Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[C:26]([CH3:31])=[N:27][N:28]([CH3:30])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: Cc1nn(C)cc1Br
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cn(C)nc3C)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1,3-dimethyl-1H-pyrazole.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.CN(C)C=O.[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>N1C=CC=CC=1>[C:15]([NH:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1)(=[O:18])[CH2:16][CH3:17]
Reactant: Nc1nc(CCl)cs1
Reactant: CCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCC(=O)Nc1nc(CCl)cs1
Temperature: 0 °C
Yield: 50.9 %

Procedure:
To a mixture of 2-amino-4-chloromethylthiazole hydrochloride (50 g), anhydrous N,N-dimethylformamide (250 ml) and anhydrous pyridine (50 ml) was added dropwise propionyl chloride (30 g) keeping the temperature below 3° C. with stirring and the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into ice water (1500 ml) and stirred. The crystal was collected by filtration and washed with water to give 2-propionylamino-4-chloromethylthiazole (28.15 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH2:22][CH3:23])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])[CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:14]([C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=[CH:6]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:22][CH3:23])[CH3:15]
Reactant: CCC(CC)(NCCCn1cnc(CCN)c1)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Product: CCC(CC)(NCCCn1cnc(CCNC(=O)c2ccccc2)c1)c1ccccc1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1-ethyl-1-phenylpropyl)propylamine (1.0 g) was reacted with benzoyl chloride (0.38 ml) in a similar manner to Example 55 to give N-(2-{1-[3-(1-ethyl-1-phenylpropylamino)propyl]imidazol-4-yl}ethyl)benzamide, as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[Br:10]N1C(=O)CCC1=O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:7]=[C:6]([Br:10])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Product: Fc1cc(F)c(Br)cc1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 96.9 %

Procedure:
Under ice cooling, a solution of 25.35 g of 1-bromo-2,4-difluorobenzene in 100 mL of concentrated sulfuric acid was added with 25.7 g of N-bromosuccinimide, and stirred for 30 minutes at this temperature and for 2 days at room temperature. After cooling on ice, the reaction solution was added with ice, and extracted with 300 mL of diethyl ether. The organic layer was successively washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting crude product was purified and separated by silica gel column chromatography (n-hexane), to afford 34.6 g of the title compound as a colorless oil.
Reaction SMILES: [ClH:1].C(OCC)C.C([NH:14][CH2:15][C:16](=[O:36])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:20])(OC(C)(C)C)=O>C(OCC)(=O)C>[ClH:1].[NH2:14][CH2:15][C:16](=[O:36])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCC(=O)CCC(=O)OCCCCCCCCCCCC(=O)O
Reaction time: 120 h

Procedure:
A 1.0 M solution of HCl in diethyl ether (5.0 mL; 5.0 mmol) was added to a stirred solution of the product of 14c (0.95 g; 2.2 mmol) in ethyl acetate (10 mL) at ambient temperature under argon. After 5 days, the mixture was filtered and the residue was triturated with diethyl ether (2×5 mL). The residue was dried overnight at 40° C. and 15 mm Hg to give 0.11 g white solid. The combined ether extracts were evaporated. LC-MS analysis indicated that the product contained ca. 25% 5-amino-4-oxopentanoic acid; the combined crops were purified by flash chromatography on a 150×25 mm silica gel 60 column eluted sequentially with 3% methanol in acetonitrile (1000 mL), 6% methanol in acetonitrile (1000 mL), then 9% methanol in acetonitrile (2000 mL), collecting 56×50 mL fractions. Fractions containing the product were evaporated and the residue was dissolved in water (10 mL). The solution was freeze-dried overnight, and 0.06 g (7.5%) product obtained (white solid, mp 110-115° C. (softens, no sharp mp)).
Reaction SMILES: [NH2:1][C:2]1[C:17](I)=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].C[Si]([C:23]#[CH:24])(C)C>C(N(CC)CC)C.C(OC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[NH2:1][C:2]1[C:17]([C:23]#[CH:24])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: Nc1c(I)cccc1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: C#Cc1cccc(C(=O)OCc2ccccc2)c1N
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
A solution of benzyl 2-amino-3-iodobenzoate (5.56 g), trimethylsilylacetylene (3.26 mL), bis(triphenylphosphine)palladium(II) dichloride (0.350 g) and copper iodide (0.299 g) in triethylamine (75 mL) was stirred under a nitrogen atmosphere at room temperature for 1.5 hr. The reaction mixture was diluted with diisopropyl ether, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (75 mL), 1.0 M tetrabutylammonium fluoride (25 mL) was added under ice-cooling, and the mixture was stirred at 0° C. for 1.5 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-15:85) to give the title compound (3.06 g, yield 77%) as colorless crystals. melting point 42-43° C.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](O)=[O:17]>S(=O)(=O)(O)O>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17]
Reactant: O=C(O)c1cnccn1
Reactant: CCCCCCCCO
Agent: O=S(=O)(O)O
Product: CCCCCCCCOC(=O)c1cnccn1
Reaction time: 8 h
Yield: 88.2 %

