Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH3:29]N(C)C=O.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46]>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[C:16]3[CH2:22][CH2:21][N:20]([C:45](=[O:46])[C:44]([CH3:49])([CH3:48])[CH3:43])[CH2:19][C:17]=3[N:18]=2)=[CH:11][C:12]=1[CH3:29])=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C(C)(C)C)C3)cc1C
Reaction time: 72 h

Procedure:
1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.042 g, 0.11 mmol) in dry N,N-Dimethylformamide (1.00 mL, 12.9 mmol) was added N,N-Diisopropylethylamine (0.0574 mL, 0.330 mmol) followed by 2,2-Dimethylpropanoyl chloride (0.0204 mL, 0.166 mmol). The reaction mixture was stirred for 3 days. The reaction mixture was concentrated and purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.19 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.16 (t, J=5.5, 1H), 4.61 (s, 2H), 3.81-3.68 (m, 6H), 3.49 (d, J=4.5, 4H), 3.19-3.06 (m, 2H), 2.69 (d, J=12.7, 2H), 1.27 (s, 9H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+467.3 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)CCc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)CCc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (161) (100 mg, 0.27 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. The residue was purified by column chromatography eluting with 15% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:21])[CH3:20])[CH:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:55][C:56]([F:61])([CH3:60])[C:57](O)=O>CN(C=O)C>[F:16][C:13]1([F:17])[CH2:14][CH2:15][CH:10]([CH2:9][N:8]2[C:7]3[CH:6]=[CH:5][C:4]([NH:18][C:19](=[O:21])[CH3:20])=[CH:3][C:2]=3[N:1]=[C:57]2[C:56]([F:61])([F:55])[CH3:60])[CH2:11][CH2:12]1
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCC(F)(F)CC1
Temperature: 80 °C

Procedure:
N-(3-Amino-4-{[(4,4-difluorocyclohexyl)methyl]amino}phenyl)acetamide (99 mg, 0.333 mmol), DIPEA (0.087 mL, 0.500 mmol), HATU (140 mg, 0.366 mmol) and 2,2-difluoropropionic acid (40 mg, 0.366 mmol) were stirred in 5 mL of DMF at rt for 1 h. The solvent was evaporated. The residue was dissolved in 3 mL of glacial AcOH and heated at 80° C. for 2 h. The solvent was evaporated. The product was dissolved in EtOAc and washed with aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was purified by silica gel flash chromatography using EtOAc as eluent. Yield: 100 mg (81%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.39-1.52 (m, 2 H), 1.57-1.63 (m, 1 H), 1.64-1.71 (m, 3 H), 2.06-2.16 (m, 3 H), 2.22 (s, 3 H), 2.29 (m, 3 H), 4.25 (d, J=7.42 Hz, 2 H), 7.31 (s, 1 H), 7.35 (d, J=8.79 Hz, 1 H), 7.60 (dd, J=8.89, 1.86 Hz, 1 H), 7.86 (d, J=1.76 Hz, 1 H).
Reaction SMILES: C[CH:2](C)[CH:3](C1C=CC=CC=1)[C:4]([NH:6][C@@H:7]1[C@H:14]2[C@H:10]([CH2:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)[CH2:13]2)[CH2:9][CH2:8]1)=O.C(O[C:36]1(O[Si](C)(C)C)[CH2:38][CH2:37]1)C.C(O)(=O)C.C([BH3-])#N>ClCCl>[CH:4]1([N:6]([CH:36]2[CH2:37][CH2:38]2)[C@@H:7]2[C@H:14]3[C@H:10]([CH2:11][N:12]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=4)[CH2:13]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3]1
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21)c1ccccc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CN2C[C@@H]3CC[C@H](N(C4CC4)C4CC4)[C@@H]3C2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS*,4S*,6aR*)-2-(3-(Trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (228 mg, 0.802 mmol) from Example 122 Step E and (1-ethoxycyclopropoxy)trimethylsilane (140 mg, 0.802 mmol) were combined in dichloromethane (1.5 mL) and 5 mL of acetic acid was added. The reaction was stirred at room temperature for 20 minutes, and then PS-cyanoborohydride (343 mg, 0.802 mmol) was added. The reaction was heated to 40° C. overnight. Silica gel chromatography eluting with 1-10% methanol (2 N ammonia)/dichloromethane to gave the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.58 (s, 1H), 7.48 (d, J=7.6, 2H), 7.42 (d, J=7.6, 1H), 3.64 (d, J=13.6, 1H), 3.51 (d, J=13.6, 1H), 2.94-2.82 (m, 3H), 2.80-2.71 (m, 2H), 2.55 (dd, J=5.4, 9.4, 3H), 2.41 (t, J=8.3, 1H), 2.16 (dd, J=4.7, 8.7, 1H), 1.97-1.70 (m, 7H), 1.70-1.59 (m, 3H), 1.40 (dd, J=6.7, 12.6, 1H); MS (ESI+) m/z 365 (M+H)+.
Reaction SMILES: [C:1]([NH:20][CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:27][CH2:28][C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[C:34]([CH3:41])[CH:33]=1)=[O:30].ClCC([O-])=O>C(Cl)(Cl)Cl>[Cl-:27].[CH3:26][N+:24]([CH3:25])([CH2:28][C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]([CH3:40])[CH3:39])=[C:34]([CH3:41])[CH:33]=1)=[O:30])[CH2:23][CH2:22][CH2:21][NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(OC(=O)CCl)ccc1C(C)C
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C
Agent: O=C([O-])CCl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NCCC[N+](C)(C)CC(=O)Oc1ccc(C(C)C)c(C)c1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
A 33.18 g (0.090 mol) portion of N-octadecanoyl-N′,N′-dimethyl-1,3-diaminopropane and 120 ml of chloroform were put into a flask, and 22.44 g (0.099 mol) of 3-methyl-4-isopropylphenyl chloroacetate was added thereto at 25° C. spending 5 minutes. The reaction mixture was stirred at 25° C. for 36 hours and then, after confirming disappearance of the most part of chloroacetate by 1H-NMR, the solvent was evaporated under a reduced pressure. The thus obtained viscous oil was dissolved in 300 ml of acetone and cooled to 5 to 10° C. to effect precipitation of a white precipitate. Thereafter, in the same manner as described in Inventive Example 1, the title compound (to be referred to as betaine ester (12) hereinafter) was obtained as a white solid. Yield 41.80 g (0.070 mol; yield 78.0%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][OH:11])[CH2:5]1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17](F)[C:14]=1[C:15]#[N:16].C(#N)C1C=CC=CC=1>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([O:11][CH2:10][CH:6]2[CH2:7][CH2:8][CH2:9][N:4]([CH3:3])[CH2:5]2)[C:14]=1[C:15]#[N:16]
Reactant: CN1CCCC(CO)C1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCCC(COc2cccc(F)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.2 %

