Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[C:15](Br)[CH:16]=[C:11]2[C:10]([CH:18]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[OH:28])[CH3:19])=[CH:9]1)=O)(C)(C)C.[Si]([O:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([N:43]2[C:47]([CH3:48])=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:45]=[N:44]2)[CH2:39][CH2:38]1)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].O.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:26][C:25]1[C:20]([CH:18]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[C:15]([C:46]4[CH:45]=[N:44][N:43]([C@H:40]5[CH2:41][CH2:42][C@H:37]([OH:36])[CH2:38][CH2:39]5)[C:47]=4[CH3:48])[CH:16]=3)[NH:8][CH:9]=2)[CH3:19])=[C:21]([OH:28])[C:22]([F:27])=[CH:23][CH:24]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC(c1c(Cl)ccc(F)c1O)c1cn(C(=O)OC(C)(C)C)c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cnc3[nH]cc(C(C)c4c(Cl)ccc(F)c4O)c3c2)cnn1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C

Procedure:
A mixture of 5-Bromo-3-[1-(6-chloro-3-fluoro-2-hydroxyphenyl)ethyl]pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (100.00 mg, 0.21289 mmol), 1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (134 mg, 0.319 mmol), Pd(PPh3)4 (12.3 mg, 0.0106 mmol), potassium carbonate (147.1 mg, 1.064 mmol) and 4:1 Dioxane:water (4:1,1,4-Dioxane:H2O, 8 mL, 80 mmol) was heated in a microwave reactor at 100° C. for 30 min. Reaction mixture was cooled to rt, 12 M HCl in H2O (0.8 mL, 10 mmol) was added, and the solution was heated at 40° C. for 2 h. Purification by Teledyne/ISCO eluting with 0-15% MeOH in DCM afforded the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.37-1.59 (m, 2H), 1.84 (d, J=7.3 Hz, 3H), 1.89-2.14 (m, 6H), 2.16-2.27 (m, 3H), 3.68 (ddd, J=10.9, 6.8, 4.3 Hz, 1H), 4.08-4.26 (m, 1H), 5.09 (br. s., 1H), 6.76-6.88 (m, 1H), 6.90-7.00 (m, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.44-7.56 (m, 2H), 8.09 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:31])([F:30])[F:29])[CH2:5][C@@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:20]3[CH:25]=[N:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)=[O:19])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1.NC1O[C@@H](C(F)(F)F)C[C@](C2C=C(NC(C3C=NC(OC)=CN=3)=O)C=CC=2F)(CF)N=1>>[NH2:1][C:2]1[O:3][C@H:4]([C:28]([F:29])([F:31])[F:30])[CH2:5][C@:6]([C:10]2[CH:11]=[C:12]([NH:17][C:18]([C:20]3[CH:25]=[N:24][C:23]([O:26][CH3:27])=[CH:22][N:21]=3)=[O:19])[CH:13]=[CH:14][C:15]=2[F:16])([CH2:8][F:9])[N:7]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Agent: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@H](C(F)(F)F)OC(N)=N3)c2)cn1
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1

Procedure:
Racemic mixture of N-(3-((4R,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide and N-(3-((4S,6R)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxy-2-pyrazinecarboxamide;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14](Cl)(=O)C>CO>[N+:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:5]1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)CC1CCCC([N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of m-nitrophenylacetic acid, 14.2 g (78.0 mmol) in 200 mL of methanol at 0° C. was added 20 mL of acetyl chloride dropwise. The reaction mixture was stirred overnight at ambient temperature and concentrated to dryness. The residue was chromatographed on silica gel using 50% ethyl acetate/hexanes as eluent to yield 14.7 g (97%) of the desired mixture of isomers as a yellow oil. 1H—NMR is consistent with structure. MS (FD) 194.8 (M−1).
Reaction SMILES: C1(CC(CC(=O)NCCC2C=CC=CC=2)C([N:15](C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.C1(CC(CC(=O)NCCC2C=CC=CC=2)C(N[C@H](C(N=[N+]=[N-])=O)CC2N=CNC=2)=O)C2C(=CC=CC=2)C=CC=1.[N-]=[N+]=[N-].Cl.[CH2:83]([O:90][CH2:91][CH:92]([OH:99])[C@@H:93](N)[CH2:94][CH:95]([CH3:97])[CH3:96])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.N(OCCC(C)C)=O.C(N(CC)CC)C>[CH2:83]([O:90][CH:91]([NH2:15])[CH:92]([OH:99])[CH2:93][CH2:94][CH:95]([CH3:97])[CH3:96])[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1
Reactant: CC(C)C[C@H](N)C(O)COCc1ccccc1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Agent: CC(C)CCON=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CCC(O)C(N)OCc1ccccc1
Reaction time: 16 h

