Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:23]([NH:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NS(=O)(=O)c1cccc(CCCCOCCCCCCBr)c1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCNCc2ccccc2)c1
Temperature: 80 °C
Yield: 50.6 %

Procedure:
3-[4-(6-Bromo-hexyloxy)-butyl]benzenesulfonamide (1.0 g) in toluene (4 ml) was added dropwise to benzylamine (0.65 g) and the resulting mixture heated at 80° C. for 6 h. The mixture was then cooled and 20% aqueous sodium hydroxide solution (50 ml) was added. The resulting mixture was extracted with ethyl acetate and the combined organic layers evaporated to dryness in vacuo. The residual oil was then purified by chromatography (DCM-IMS-NH3(aq) 100:10:1) to give the title compound (0.54 g) LC RT=3.89 min.
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13](Cl)=[N:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:11]=2[C:10]([CH3:21])=[CH:9]1)=O)(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>O1CCOCC1.CCOC(C)=O.[OH-].[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:13]2[C:12]3[NH:8][CH:9]=[C:10]([CH3:21])[C:11]=3[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Temperature: 110 °C

Procedure:
A mixture of 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester (200 mg) and 3-chloroaniline (0.68 ml) in 1,4-dioxane (3 ml) was heated at 110° C. for 16 hours. The reaction mixture was diluted with EtOAc and basified with 1M NaOH, the aqueous layer was extracted and acidified to pH1 using 1M HCl to afford a precipitate. The precipitate was filtered off and washed with water until neutral. The solid was then sucked dry and dried over sodium hydroxide at 50° C. under vacuum to afford the title compound (197 mg).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[NH:16])OCC)=[CH:7][CH:6]=1)([O-:4])=[O:3].CO[CH:19](OC)[CH2:20][NH2:21]>C(O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]2[NH:16][CH:19]=[CH:20][N:21]=2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CCOC(=N)Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(CN)OC
Agent: Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cc2ncc[nH]2)cc1
Temperature: 60 °C
Yield: 51.6 %

Procedure:
To a solution of ethyl 2-(4-nitrophenyl)-acetimidate hydrochloride (3.5 g, 14.3 mmol) in ethanol (15 mL) was added amino acetaldehyde dimethyl acetal (1.87 mL, 17.2 mmol) and the reaction heated at reflux for 18 h. The reaction mixture was concentrated which was mixed with 2N hydrochloric acid (30 mL) and heated to 60° C. for 18 h. The solvent was evaporated, diluted with water and extracted with ethyl acetate. The organic layer was separated, the aqueous layer basified with sodium carbonate and extracted with chloroform (×2). The combined chloroform extracts was dried over sodium sulfate, filtered and evaporated under reduced pressure to obtain 2-(4-nitro-benzyl)-1H-imidazole (1.5 g, 51%) as a brown solid.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=O)O1.[Br:11][C:12]1[CH:19]=[CH:18][C:15](C=O)=[CH:14][CH:13]=1.Cl>C(O)(=O)C.O>[Br:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:4][CH2:5][C:6]([OH:7])=[O:8])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCc1ccc(Br)cc1
Yield: 52 %

Procedure:
2,2-dimethyl-[1,3]dioxane-4,6-dione (120 g, 0.84 mol) and 4-bromo-benzaldehyde (153.4 g, 0.84 mol) were dissolved in 300 mL of TEA and acetic acid. The reaction mixture was refluxed for overnight. At which point, the reaction mixture was diluted with water (4 L) and acidified with 6M HCl (1 L) until pH=2. The precipitated solid was filtered off and washed with diluted HCl, then dissolved in 5% NaHCO3 solution. The aqueous salt solution was washed with ether (4×500 mL), filtered and acidified with diluted HCl. Then filtered and dried under vacuum to provide 100 g (67%) of the desired product 3-(4-bromophenyl)propanoic acid (1A): 1H NMR (DMSO-d6, 400 MHz), 62.5 (m, 2H), 2.8 (m, 2H), 7.2 (m, 2H), 7.5 (m, 2H), 12.2 (s, 1H).
Reaction SMILES: [CH2:1]([CH:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]=[C:33]=[O:34]>ClCCl>[C:31]1([NH:32][C:33]([N:13]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:28])[F:29])=[CH:17][CH:16]=3)[CH2:9][CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:34])[CH:9]=[CH:8][CH:1]=[CH:2][CH:3]=1
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(Cc3ccccc3)C2)cc1
Reactant: CN=C=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound was made in the following manner: 100 mg of 3-benzyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine dissolved in dichloromethane, 1.1 equiv. methylisocyanate added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was identified by ES MS(+) (m/z 530).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][C:12]1[CH:16]=[C:15]([CH3:17])[O:14][N:13]=1.CCOCC>CN(C=O)C>[Br:1][C:16]1[C:12]([CH2:11][O:10][CH3:9])=[N:13][O:14][C:15]=1[CH3:17]
Reactant: COCc1cc(C)on1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCc1noc(C)c1Br
Temperature: 60 °C
Yield: 92.5 %

