Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[OH:36][C:37]1[CH:45]=[CH:44][C:40]([C@H:41]([NH2:43])[CH3:42])=[CH:39][CH:38]=1>C(Cl)Cl.CCOC(C)=O>[C:14]([NH:13][C@@H:12]([C:11]([NH:43][C@@H:41]([C:40]1[CH:44]=[CH:45][C:37]([OH:36])=[CH:38][CH:39]=1)[CH3:42])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: C[C@@H](N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (33 g; 66.8 mmol; from step (a) above) and (R)-4-hydroxy-α-methylbenzylamine (9.3 g; 68.2 mmol) were combined in CH2Cl2 (600 mL). The resulting yellow solution was stirred at room temperature for 4 hours. When the coupling was complete, as determined by TLC, the solution was concentrated under vacuum to give the crude product. The crude material was dissolved in EtOAc, washed with 0.5N NaOH (2×300 mL), saturated KHSO4 (2×300 mL), brine (2×300 mL), dried over Na2SO4, filtered and concentrated to yield 30.1 g (61.9 mmol; 93%) of the sub-title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=2)[CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][CH:16]=2)[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: CCCCOc1ccc(N(Cc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
1-(tert-Butoxycarbonyl)-4-[(4-butoxyphenyl)amino]piperidine (696 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([S:11][C:12]([F:15])([F:14])[F:13])=[C:9]([CH3:16])[N:8]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2].FC(F)(F)C(O)=[O:32].OO>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([S:11]([C:12]([F:15])([F:13])[F:14])=[O:32])=[C:9]([CH3:16])[N:8]([C:17]2[C:22]([F:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[Cl:28])[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1SC(F)(F)F
Agent: OO
Solvent: ClCCl
Product: CCOC(=O)c1nn(-c2c(F)cc(C(F)(F)F)cc2Cl)c(C)c1S(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 6 h
Yield: 99 %

Procedure:
To a solution of 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethylsulfanyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g, 2.7 mmol) in dichloromethane (6 mL) was added trifluoroacetic acid (2.4 mL) at 0° C. To the reaction mixture was added an aqueous solution of hydrogen peroxide (30 wt %, 0.9 g, 8.3 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 6 h. The reaction was quenched by addition of a solution of sodium bisulfite (0.8 g) in water (12 mL). The resulting mixture was extracted with dichloromethane. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography, elution with heptanes/EtOAc, to give 1-(2-Chloro-6-fluoro-4-trifluoromethyl-phenyl)-5-methyl-4-trifluoromethanesulfinyl-1H-pyrazole-3-carboxylic acid ethyl ester as a white solid (1.2 g, 2.6 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.1 Hz, 3H), 2.51 (s, 3H), 4.36-4.55 (m, 2H), 7.54 (dd, J=8.3, 1.6 Hz, 1H), 7.72 (s, 1H). 19F NMR (376 MHz, CDCl3) δ ppm −113.2 (d, J=7.9 Hz, 0.5F), −112.8 (d, J=9.2 Hz, 0.5F), −74.0 (s, 1.5F), −73.8 (s, 1.5F), −63.8 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C([O:22][C:23]([C:25]1[CH:48]=[CH:47][C:28]2[N:29]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]3)[C:30]([C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([CH:39]=O)[CH:33]=3)=[N:31][C:27]=2[CH:26]=1)=[O:24])C.[OH-].[K+].Cl>C(O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[C:11]([C:12]3[CH:13]=[CH:39][C:34]4[C:35](=[CH:36][CH:37]=[C:32]([C:30]5[N:29]([CH:41]6[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]6)[C:28]6[CH:47]=[CH:48][C:25]([C:23]([OH:24])=[O:22])=[CH:26][C:27]=6[N:31]=5)[CH:33]=4)[N:38]=3)=[CH:10][C:9]([N+:15]([O-:17])=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(N)c(C=O)c1)n2C1CCCCC1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc([N+](=O)[O-])ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
1-(4′-Chloro-4-nitro-biphen-2-yl)-ethanone (69 mg, 0.25 mmol) and 2-(4-amino-3-formyl-phenyl)-1-cyclohexyl-1H-benzoimidazole-5-carboxylic acid ethyl ester (98 mg, 0.25 mmol) were dissolved in 500 μL ethanol and 500 μL 10% ethanolic KOH were added. The reaction was stirred at 75° C. overnight. The reaction was acidified with 4N hydrochloric acid, extracted three times with ethyl acetate, the organic extracts were dried with sodium sulfate and then evaporated. Purification via reverse-phase HPLC gave 34 mg product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([OH:15])[CH:9]=2)=[O:4].[CH:22]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:28]1[CH:29]=[CH:30][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:26][CH:27]=1)[CH:9]=2)=[O:4]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc2ccc(O)cc2c(CC2CCCC2)n1
Product: COC(=O)c1cc2ccc(Oc3ccc(C(C)C)cc3)cc2c(CC2CCCC2)n1

