90 (m, 1H), 7.81 (br s, 1H), 7.50 (t, J=8.1 Hz, 1H), 7.31-7.37 (m, 2H), 5.21 (br s, 1H), 4.72 (br s, 1H), 3.85 (s, 3H), 3.35 (br s, 1H), 2.76 (s, 3H), 2.45 (d, J=15.6 Hz, 1H), 2.24-2.49 (m, 1H), 2.12-2.24 (m, 1H), 1.85-1.96 (m, 1H), 1.57-1.66 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1.Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:32]=2[C:33]([NH:35][CH2:36][C:37]#[CH:38])=[O:34])[C:27]([Cl:44])=[CH:26][N:25]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][C:20]([NH:22][C:24]4[N:29]=[C:28]([NH:30][C:31]5[C:32]([C:33](=[O:34])[NH:35][CH2:36][C:37]#[CH:38])=[CH:39][CH:40]=[CH:41][C:42]=5[F:43])[C:27]([Cl:44])=[CH:26][N:25]=4)=[CH:21][C:16]=3[O:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH2:3]1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCCC(OC(=O)N2CCCOc3cc(N)ccc32)C1
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)OCCCN3C(=O)OC2CCCN(C)C2)ncc1Cl

Procedure:
The title compound was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid 1-methyl-piperidin-3-yl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1410. Product isolated as an orange foam (107 mg, 54%). LCMS (m/e) 608 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.68-8.42 (m, 1H), 8.10 (s, 1H), 7.46-7.18 (m, 4H), 7.15-6.94 (m, 2H), 6.93-6.78 (m, 1H), 6.56-6.43 (m, 1H), 4.92-4.70 (m, 1H), 4.20-3.97 (m, 4H), 3.85-3.55 (m, 2H), 2.89-2.77 (m, 1H), 2.64-2.48 (m, 1H), 2.37-2.12 (m, 5H), 2.11-1.73 (m, 5H), 1.65-1.40 (m, 1H), 1.30-1.12 (m, 1H); 19F-NMR (CDCl3, 400 MHz) 6-113.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]([O:31]C(C)(C)C)=[O:30])=[CH:26][C:25]=2[CH:36]=1>CC#N>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[O:28][C:27]([C:29]([OH:31])=[O:30])=[CH:26][C:25]=3[CH:36]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)c1cc2cc(N)ccc2o1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3oc(C(=O)O)cc3c2)=C(c2ccccc2)S1(=O)=O
Temperature: 160 °C
Yield: 28.9 %

Procedure:
A mixture of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.000 g, 3.336 mmol), tert-butyl 5-amino-1-benzofuran-2-carboxylate (0.778 g, 3.336 mmol) and TEA (0.340 ml, 2.471 mmol) in MeCN (5 ml) was heated in a microwave reactor at 160° C. for 1.5 h. The reaction mixture was evaporated and the residue was purified by flash chromatography using 5:1 DCM/EtOAc (+1% AcOH) as eluent to give the title compound (0.425 g, 29%). 1H NMR (500 MHz CD3OD); δ 13.54 (bs, 1H), 9.63 (s, 1H), 7.34 (s, 1H), 7.29 (d, 1H), 7.14-6.97 (m, 6H), 3.71 (t, 2H), 1.75 (qnt, 2H), 1.42 (sex, 2H), 0.95 (t, 2H); Mass Spectrum: M−H+ 439
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([O:27]C)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[O:8])[CH2:2][CH2:3][S:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1

Procedure:
According to General Method 5A, 5.16 g (12.4 mmol) of the compound from Example 15A and 13.9 g (124 mmol) of potassium tert-butoxide were reacted. The reaction led selectively to the cis isomer. Yield: 4.90 g (98% of theory)
Reaction SMILES: [F-:1].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[C:24]([N+]([O-])=O)[C:21]=1[C:22]#[N:23]>C(OCC)(=O)C>[Br:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[C:24]([F:1])[C:21]=1[C:22]#[N:23]
Reactant: [F-]
Reactant: COc1cc([N+](=O)[O-])c(C#N)c(Br)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(C#N)c(Br)c1OC
Temperature: 25 °C
Yield: 85 %