Procedure:
A four-necked flask was charged with 426 g (3.271 mole) of 1-octanol, 100 g (0.806 mole) of pyrazinecarboxylic acid and 5.0 g (0.05 mole) of concentrated sulfuric acid and the internal temperature was maintained under stirring at 97°-100° C. for 8 hours. The reaction mixture was then cooled and transferred to a separatory funnel, in which it was washed with two portions, or a total of 330 g, of 8% aqueous solution of sodium carbonate. The oil layer which separated was washed with water and subjected to distillation under reduced pressure to give 168 g of octyl pyrazinecarboxylate. Yield: 88% (based on pyrazinecarboxylic acid).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](O)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)C(=O)O
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and isobutyric acid as a white solid (58%). MS 388 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoate (1.20 g, 2.7459 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (13.7 ml) and 1,4-dioxane (30 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (200 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (1.02 g, 2.4113 mmol, 88%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[O:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:15][CH2:14]1>CC1C=CC=CC=1>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:19][CH:16]1[CH2:17][CH2:18][N:13]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1
Reactant: O=C(c1ccc(F)cc1)N1CC1
Reactant: c1ccc2oc(NC3CCNCC3)nc2c1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCC(Nc2nc3ccccc3o2)CC1)c1ccc(F)cc1
Yield: 34 %

Procedure:
A mixture of 1.65 parts of 1-(4-fluorobenzoyl)aziridine (solution in benzene 1.2M), 2.1 parts of N-(4-piperidinyl)-2-benzoxazolamine and 90 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was crystallized from 2-propanol. The product was filtered off and recrystallized from 2-propanone, yielding 1.3 parts (34%) of N-[2-[4-[(2-benzoxazolyl)-amino]-1-piperidinyl]ethyl]-4-fluorobenzamide; mp. 173.3° C. (448).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH3:15])=[O:13].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>N1C=CC=CC=1>[CH3:16][S:17]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:19])=[O:18]
Reactant: COC(=O)Cn1ccc2c(N)cccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)Cn1ccc2c(NS(C)(=O)=O)cccc21
Yield: 71 %

Procedure:
To a solution of crude methyl 2-(4-amino-1H-indol-1-yl)acetate (obtained as reported in Example 15, Step 2, theoretical amount 3.08 mmol) in pyridine (10 ml), methanesulfonyl chloride (464 μl, 5.95 mmol) was added, and the mixture was reacted overnight at room temperature. The solvent was evaporated, and the residue was partitioned between 1N HCl (10 ml) and ethyl acetate (20 ml); the aqueous phase was extracted with ethyl acetate (3×20 ml) and the combined organic layers were dried over sodium sulfate. After evaporation of the solvent, crude methyl 2-(4-(methylsulfonamido)-1H-indol-1-yl)acetate was obtained and used in the next step without any additional purification (620 mg, 2.196 mmol, 71% yield over 3 steps). MS/ESI+ 283.1 [MH]+.
Reaction SMILES: [NH2-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][N:5]=1.N(C1C=C(C)C(F)=CN=1)[N+]([O-])=[O:14]>>[NH2:3][C:4]1[C:9]([OH:14])=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][N:5]=1
Reactant: Cc1cc(N)ncc1F
Reactant: Cc1cc(N[N+](=O)[O-])ncc1F
Agent: [NH2-]
Agent: [Na+]
Product: Cc1c(F)cnc(N)c1O