Procedure:
1-cyclopentylmethyl-7-hydroxy-isoquinoline-3-carboxylic acid methyl ester (prepared in example E-1) was treated with 4-isopropylphenylboronic acid by the general procedure G to yield 7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford 7-(4-isopropyl-phenoxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid. This acid was coupled with Compound E-6 by the general procedure A to yield 2(S)-{[1-cyclopentylmethyl-7-(4-isopropyl-phenoxy)-isoquinoline-3-carbonyl-amino}-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester was hydrolyzed by the general procedure C to afford the title compound.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[OH:17]>O>[F:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([N+:1]([O-:4])=[O:2])[C:11]=1[OH:17]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)c(F)c1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.4 %

Procedure:
70% Nitric acid (d=1.42) (5.5 ml, 87.4 mmol) was dropwise added to an acetic acid (105 ml) solution of 2-fluoro-4-methyl-phenol (10.5 g, 83.2 mmol), taking 20 minutes, followed by stirring at room temperature for 30 minutes. Water was added to the reaction liquid, followed by extraction three times with diethyl ether, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (10:1) was concentrated under reduced pressure to obtain the entitled compound (5.47 g, 31%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1)=[O:5])[CH3:2].C1C(=O)N([Cl:23])C(=O)C1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:10][N:9]=[C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[C:7]=1[Cl:23])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]nc(-c2cccs2)c1Cl

Procedure:
Following protocol L, 3-Thiophen-2-yl-1H-pyrazole-5-carboxylic acid ethyl ester was treated with NCS in DMF to yield the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:13]1(C)C=CC=C[CH:14]=1>CS(C)=O>[CH:13]([C:2]1[C:11]([OH:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:14]
Reactant: Cc1ccccc1
Reactant: Oc1cc2ccccc2nc1Cl
Solvent: CS(C)=O
Product: C=Cc1nc2ccccc2cc1O

Procedure:
2-Vinylquinolin-3-ol was prepared from 2-chloroquinolin-3-ol according to the procedure described for Example 6, Step 5 using 10:1 PhMe:DMSO as solvent. LCMS (M+H)+=172.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5](O)=[S:6].Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[S:6]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C)cc1C(O)=S
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=S)c4cc(C)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylthiobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1>O.CO>[CH3:3][N:4]1[CH2:9][CH2:8][C@H:7]([OH:10])[C@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1
Reactant: CN1CCC(=O)C(c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CC[C@H](O)[C@H](c2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Sodium borohydride (9.46 g) is added portionwise to a solution of the compound of formula IV, (-methyl-3-phenyl-4-piperidone (94.6 g, described by A. A. Patchett and F. F. Gianuso, supra), in water-methanol 1:9 (250 ml). The mixture is stirred for 30 minutes and the methanol is evaporated. The aqueous residue is diluted with water, 6N hydrochloric acid and washed with ether. The aqueous phase is made alkaline and extracted with chloroform. The chloroform extract is evaporated and crystallized from ether to give cis-1-methyl-3-phenyl-4-piperidinol, mp 131-133° C. Anhydrous hydrogen chloride is added to the mother liquors and the precipitate is crystallized from methanol-ether to give trans-1-methyl-3-phenyl-4-piperidnol hydrochloride, mp 131-133° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][CH:16]=2)=[O:14])=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:29]O>CO.C(OCC)(=O)C>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][N:29]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:12]=2)=[CH:16][CH:17]=1)[CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NO
Reactant: CCCCCOc1ccc(C(=O)CC(=O)c2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCOc1ccc(-c2cc(-c3ccc(C(=O)OC)cc3)no2)cc1
Yield: 74.6 %