Procedure:
To a suspension of 31 mg of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide in 1 ml of N,N-dimethylformamide were added successively dropwise 0.044 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.011 ml of isoamyl nitrite, and the mixture was stirred. After disappearance of hydrazide compound, the reaction mixture was cooled to +30° C., and neutrlized by adding 0.031 ml of triethylamine to prepare a solution of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)-propionyl]-L-histidine azide. The azide solution prepared was added dropwise to a solution of 16 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexyl benzyl ether hydrochloride and 0.011 ml of triethylamine in 1 ml of N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. A 5% aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatograpy (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 18 mg of (2RS, 3S)-3-{N-(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexyl benzyl ether as a white powder.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:5])[CH3:4].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:4][C:3](=[O:5])[C:2]([CH3:13])([CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(=O)C(C)(C)Cc1ccccc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccccc1)C(=O)CBr
Temperature: 25 °C
Yield: 100 %

Procedure:
100 g (0.57 mol) of 3,3-dimethyl-4-phenylbutan-2-one (Example 5) are dissolved in 0.8 liter of chloroform, and 29 ml (91.9 g; 1.14 mols) of bromine are added slowly at room temperature. The mixture is stirred for a further hour at room temperature and is concentrated. 145.5 g (quantitative) of 1-bromo-3,3-dimethyl-4-phenylbutan-2-one are obtained, and this directly reacted further, without isolation. ##STR24##
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4].C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>O1CCCC1>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[C:10]([N:12]([C:29](=[O:32])[CH2:30][CH3:31])[S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])[C:9]([CH3:20])=[CH:8][C:7]=1[CH3:21])(=[O:5])=[O:4]
Reactant: CCC(=O)Cl
Reactant: CNS(=O)(=O)c1cc(NS(=O)(=O)C(F)(F)F)c(C)cc1C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)N(c1cc(S(=O)(=O)NC)c(C)cc1C)S(=O)(=O)C(F)(F)F
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of N-methyl-2,4-dimethyl-5-(trifluoromethanesulfonamido)benzenesulfonamide (2 g) and triethylamine (0.7 g) in tetrahydrofuran (20 ml), propionyl chloride (0.45 g) was added, and the resultant mixture was allowed to stand at room temperature overnight. The reaction mixture was concentrated, admixed with 5% hydrochloric acid and extracted with chloroform. The extract was concentrated to give an oily substance, which was purified by silica gel chromatography. Recrystallization from a mixture of toluene and hexane gave 1.17 g of N-methyl-2,4-dimethyl-5-(N-propionyl-N-trifluoromethanesulfonylamino)benzenesulfonamide (Compound No. 81). M.P., 101°-103° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:35](OCC)[O:36]CC)=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:35]=[O:36])=[C:5]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC(C)=C(C(=O)OCCOCc2ccccc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a solution of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (6.0 g) in acetone (60 ml) was added 6N hydrochloric acid (6 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 7.5 to 8 with an aqueous sodium bicarbonate solution, and acetone was distilled off under reduced pressure. The resultant solution was diluted with water (150 ml) to separate out oily precipitates, which were extracted twice with ethyl acetate (100 ml and 50 ml, respectively). The organic layer was washed with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give oily 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (5.02 g).
Reaction SMILES: FC(F)(F)C(O)=O.[OH-].[K+].[CH:10]1([CH:15]([NH:17][C:18]2[CH:38]=[CH:37][C:21]([C:22]([CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])=[O:23])=[CH:20][CH:19]=2)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([CH:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23])=[CH:37][CH:38]=2)[CH3:16])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)C(=O)c1ccc(NC(C)C2CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(=O)c1ccc(NC(C)C2CCCC2)cc1
Reaction time: 3 h

Procedure:
A solution of 3.0 g. tert-butyl ethyl 4-(1-cyclopentylethylamino)benzoylmalonate 10 ml. of trifluoroacetic acid is warmed with stirring for 3 hours. The solution is poured onto ice and neutralized with potassium hydroxide. The resulting precipitate is collected by filtration, washed with water and dried. Recrystallization from chloroform affords ethyl 4-(1-cyclopentylethylamino)-benzoylacetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:13][C@@H:8]2[NH:9][C:10](=[O:12])[O:11][C@@H:7]2[C@H:6]1Br)=[O:4]>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH2:13][C@@H:8]2[NH:9][C:10](=[O:12])[O:11][C@H:7]2[CH:6]=1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H]2NC(=O)O[C@@H]2[C@H]1Br
Solvent: ClCCl
Product: COC(=O)C1=C[C@@H]2OC(=O)N[C@H]2C1
Yield: 97.5 %