Procedure:
When 3-amino-4-picoline is subjected to diazotization in fluoboric acid as in Example I-1, there is obtained 3-fluoro-4-picoline. Treatment of the latter intermediate with sodium amide as in Example I-1, gives 2-amino-5-fluoro-4-picoline. Following the procedure of Example I-15, but substituting 2-nitramino-5-fluoro-4-picoline, there is obtained 2-amino-5-fluoro-4-methyl-3-pyridinol.
Reaction SMILES: [F:1][C:2]1([F:46])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([OH:33])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH2:4][CH2:3]1.C1(C)C=CC(S(O[CH2:57][C@H:58]2[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:46][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:57][C@H:58]5[CH2:62][O:61][C:60]([CH3:64])([CH3:63])[O:59]5)=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]=2[C@@H:34]([F:45])[C:35]2[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of 115 mg (0.177 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 23, in 0.5 ml of N,N-dimethylformamide, 111 mg (0.388 mmol) of (R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate and 73.5 mg (0.532 mmol) of potassium carbonate were added, and the mixture was stirred at 90° C. for 4 hours. After completion of the reaction, the reaction solution was poured into water and extracted with toluene twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=80/20-59/41 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 113.3 mg of the title compound as a white solid (yield: 84%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.Br[C:10]1[C:11]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[Cl:28])(=[O:20])=[O:19])=[N:12][CH:13]=[C:14]([CH3:16])[N:15]=1>>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:11]1[C:10]([O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:15][C:14]([CH3:16])=[CH:13][N:12]=1)(=[O:19])=[O:20]
Reactant: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(Br)n1
Reactant: OCc1cccnc1
Product: Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1

Procedure:
Prepared by the method of Example 20 using pyridine-3-methanol (0.05 g) and N-(3-bromo-5-methyl-2-pyrazinyl)-2,3-dichlorobenzenesulphonamide (0.1 g). Yield 0.023 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)(O)[O-].[Na+].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].O>C1COCC1>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCNc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 2-fluoronitrobenzene (2.0 g, 14 mmol) and sodium bicarbonate (5.9 g, 71 mmol) in 30 mL THF under nitrogen was added N1, N1-dimethylethane-1,2-diamine (1.7 mL, 16 mmol). The reaction was allowed to stir at ambient temperature for 3 h, and then a water-cooled reflux condenser was added and the mixture was heated to 70° C. for 16 h. The reaction was cooled to ambient temperature, filtered through paper, and concentrated in vacuo to give N-(2-(dimethylamino)ethyl)-2-nitrobenzenamine as a yellow oil. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][OH:20])=[O:17])=[N:14][CH:15]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1.O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[C:10]1[C:11]([CH3:21])=[CH:12][C:13]([C:16]([NH:18][CH2:19][O:20][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)NCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: OCc1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(C(=O)NCOCc2cccnc2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Yield: 24.7 %

Procedure:
A benzene solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-N-(1-hydroxymethyl)-4-methylpyridine-2-carboxamide (155 mg, 0.344 mmol) obtained in Example 85, 3-pyridinemethanol (40 μl, 0.413 mmol) and p-toluenesulfonic acid dihydrate (98 mg, 0.516 mmol) was heated to reflux for 2 hours while distilling off water. The reaction solution was returned to room temperature, subsequently saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 70% ethyl acetate/hexane was concentrated under reduced pressure. Ether was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (46 mg, 0.085 mmol, 25%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]3[S:36][CH:37]=[CH:38][CH:39]=3)[CH:30]=2)=[N:26][C:25]=1[CH2:40][CH2:41]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:41][CH2:40][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[S:36][CH:37]=[CH:38][CH:39]=4)[CH:30]=3)[O:28][C:24]=2[CH3:23])=[CH:9][CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3cccc(-c4cccs4)c3)oc2C)cc1)Oc1ccccc1
Temperature: 55 °C
Reaction time: 16 h