Procedure:
A partially dried solution of tetrabutylammonium flouride (24 ml, 1M in THF stored over 4A sieves) was added to 2-bromo-3,4-dimethoxy-6-nitrobenzonitrile (prepared according to step (c), 1.73 g, 6.02 mmol) with stirring at room temperature. After 1 hour ethyl acetate was added and the mixture washed with 1M aqueous HCl (50 ml). The aqueous wash was extracted with ethyl acetate (50 ml) and the combined organics then washed with aqueous NaHCO3 (50 ml) before being dried over MgSO4 and concentrated in vacuo. The crude residue was recrystallised from toluene:tert-butylmethylether (1:1) to give 1.34 g of the subtitle product (85%).
Reaction SMILES: [C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH:32]C(OC(C)(C)C)=O)[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:41])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:13][CH:12]([NH2:32])[C:11]2=[O:40])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
1-(2-Toluoylmethyl)-2-oxo-3-tert-butoxycarbonylamino-5-benzyloxycarbonyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (12.9 g) was suspended in 4N HCl-dioxane (100 ml), the suspension was stirred for one hour at 50° C. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with saturated aqueous sodium bicarbonate, extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain 9.78 g of the titled compound (Yield: 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:7]=1[CH3:14])[CH3:2].C([Mg]Cl)(C)C.C([Li])(C)(C)C.CN(C)[CH:28]=[O:29]>O1CCCC1.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[NH:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH:28]=[O:29])=[CH:8][C:7]=1[CH3:14])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)Nc1c(C)cc(Br)cc1C
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)Nc1c(C)cc(C=O)cc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To (4-bromo-2,6-dimethyl-phenyl)-carbamic acid ethyl ester (1t, 1.0 g) dissolved in dry tetrahydrofuran (25 mL) under argon was added isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.9 mL) over 5 minutes and then stirred for 30 minutes. The reaction mixture was cooled to −78° C. and tert-butyllithium (1.7 M in heptane, 4.5 mL) was added dropwise while keeping the internal temperature below −65° C. The temperature of the reaction was raised to −10° C. after complete addition, and then cooled to −78° C. again followed by addition of N,N-dimethylformamide (0.6 mL). The reaction was stirred for 30 minutes at −78° C., 30 minutes at 25° C. and then poured onto crushed ice mixed with acetic acid (25 mL). The mixture was stirred for 30 minutes, extracted with ethyl acetate (3×100 mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was subjected to flash chromatography to furnish 0.60 g (73% yield) of the title compound as a white solid. LC-MS (m/z) 222 (MH+); tR=2.14, (UV, ELSD) 86%, 99%. 1H NMR (500 MHz, CDCl3): 1.30 (t, 3H), 2.34 (s, 6H), 4.21 (q, 2H), 6.28 (b, 1H), 7.59 (s, 2H), 9.92 (s, 1H).
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[OH-].[K+].[C:14](=S)=[S:15]>C(O)C>[N:1]1[N:2]=[C:14]([SH:15])[N:7]2[C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=3[S:4][C:3]=12
Reactant: S=C=S
Reactant: NNc1nc2ccccc2s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Sc1nnc2sc3ccccc3n12

Procedure:
2-Hydrazinobenzothiazole (300 grams), potassium hydroxide (100 grams), and 225 milliliters of carbon disulfide were refluxed for 60 hours in 5500 milliliters of ethanol. A light yellow solid began precipitating out shortly after the beginning of reflux. The solid was collected by filtration and dissolved in water to which 1500 milliliters of 0.5N hydrochloric acid were added. The mixture thickened; the desired s-triazolo(3,4-b)benzothiazole-3-thiol product was collected by filtration, m.p., 242° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.[C:17]([Zn]C#N)#[N:18]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:17]#[N:18])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: N#C[Zn]C#N
Reactant: Clc1cccc2c1CCOC2C1=NCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-chloroisochroman-1-yl)-4,5-dihydro-1H-imidazole (50 mg), dicyanozinc (25 mg), bis(tri-t-butylphosphine)palladium(0) (3 mg) and DMF (2 ml) was stirred in microwave reactor at 160° C. for 30 minutes. The title compound was purified with separation methods F and G. (Yield 22 mg).