Procedure:
Sodium hydride (60%; 316 mg; 7.9 mmol) was suspended in DMF and cooled to 0° C. 1-Methylpiperidin-3-ylmethanol (998 mg; 7.5 mmol) was added dropwise to the sodium hydride mixture. The solution was allowed to warm to room temperature and stirred for 30 minutes. The solution was then cooled to 0° C. 2,6-Difluorobenzonitrile (1.1 g; 7.9 mmol) in DMF was cooled to 0° C. and the alcohol mixture was added dropwise to the benzonitrile solution and allowed to warm to room temperature overnight. The solution was poured into water and extracted with dichloromethane and solvent removed. Purification by column chromatography (10% ethyl acetate/hexane) to yield 79 milligrams of 2-fluoro-6-(1-methylpiperidin-3-ylmethoxy)benzonitrile.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH2:5]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([F:20])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:21][Sn]Cl>O.Cl>[ClH:21].[CH2:5]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][NH2:1])=[C:15]([F:20])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
A solution of NaNO2 (1.38 g) in H2O (8 mL) was added to a suspension of 4-benzyloxy-2-fluoroaniline (5.0 g) in 6N HCl (24 mL) at 0° C. After 30 minutes stirring, a solution of SnCl2 (7.7 g) in 6N HCl (24 mL) was added to the mixture at 0° C. The mixture was allowed to warm to room temperature and stirred for 1.5 hours to produce a precipitate. The precipitate was collected by filtration to yield 4.15 g of the title compound.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C)C=O>[N:22]([CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)=[N+:23]=[N-:24]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(COS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
A mesyl compound (Example 3, 1 g) and sodium azide were added to dimethylformamide (20 ml), and the mixture was stirred at 100° C. for 50 minutes. After completion of the reaction, pressure was reduced to concentrate the mixture. The concentrate was diluted with a solvent mixture of chloroform and methanol (5:1), washed with water, and dried. When the solvent was evaporated, 759 mg of the title compound was obtained (91.6%). This substance was recrystallized from a solvent mixture of chloroform-n-hexane, obtaining yellow powdery crystals having a melting point of 192°-194° C.(dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[NH2:40][OH:41].C(O)(=O)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:40][OH:41])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cn2)cc1)NC(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)NO)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48.3 %