Procedure:
N-bromosuccinimide (590 mg, 3.31 mmol) was added to 3-methoxymethyl-5-methyisoxazole (351 mg, 2.76 mmol) in DMF (3.5 mL) at room temperature under nitrogen. The reaction was heated at 60° C. for 15 h then allowed to cool to room temperature. Ether (50 mL) was added to the reaction mixture, then washed with water (3×10 mL), saturated aqueous sodium hydrogen carbonate (10 mL), and brine (10 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 526 mg (92% yield) of 4-bromo-3-methoxymethyl-5-methylisoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 4.50 (s, 2H), 3.41 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1.[H-].[Na+].[CH3:32]I>CN(C=O)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH3:32])[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(N(C)S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reaction time: 0.25 h
Yield: 100 %

Procedure:
The title compound of Example 102 (56 mg, 0.13 mmol) in DMF (0.2 mL) was treated with NaH (60% dispersion in oil, 6 mg, 0.16 mmol). After about 15 min, methyl iodide (0.012 mL, 0.2 mmol) was added. After complete reaction, silica gel chromatography gave the title compound (55 mg, 0.13 mmol) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96-2.17 (s, 3H) 2.98 (s, 3H) 3.25 (s, 3H) 3.49 (s, 3H) 6.82 (d, J=8.84 Hz, 1H) 7.21-7.40 (m, 3H) 7.40-7.54 (m, 2H) 7.59 (s, 1H) 7.82 (d, J=2.53 Hz, 1H) LCMS (M+H)+ 435
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([F:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][N:15]([CH3:24])[C:16]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17].C(N(CC)CC)C.C1COCC1>C(Cl)(Cl)Cl.C(=O)([O-])O.[Na+].CN(C=O)C>[CH3:14][N:15]([CH3:24])[C:16]([CH:18]1[CH2:19][CH2:20][N:21]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([F:13])=[CH:7][CH:8]=3)[N:3]=[C:2]([Cl:1])[N:11]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: Fc1ccc2c(Cl)nc(Cl)nc2c1
Reactant: CN(C)C(=O)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CCN(c2nc(Cl)nc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 104.9 %

Procedure:
A mixture of 2,4-dichloro-7-fluoroquinazoline (250 mg), piperidine-4-carboxylic acid dimethylamide (189 mg), triethylamine (0.24 mL), THF (6 mL), and DMF (4 mL) was stirred at room temperature for 13 h. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted 3 times with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7:3) to obtain colorless solid 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (407 mg). (2) A mixture of 1-(2-chloro-7-fluoroquinazolin-4-yl)piperidine-4-carboxylic acid dimethylamide (250 mg), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (265 mg), N,N-diisopropylethylamine (0.32 mL), and n-butanol (1.2 mL) was heated at 120° C. for 57 h with stirring. The reaction mixture was diluted with a mixture of chloroform and saturated aqueous sodium hydrogencarbonate, and then the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=4:1−ethyl acetate, and silica gel, chloroform/methanol=95:5). The resulting purification product was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.1 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 3.5 h. The solvent was evaporated under reduced pressure to obtain the amorphous title compound (110 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:21])=[C:6]([C@:8]2([CH3:20])[C@H:13]3[C:14]([F:18])([F:17])[CH2:15][CH2:16][C@H:12]3[O:11][C:10]([NH2:19])=[N:9]2)[CH:7]=1.[F:22][CH2:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:19][C:10]1[O:11][C@@H:12]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[C@@H:13]2[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[N:25][C:24]([CH2:23][F:22])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:21])([CH3:20])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Reactant: O=C(O)c1cnc(CF)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(CF)cn3)ccc2F)N=C(N)O[C@@H]2CCC(F)(F)[C@@H]21
Yield: 75 %