Procedure:
The solution of 1-(4-Methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (1.00 g) and hydroxylamine hydrochloride (567 mg) in methanol (10 ml) was refluxed for 10 hours. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml×2), brine (50 ml). The organic layer was dried over magnesium sulfate and the solvents were removed under reduced pressure. The residue was triturated with acetonitrile (10 ml), collected by filtration, and dried under reduced pressure to give Methyl 4-[5-(4-pentyloxyphenyl)isoxazol-3-yl]benzoate (0.74 g).
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[N:11]([CH3:12])[C:10](=[O:13])[NH:9][C:8](=[O:14])[CH:7]=1.[N:15]([O-])=O.[Na+]>O>[NH2:15][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[N:11]([CH3:12])[C:6]=1[NH2:5]
Reactant: O=N[O-]
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(N)c(N)c(=O)[nH]c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Glacial acetic acid (4.5 ml, 75 mmol) was added to a suspension of 6-amino-1-methyluracil (5.66 g, 50 mmol) in hot water (100 ml). Sodium nitrite (4.14 g) was added in portions and the reaction mixture was stirred for 1 hour. The precipitate was collected by filtration, washed with water (75 ml) and then suspended in water (100 ml). The mixture was warmed to 50° C. and sodium dithionite (10 g) was added in portions keeping the temperature of the reaction between 50-55° C. The mixture was stirred at 50° C. for 1 hr and then cooled to room temperature and filtered. The solid was washed with water (2×25 ml), acetone (2×25 ml) and dried under vacuum to provide 5,6-diamino-1-methyluracil (5.6 g).
Reaction SMILES: C([N:11]1[CH2:18][C:17]([OH:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O>[C].[Pd]>[OH:25][C:17]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1CC(O)(c2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: O=C(O)[C@@H]1CC(O)(c2ccccc2)CN1

Procedure:
A solution of the N-carbobenzyloxy-4-hydroxy-4-phenyl-L-proline from part (a) is treated with a 5% palladium carbon catalyst and hydrogenated according to the procedure of Example 1(b) to yield 4-hydroxy-4-phenyl-L-proline.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:54])[C:41]([F:53])([F:52])[C:42]([F:51])([F:50])[C:43]([F:49])([F:48])[C:44]([F:47])([F:46])[F:45]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:54])([F:39])[C:41]([F:52])([F:53])[C:42]([F:50])([F:51])[C:43]([F:48])([F:49])[C:44]([F:47])([F:46])[F:45])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F

Procedure:
2.0 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 30 mL of dichloromethane, 2.18 g of pyridine was added, and the above prepared crude (perfluoropentyl)phenyliodonium trifluoromethanesulfonate was added at room temperature until 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole disappeared (disappearance was confirmed by thin layer chromatography). Then, the solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:3) to obtain 0.64 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:10])[F:9])[N:3]=1.[CH2:11]([N:15]1[N:19]=[C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]2=[N:16]1)[CH2:12][C:13]#[CH:14]>>[F:9][CH:8]([F:10])[C:4]1[N:3]=[C:2]([C:14]#[C:13][CH2:12][CH2:11][N:15]2[N:16]=[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]3=[N:19]2)[CH:7]=[CH:6][CH:5]=1
Reactant: C#CCCn1nc2ccccc2n1
Reactant: FC(F)c1cccc(Br)n1
Product: FC(F)c1cccc(C#CCCn2nc3ccccc3n2)n1
Yield: 8.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(difluoromethyl)-pyridine (121 mg, 0.58 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (100 mg, 0.58 mmol, Example 109(D)). Reaction time: 2 hours. The crude residue was purified by preparative chromatography plate (DCM/MeOH 99:1) to yield 15 mg (49 μmol, 8%) of 2-(4-(6-(difluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a white solid (M.P.: 101.8-102.9° C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>CN(C=O)C>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[F:18])=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3F)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.05 g, 0.18 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (0.028 g, 0.18 mmol) using DMF (3 mL) as solvent using the method of Example 34(d). Yield 0.056 g. 1H NMR (400 MHz; CDCl3): δ 1.16 (d, 3H), 2.46 (s, 3H), 4.29 (m, 2H), 4.49 (m, 1H), 6.70 (dd, 1H), 7.17 (bs, 1H), 7.50 (m, 2H), 8.06 (m, 1H).
Reaction SMILES: [CH2:1]([O:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].BrC1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>>[CH:11]1([CH2:10][O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=CCCCCCCOCC1CCCCC1
Product: O=[N+]([O-])c1ccc(CCCCCCCOCC2CCCCC2)cc1
Yield: 64.9 %