Procedure:
The acid compound 19 (1.0 g, 2.328 mmol) was dissolved in dry DMF and stirred under an atmosphere of argon. N-Methylmorpholine (1.02 mL, 9.32 mmol) was added. After 20 min, hydroxylamine hydrochloride (0.323 g, 4.66 mmol) was added and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and residual material was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (1×30 mL). The organic layer was dried and concentrated to yield the crude material. Flash chromatography on SiO2 gel using hexanes-ethyl acetate (70-60%) mixture containing 1% acetic acid furnished the desired hydroxamic acid compound 20 (0.5 g, 98%) 1H NMR (400 MHz, DMSO-d6): 8.47 (br, 1H) 8.14 (dd, J=8.8 and 2.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.8 Hz, 1H), 7.05 (m, 3H), 4.56 (m, 1H), 2.93 (s, 3H) 2.85-2.75 (m, 2H), 2.79 (s, 3H), 1.32 (s, 9H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:34][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28]([CH:30]2[CH2:32][CH2:31]2)=[O:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:34])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)C2CC2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
{2′-[(Cyclopropanecarbonyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.408 g, 0.88 mmol) was dissolved in THF (4 mL) and cooled to −78° C. Sodium bis(trimethylsilyl)amide (1M in THF; 1.06 mL, 1.06 mmol) was added, followed by iodomethane (0.06 mL, 0.97 mmol), and the reaction was stirred at −78° C. for 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and warmed to room temperature. The mixture was extracted three times with EtOAc, and the combined organic layers were dried, concentrated, and purified by silica gel chromatography (10-40% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]2)[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:6]3[O:10][CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]4[C:7]=3[CH:8]=[CH:9][C:2]=2[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: N#Cc1c(N)cccc1OC1C=CCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2ccc3c(c2c1N)OC1CCCCC31

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohex-2-en-1-yloxy)benzonitrile (Example 131b) and ethyl 3-oxobutanoate as a pale yellow solid (11%). MS 327 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(#N)C>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[N:13]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-(trifluoromethyl)benzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=98%, [M+H]+=433.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:12]Cl>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11][Cl:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(SCl)cc1
Yield: 94.2 %

Procedure:
To a mixture of 332 grams (2.0 moles) of 4-(tert-butyl)thiophenol and 800 ml of carbon tetrachloride was slowly added with stirring and cooling a solution of 150 grams (2.0+ moles) of chlorine in 600 ml of carbon tetrachloride at 0° C. After chlorine addition was complete the mixture was stirred at 0°-10° C. for two hours, hydrogen chloride and carbon tetrachloride removed in vacuo and the residue was distilled in a one-foot packed column to give 378 grams of 4-(tert-butyl)phenylsulfenyl chloride, b.p. 95°-97°/1.0 mm (yield 94%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH2:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:25])[O:22][C:21](=[O:23])[CH2:20][C:19](=[O:24])[O:18]1.[CH2:26](OC(OCC)OCC)C>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:15][CH:26]=[C:20]2[C:21](=[O:23])[O:22][C:17]([CH3:25])([CH3:16])[O:18][C:19]2=[O:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCO
Product: CC1(C)OC(=O)C(=CNc2cccc(OCc3ccccc3)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 3-(Benzyloxy)benzenamine (970 g, 4.9 mol, Wuhan Xinghuayuan Tech. Co. Ltd.) and 2,2-dimethyl-1,3-dioxane-4,6-dione (842.3 g, 5.8 mol) in anhydrous EtOH (970 mL) was added triethoxymethane (865.7 g, 5.8 mol). The suspension was heated to reflux for 1 hour. The reaction mixture was then cooled to room temperature, and continued to stir for additional 2 hours. The suspension was filtered, and the solid was stirred in anhydrous EtOH (970 mL) for 2 hours, collected by filtration. The solid was dried in vacuo at 45° C. to give the title compound as a pale yellow solid (1.7 kg, 96.5%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=[O:21].[C:22]([O:26][C:27]([NH:29][NH:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23].O>ClCCl>[C:22]([O:26][C:27]([NH:29][N:30]([C:31]1[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=1)[C:18]([CH:11]1[C:10](=[O:21])[C@@:9]2([CH3:8])[C:15]([CH3:17])([CH3:16])[C@@H:12]1[CH2:13][CH2:14]2)=[O:19])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Reactant: CC(C)(C)OC(=O)NNc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NN(C(=O)C1C(=O)[C@]2(C)CC[C@H]1C2(C)C)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Triethylamine (10.75 mL, 77 mmol) was added in two portions to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 5.5 g, 25.6 mmol) in dichloromethane (55 mL), giving a thick precipitate. N′-(3,5-dichloro-phenyl)-hydrazinecarboxylic acid tert-butyl ester (Intermediate 35; 5.5 g, 19.8 mmol) was added, along with dichloromethane (25-30 mL). The reaction mixture was placed in an oil-bath at 50° C., heated at this temperature overnight and then allowed to cool to room temperature and stir for 20 min. The reaction mixture was poured into water (100 mL) and two layers were separated. The organic layer was washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and then dried under high vacuum to give N′-(3,5-dichloro-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (10 g, 111% of the expected amount) as an orange foam, which was used directly in the next step without further purification.
Reaction SMILES: Cl[C@H:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[SH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[S:18][CH:2]([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: C[C@@H](Cl)C(=O)O
Reactant: Cn1c(S)nnc1-c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(Sc1nnc(-c2cccs2)n1C)C(=O)O
Reaction time: 2.5 h
Yield: 12.2 %