Procedure:
The coupling of (4S,4aR,7aR)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-4,4a,5,6,7,7a-hexahydro-cyclopenta[e][1,3]oxazin-2-ylamine (intermediate XIIIa-1) and 5-fluoromethyl-pyrazine-2-carboxylic acid (CAS 1262803-66-6) following procedure Q yielded the title compound as a white solid (75% yield). MS: m/z=438.2 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[C:10]([C:14]1([CH2:18]O)[CH2:17][O:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]>>[C:10]([C:14]12[CH2:15][O:16][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7])([O:9][CH2:18]1)[O:8][CH2:17]2)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)C1(CO)COC1
Reactant: C#CCCCCC(=O)O
Product: C#CCCCCC12OCC(C(C)(C)C)(CO1)CO2

Procedure:
Using the procedure described in stage (vi) of Example I and starting from hept-6-ynoic acid and 3-t-butyl-3-hydroxymethyloxetane (2-t-butyl-2-hyddroxymethylpropan-1,3-diol was prepared by the method of Y. Ozoe and M. Eto Agric.Biol. Chem, 1982, 46, 411), 4-t-butyl-1-(hex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane was prepared.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[N:20]=[CH:19][C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=3)[C:12]2=[O:26])[C:3]=1[CH:4]=[O:5].[CH3:27][C@H:28]1[CH2:33][N:32]([CH:34]2[CH2:37][O:36][CH2:35]2)[C@H:31]([CH3:38])[CH2:30][N:29]1[C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:46]2[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:51]=2)=[N:43][CH:44]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[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].O.C(#N)C>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([F:25])[CH:15]=1)[C:12](=[O:26])[N:11]([C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:2]([C:50]3[CH:51]=[C:46]([NH:45][C:42]4[CH:41]=[CH:40][C:39]([N:29]5[CH2:30][C@@H:31]([CH3:38])[N:32]([CH:34]6[CH2:37][O:36][CH2:35]6)[CH2:33][C@@H:28]5[CH3:27])=[CH:44][N:43]=4)[C:47](=[O:62])[N:48]([CH3:61])[CH:49]=3)[C:3]=1[CH:4]=[O:5])[N:20]=[CH:19]2)([CH3:22])([CH3:24])[CH3:23]
Reactant: C[C@@H]1CN(c2ccc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cc(F)cc(Br)c3C=O)ncc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(-n5ncc6cc(C(C)(C)C)cc(F)c6c5=O)c4C=O)cn(C)c3=O)nc2)[C@@H](C)CN1C1COC1
Temperature: 25 °C

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b (84 mg, 0.20 mmol), 3-(5-((2S,5R)-2,5-dimethyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (99 mg, 0.20 mmol), Pd(dppf)Cl2 (15 mg, 0.02 mmol), K3PO4 (127 mg, 0.6 mmol), sodium acetate (49 mg, 0.6 mmol), acetonitrile (5 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to 108a as a white solid (54 mg, 38%). MS: [M+H]+ 710.3
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)(=[O:12])=[O:11].C(ON=O)(C)(C)C>>[CH3:9][O:8][C:6]1[CH:5]=[C:4]2[C:3]([S:10](=[O:12])(=[O:11])[NH:13][C:14]3[C:15]2=[CH:16][CH:17]=[C:18]2[C:23]=3[N:22]=[CH:21][CH:20]=[CH:19]2)=[CH:2][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc3cccnc23)c(N)c1
Agent: CC(C)(C)ON=O
Product: COc1ccc2c(c1)-c1ccc3cccnc3c1NS2(=O)=O
Yield: 12.5 %