Procedure:
DUB (75 ml, 0.5 mol) was added dropwise to a cooled solution (5° C.) of (3aS,5R,6S,6aS)-6-bromo-2-oxohexahydrocyclopentaoxazole-5-carboxylic acid methyl ester (110 g, 0.42 mol) in dichloromethane (400 ml). A mild exotherm was observed. After a further 15 mins reaction was complete. The reaction mixture was washed with 1 M HCl (aq) (2×150 ml), the aqueous washings back-extracted with dichlormethane (3×100 ml) and the combined organic extracts dried over magnesium sulfate. Following filtration, concentration of the organic solution gave the title compound as an off-white solid (75 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([O:27]C)[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)=[C:15]3[N:10]([N:11]=[C:12]([OH:27])[CH:13]=[CH:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(-c3ccc(S(C)(=O)=O)cc3)c(-c3ccc(F)cc3)nn2n1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3nc(O)ccc23)cc1
Temperature: 200 °C
Yield: 38.4 %

Procedure:
A mixture of 2-(4-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (321 mg) and pyridine hydrochloride (1.4 g) was heated to and at 200° C. in a sealed vessel (Reactivial™) for 3 hours. The cooled reaction was poured into water (20 ml), and extracted with ethyl acetate (3×30 ml). The combined organic extracts dried (MgSO4), filtered and evaporated in vacuo to give a solid which was triturated with diethyl ether to give the title compound as a beige solid (119 mg).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.[C:10]12[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[NH:15]C(=O)O[C:11]2=[O:12]>C(O)C>[NH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:10]=1[C:11]([NH:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[O:12]
Reactant: NCCCn1cncn1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCn1cncn1
Temperature: 70 °C

Procedure:
A mixture of about 2.5 g of 1H-1,2,4-triazole-1-propanamine, about 3.26 g of isatoic anhydride and about 20 ml of ethanol was heated in an oil bath at about 70° C. for about 30 minutes and then concentrated. The residue was recrystallized from ethyl acetate and the desired product, mp 96°-98° C., was obtained.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO>[F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:10])([F:9])[F:11])[C:3]=1[CH2:12][OH:13]
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cn1nc(C(F)(F)F)c(CO)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A solution of 36.8 g (187.6 mmoles) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 200 ml of methanol was added, with ice-cooling, into a solution of 3.9 g (102.6 mmoles) of sodium borohydride dissolved in 500 ml of methanol. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 35.4 g (yield: 95.4%) of (5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=[CH2:3].[C:36](Cl)(=[O:38])[CH3:37].C(N(C(C)C)CC)(C)C>ClCCCl>[C:36]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C@@H:24]([N:6]2[C@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C@@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=3)[CH2:9][C@@:4]([CH2:1][CH:2]=[CH2:3])([CH3:35])[C:5]2=[O:34])[CH2:32][CH3:33])[CH2:31][CH2:30]1)(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCNCC2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN2CCN(C(C)=O)CC2)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one (Example 95, Step B) (80 mg, 0.155 mmol) in DCE (1.5 mL) was added acetyl chloride (22.1 μL, 0.31 mmol) followed by diisopropylethylamine (54.1 μL, 0.311 mmol). The reaction mixture was stirred at room temperature for 16 hours and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][C:26]([OH:28])=O)=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:29][NH:30][CH3:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:29][N:30]([CH3:31])[C:26](=[O:28])[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:24][N:23]=1
Reactant: CNC
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)O)nc2)c1
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(CC(=O)N(C)C)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of 2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetic acid (8.4 mg, 0.020 mmol), dimethylamine (0.05 ml, 0.100 mmol, 2M), EDC (8.6 mg, 0.045 mmol), HOBT (7.8 mg, 0.051 mmol), DIEA (10 μl, 0.057 mmol) in 1,4-dioxane (0.8 ml) was stirred at room temperature for 16 hours. The mixture was purified by reversed phase HPLC to afford N,N-dimethyl-2-(5-(3-methyl-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)pyridin-2-yl)acetamide (8.4 mg, 0.016 mmol). MS ESI calc'd. for C21H21F3N5O [M+H]+ 416. found 416. 1H NMR (600 MHz, CD3OD): δ 8.97 (s, 1H), 8.71 (d, J=4.8 Hz, 1H), 8.62 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 7.89 (d, J=6.0 Hz, 1H), 7.60 (s, 1H), 7.26 (s, 1H), 7.13 (d, J=4.8 Hz, 1H), 4.25 (s, 2H), 3.18 (s, 3H), 3.00 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21]CC(O)=O.[C:26]([OH:35])(=[O:34])[C:27]1[C:28](=[CH:30][CH:31]=[CH:32][CH:33]=1)S>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:15])=[CH:4][C:3]=1[S:21][C:33]1[CH:32]=[CH:31][CH:30]=[CH:28][C:27]=1[C:26]([OH:35])=[O:34]
Reactant: O=C(O)CSc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: O=C(O)c1ccccc1S
Product: O=C(O)c1ccccc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O