Procedure:
(R)-2-chloro-propionic acid (500 mg, 4.6 mmol), 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (1.09 g, 5.58 mmol) and potassium carbonate (1.94 g, 14.03 mmol) were dissolved in acetonitrile (15 ml) at room temperature. Reaction proceeded for 2.5 h and was partitioned between ethyl acetate (350 ml) and water 3 times, washed with 1 M HCl, once with saturated brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. Reaction was not completed at this stage and the crude was stirred in DMF (10 ml) overnight. Extraction was repeated and purification was performed by SPE (solid phase extraction) chromatography on silica gel using 300 ml ethyl acetate, 100 ml 1%, and 100 ml 3% formic acid in ethyl acetate, yielding title compound (150.7 mg, 12%) 1H-NMR (CDCl3), d (ppm): 7.52 (dd, 2H), 7.19 (m, 1H), 4.21 (q, 1H), 3.78 (s, 3H), 1.64 (d, 3H).
Reaction SMILES: ClCCl.CS(C)=O.C(N(C(C)C)CC)(C)C.[OH:17][C@@H:18]([C@@H:29]([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:30][CH2:31][CH2:32][CH3:33])[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[OH:28])=[O:20]>CS(C)=O>[O:20]=[C:19]([NH:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])[C:18](=[O:17])[C@@H:29]([NH:34][C:35](=[O:52])[C@@H:36]([NH:41][C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[CH2:37][CH:38]([CH3:39])[CH3:40])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@H](O)C(=O)N[C@H]1CCCC[C@@H]1O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)C(=O)N[C@H]1CCCCC1=O
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.7 %

Procedure:
Under argon gas stream, to 4 ml of an anhydrous dimethylsulfoxide-dichloromethane (1:1) solution containing 567 mg (3.6 mmol) of sulfur trioxide pyridine complex salt were successively added dropwise at 0° C. 0.62 ml (3.6 mmol) of diisopropylethylamine, and then, 2 ml of an anhydrous dimethylsulfoxide solution containing 150 mg (0.3 mmol) of (2S)-N-[(2S,3S)-2-hydroxy-1-[N-[(1S,2S)-2-hydroxycyclohexane-1-yl]amino]-1-oxo-3-heptyl]-4-methyl-2-[N-(phenylmethoxycarbonyl)amino]pentanamide, and the mixture was stirred at the same temperature for 5 hours. After completion of the reaction, 25 ml of ice-water was added to the reaction mixture, and the resulting mixture was extracted with 20 ml of ethylacetate three times. The organic layers were combined, washed successively with 50 ml of a 10%-aqueous citric acid solution, 50 ml of a saturated aqueous sodium hydrogen carbonate solution, and then 50 ml of a saturated NaCl solution, dried over anhydrous sodium sulfate, and then, concentrated under reduced pressure. The residue was applied to neutral silica gel column chromatography, and eluted by a hexane-ethyl acetate (11:9) eluent to obtain 120 mg of the title compound, and further recrystallized from 5 ml of ethyl acetate-hexane (3:2) to obtain 90 mg (Yield: 60.5%) of the title compound.