Procedure:
In a similar fashion using route 16 general procedure 36, 2-amino-4-methoxy-N-quinolin-8-yl-benzenesulfonamide (Example Compound 13) (60 mg, 0.18 mmol) and tert-butylnitrite (32 μl, 0.27 mmol) gave the title compound (7 mg, 10%) after purification by column chromatography with DCM as the eluent followed by a further column with heptane/EtOAC (9:1-0:1) gradient elution and then preparative HPLC (acidic conditions).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1.B(F)(F)F.CCOCC.C(O)C>[N+](C)([O-])=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]1[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]1
Reactant: O=C1C=CCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCO
Solvent: C[N+](=O)[O-]
Product: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 5-fluoroindole (6.0 g, 44.4 mmol) and 2-cyclopenten-1-one (4.5 mL, 53.3 mmol) in nitromethane (22 mL) was cooled to −20° C. in a carbon tetrachloride-dry ice bath. A mixture of boron trifluoride etherate (1.6 mL, 11.1 mmol) and ethanol (2.2 mL, 43 mmol) was added dropwise from an addition funnel. The reaction mixture was stirred at −20° C. for 2 hours, then was quenched with 5% aqueous sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), then were dried over anhydrous sodium sulfate, filtered and concentrated to give 9.5 g of the title compound. Trituration with ethyl acetate afforded 5.6 g (58%) of the title compound as a yellow solid. An analytical sample was recrystallized from ethyl acetate/methanol: mp 119–120° C.; MS (ESI) m/z 218 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(Cl)ccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(Cl)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of methyl 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (152 mg, 0.37 mmol) in tetrahydrofuran (30 mL) was added sodium hydroxide (48.6 mg, 1.22 mmol) and water (2 ml) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(5-chlorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (60 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[C:5]2[C:21]1[CH:22]=[N:23][N:24](C(OC(C)(C)C)=O)[CH:25]=1.[ClH:33]>CCOC(C)=O>[ClH:33].[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:12]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:13])=[O:14])[CH:6]=[C:5]2[C:21]1[CH:22]=[N:23][NH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)c(F)cc23)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(F)c(F)cc21
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-(5,6-difluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazole-1-carboxylate (Intermediate 29; 203 mg; 0.44 mmol) in EtOAc (2 mL) was added HCl in EtOAc (4 M; 1 mL). The resulting mixture was stirred for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford 150 mg (88%) of the title compound as a red solid.
Reaction SMILES: Cl.[OH:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:6][N:5]=[C:4]1[Cl:15].[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[Cl:15][C:4]1[N:3]([O:2][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][N:5]=1
Reactant: Cc1ccc(-c2cnc(Cl)n2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: Cl
Product: Cc1ccc(-c2cnc(Cl)n2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-2-chloro-5-(4-methylphenyl)imidazole, hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (80%, oil).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16](F)[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35].C(Cl)Cl.CCOCC.CO>CCCCO.CS(C)=O>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]([NH:31][C@H:32]([CH2:37][CH3:38])[CH:33]([OH:36])[CH2:34][CH3:35])[N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)[C@H](N)CC
Reactant: CC(C)n1cnc2c(NCc3ccccc3)nc(F)nc21
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CCC(O)[C@@H](CC)Nc1nc(NCc2ccccc2)c2ncn(C(C)C)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of benzyl-(2-fluoro-9-isopropyl-9H-purin-6-yl)-amine (40 mg, 1 eq, 0.14 mmol) in n-BuOH/DMSO (3.75 mL, 4:1) at room temperature under an argon atmosphere was added DIEA (0.24 mL, 9.8 eq, 1.38 mmol) followed by (3RS,4R)-4-amino-hexan-3-ol (110 mg, 6.7 eq, 0.93 mmol). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h, when TLC DCM:ether:MeOH (55:40:5) indicated that the reaction had gone to completion The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between EtOAc (50 mL) and brine/water (1:1, 100 mL), the aqueous phase was extracted with more EtOAc (2×50 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel eluted with hexane:ether:MeOH (50:50:0→50:50:2) to afford the title compound as a white solid; Yield: 31 mg (58%).(57% de 4R,3S: 43% de 4R,3R). 1H-NMR (d-CDCl3, 250 MHz): δ 0.92-1.08 (m, 6H, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.56 (d, 6H, J=6.79 Hz, +—CH(CH3)2), 1.44-1.69 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.45 (d, 1H, J=6.32 Hz, OH) 3.56-3.70 (m, 1H, —NHCH(CH2CH3) CH(CH2CH3)OH), 3.91-4.06 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.58-4.69 (m, 1H, —CH(CH3)2), 4.73-5.01 (m, 2H, —HNCH2-Bz), 5.16-5.32+6.01-6.22 (2×m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.22-7.43 (m, 6H, 5×Bz-H+HNCH2-Bz), 7.52 (s, 1H, —N═CH—N). FABMS m/z (relative intensity): 383 ([M+H]+, 100), 323 (55), 296 (21). Accurate Mass (M+H): Actual: 383.2559, Measured: 383.2542.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]#[CH:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:31][C:30]#[CH:29])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and propargyl bromide (53 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo to yield the desired morpholine example 39 as a colorless oil (20 mg).