Procedure:
5.2.54 2-(1-hydroxy-4-(thiophene-2-sulfonamido)naphthalen-2-ylthio)benzoic acid (14l) was prepared according to the procedure of procedure B for 10a except using thiosalicylic acid, which afforded the title compound 19 mg (99%) as a white solid, m.p.: 215° C. (dec.).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[C:29]([OH:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:29]2[C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=[CH:27][CH:28]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cccc(O)c1F
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1F
Yield: 70.5 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (321 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-3-hydroxyphenyl)propanoate (430 mg) and cesium carbonate (980 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (350 mg) as a white solid.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Cl:46])[CH:22]=2)(OC(C)(C)C)=O.O[CH2:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH:54]([NH:57]C(=O)OC(C)(C)C)[CH2:53][CH2:52]1>>[Cl:46][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:29]1[C:28]([O:30][CH2:48][CH2:49][CH2:50][N:51]3[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53][CH2:52]3)=[C:27]3[NH:31][C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]2=1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Reactant: CC(C)(C)OC(=O)NC1CCN(CCCO)CC1
Agent: c1ccc2[nH]ccc2c1
Product: NC1CCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)CC1

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dichloro-6-hydroxyindolo[2,3-b]carbazole and the reagent is tert-butyl 1-(3-hydroxypropyl)piperidin-4-ylcarbamate. 1H-NMR (400 MHz, CDCl3) δ ppm 9.70 (s, 2H), 8.33 (s, 1H), 8.07 (d, J=2.0 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.33 (dd, J=8.6, 2.2 Hz, 2H), 4.33 (t, J=5.4 Hz, 2H), 3.24-3.13 (m, 2H), 3.03-2.89 (m, 1H), 2.84 (t, J=6.0 Hz, 2H), 2.30-2.16 (m, 2H), 2.15-2.06 (m, 2H), 2.04-1.93 (m, 2H), 1.78-1.65 (m, 2H); MS (ESI) m/z 479.1 (M−H)−; MS (ESI) m/z 481.0 (M+H)+
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]2[C:18]([CH:19]=[N:20][C:21]([S:24]([CH3:26])=[O:25])=[N:22]2)=[CH:17][CH:16]=1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:26][S:24]([C:21]1[N:20]=[CH:19][C:18]2=[CH:17][CH:16]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]([OH:27])=[O:5])[N:23]2[N:22]=1)=[O:25]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)OC(C)(C)C)n2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1ncc2ccc(-c3ccccc3OCC(=O)O)n2n1
Reaction time: 18 h
Yield: 77.3 %

Procedure:
[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid tert-butyl ester (0.298 g, 0.769 mmol), Methylene chloride (11 mL, 170 mmol), and Trifluoroacetic Acid (2.20 mL, 28.5 mmol) were combined and stirred for 18 hours. The product was extracted into dichloromethane and purified by normal phase silica gel chromatography eluting with methanol/dichloromethane to yield a brown solid, [2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenoxy]-acetic acid (197 mg, 77%). LCMS: m/z=332.06 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 9.30 (s, 1H), 7.86 (d, 1H, J=7.6 Hz), 7.54 (d, 1H, J=4.7 Hz), 7.46 (m, 1H), 7.31 (d, 1H, J=4.7 Hz), 7.14 (m, 2H), 4.77 (s, 2H), 2.92 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][CH2:8][C:7]([C:15]([OH:17])=[O:16])=[CH:6]2.[S]>>[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH:6]=[C:7]([C:15]([OH:17])=[O:16])[CH:8]=[CH:9]2
Reactant: COc1cc2c(cc1OC)CCC(C(=O)O)=C2
Agent: [S]
Product: COc1cc2ccc(C(=O)O)cc2cc1OC
Temperature: 215 °C
Yield: 94.9 %

Procedure:
A mixture of 6,7-dimethoxy-1,2-dihydro-3-naphthoic acid (1.7 g) and powdery sulfur (0.47 g) is heated at 215° C. for 30 minutes to afford 6,7-dimethoxy-2-naphthoic acid (1.6 g), which is recrystallized from ethanol to give colorless prisms, m.p. 245°-247° C.