Procedure:
General procedure M was used to convert 5.73 mmol of 11 and 6.30 mmol of 1-bromo-4-nitrobenzene to 3.72 mmol (65%) of the title compound.
Reaction SMILES: I[C:2]1[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[N:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].[C:16]([O:20][CH2:21][CH3:22])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>CN(C=O)C.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>[NH2:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2](/[CH:18]=[CH:17]/[C:16]([O:20][CH2:21][CH3:22])=[O:19])=[C:3]([NH:10][C@@H:11]2[CH2:15][CH2:14][O:13][CH2:12]2)[N:4]=1
Reactant: C=CC(=O)OCC
Reactant: Cc1nc(N)nc(N[C@@H]2CCOC2)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@@H]1CCOC1
Temperature: 95 °C
Yield: 94 %

Procedure:
To a solution of (R)-5-iodo-6-methyl-N4-(tetrahydrofuran-3-yl)pyrimidine-2,4-diamine (4.53 g, 14.2 mmol), ethyl acrylate (4.25 g, 42.5 mmol) and triethylamine (4.30 g, 42.5 mmol) in DMF (150 mL) was added Pd(PPh3)4 (1.635 g, 10 mol %) under nitrogen at room temperature. The resulting mixture was heated to 95° C. for 18 h under a nitrogen atmosphere. After the reaction was complete by LC/MS, the resulting mixture was concentrated under reduced pressure and directly subjected to column chromatography purification to give (R,E)-ethyl 3-(2-amino-4-methyl-6-(tetrahydrofuran-3-ylamino)pyrimidin-5-yl)acrylate (3.90 g, 94% yield). MS (EI) for C14H20N4O: 293.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12][C@@H:13]([C:17]([OH:19])=[O:18])[C@H:14]([CH3:16])[OH:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:12][C@H:13]([C@@H:14]([OH:15])[CH3:16])[C:17]([OH:19])=[O:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Temperature: 75 °C
Reaction time: 24 h

Procedure:
2-chloro-4-fluoro-3-methylbenzonitrile (CAS 796600-15-2, 45 g, 265.4 mmol) was mixed together with H-D-Thr-OH (37.92 g, 318.4 mmol) in DMSO (250 mL). K2CO3 (73.35 g, 530.7 mmol) was added to the reaction mixture and the reaction mixture stirred at 75° C. for 24 h. The reaction mixture was cooled to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed on silica gel with a gradient of hexanes/EtOAc and then with EtOAc, 100% to get the purified final product (39.0 g, 54%) 1H NMR (500 MHz, Acetone-d6, δ in ppm) 7.49 (d, 9 Hz, 1H), 6.70 (d, J=9 Hz, 1H), 5.38 (d, J=10 Hz, 1H), 4.47 (d, J=6 Hz, 1H), 4.25 (m, 1H), 2.34 (s, 3H), 1.33 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:16]3[CH2:18][CH2:17]3)[CH:11]=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1>O1CCOCC1>[C:1]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH:16]3[CH2:17][CH2:18]3)[CH2:11][NH:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(c1)S(=O)(=O)N=CN2C1CC1
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2c(c1)S(=O)(=O)NCN2C1CC1
Reaction time: 16 h

Procedure:
Acetyl chloride (0.5 mL) is added to a solution of 7-amino-4-cyclopropyl-4H-1,2,4-benzothiadiazine 1,1-dioxide (0.5 g), prepared in the Step above, in dioxane (20 mL) and stirring is carried out at ambient temperature for 16 hours. After removing the solvent by distillation under reduced pressure, the residue is taken up in water, and the precipitate, of 7-acetamido-4-cyclopropyl-4H-1,2,4-benzothiadiazine 1,1-dioxide, is collected by filtration, washed with water and dried. It is used directly in a subsequent step, according to the procedure described in Step D of Example 1, in order to obtain the expected product.