Procedure:
3-(4-Hydroxyphenyl)-2-methyl-2-phenoxypropionic acid ethyl ester (495 mg, 1.7 mmol) (see Ex. 1, Part C), toluene-4-sulfonic acid 2-[5-methyl-2-(3-thiophen-2-ylphenyl)oxazol-4-yl]ethyl ester (2.2 mmol) and Cs2CO3 (700 mg, 2.2 mmol) are combined in anhydrous DMF (25 mL) and stirred for 16 h at 55° C. under an atmosphere of nitrogen. The mixture was then cooled and diluted with ethyl acetate (100 mL), and washed with water then brine. The organic layer was dried with Na2SO4 and concentrated in vacuo to a viscous yellow oil. The residue was purified by flash column chromatography (100 g silica, 60×15 mL fractions, gradient elution 0–20% ethyl acetate in hexanes) to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.42–7.41 (m, 1H), 7.31 (d, J=5.2 Hz, 1H), 7.23–7.09 (m, 5H), 6.96 (t, J=7.2 Hz, 1H), 6.85–6.81 (m, 4H), 4.25 (t, J=6.8 Hz, 2H), 7.20 (q, J=7.2 Hz, 2H), 3.26 (d, J=14.0 Hz, 1H), 3.10 (d, J=14.0 Hz, 1H), 3.00 (t, J=6.8 Hz, 2.40 (s, 3H), 1.38 (s, 3H), 1.21 (t, J=7.2 Hz, 3H); MS (EI) 568.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30](O)=[O:31])[C:18]([C:33]([F:36])([F:35])[F:34])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:38](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH2:29][C:30]([NH2:38])=[O:31])[C:18]([C:33]([F:35])([F:34])[F:36])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(2-(2-((3-(4-Methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetic acid (I68) (75.0 mg, 169 μmol) was dissolved in DMF (1 mL) then HATU (129 mg, 339 μmol), DIPEA (57 uL, 339 μmol) and ammonium chloride (181 mg, 3.39 mmol) were added. The resulting mixture was stirred at room temperature overnight then the volatiles were evaporated under reduced pressure.
Reaction SMILES: Cl.C([O:9][P:10]([CH2:19][C@H:20]([OH:23])[CH2:21][NH2:22])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11])C1C=CC=CC=1.C([NH:34][C@@H:35]([C:39](O)=[O:40])[CH:36]([CH3:38])[CH3:37])(OCC1C=CC=CC=1)=O>>[NH2:34][C@H:35]([CH:36]([CH3:38])[CH3:37])[C:39]([NH:22][CH2:21][C@@H:20]([OH:23])[CH2:19][P:10]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)(=[O:11])[OH:9])=[O:40]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Agent: Cl
Product: CC(C)[C@@H](N)C(=O)NC[C@@H](O)CP(=O)(O)CC1CCCCC1

Procedure:
Step 4, Method B of Example 1 was substantially repeated in this Example 4 except for employing ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride and N-Cbz-D-valine as the starting materials. Subsequent hydrogenation of the resulting benzyl ester in accordance with the procedures of Step 5, Method A of Example 1 yielded the title compound. 1H NMR (CD3OD, 300 MHz): δ 4.15-4.01 (m, 1H), 3.58 (d, 1H), 3.55-3.43 (m, 1H), 3.32-3.15 (m, 1H), 2.25-2.07 (m, 1H), 2.02-1.85 (m, 2H), 1.83-1.58 (m, 6H), 1.56-1.45 (m, 2H), 1.42-1.18 (m, 3H), 1.10 (d, 6H), 1.08-0.96 (m, 2H). 31P NMR (CD3OD, 300 MHz): δ 40.91. LCMS m/z: [M+H]+=335.1.