Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:30]=[CH:29][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][C@H:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:31]([F:34])([F:33])[F:32])([CH3:3])[CH3:2].C1C(=O)N([Cl:42])C(=O)C1>C(Cl)Cl>[Cl:42][C:14]1[C:13]2[CH:12]=[C:11]([O:10][CH2:9][C:8]3[CH:29]=[CH:30][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[C:6]([C:31]([F:34])([F:32])[F:33])[CH:7]=3)[CH:19]=[CH:18][C:17]=2[N:16]2[CH2:20][CH2:21][C@H:22]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C[C@H]1CCn2c1cc1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCn2c1c(Cl)c1cc(OCc3ccc(OC(C)C)c(C(F)(F)F)c3)ccc12
Reaction time: 0.5 h
Yield: 96.4 %

Procedure:
To a solution of (R)-ethyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (52.8 g, 111 mmol) in DCM (350 mL) at −5° C. (ice-salt bath) was added a solution of NCS (14.8 g, 111 mmol) in DCM (350 mL) slowly over 20 min via addition funnel. After stirring for 0.5 h the mixture was washed w/sat. aq. sodium thiosulfate (300 mL). The organics were concentrated to about 300 mL and filtered using a column (60 cm×80 cm) containing sodium sulfate (top layer), sand (middle layer), and silica gel (bottom) using DCM as the eluant. The filtrate was concentrated to give (R)-ethyl 2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (54.6 g, 107 mmol, 96% yield) as a white/mildly yellow solid. Exact mass calculated for C26H27ClF3NO4: 509.2, found: LCMS m/z=510.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.28 (t, J=7.1 Hz, 3 H), 1.37 (d, J=6.1 Hz, 6 H), 2.34 (m, 1 H), 2.52 (dd, J1=16.3, J2=10.2 Hz, 1 H), 2.93 (m, 1 H), 3.22 (dd, J1=16.3, J2=4.0 Hz, 1 H), 3.81 (m, 1 H), 4.00 (m, 1 H), 4.12 (m, 1 H), 4.20 (qd, J1=7.1, J2=1.7 Hz, 2 H), 4.65 (sep, J=6.1 Hz, 1 H), 5.04 (s, 2 H), 6.89 (dd, J1=8.8, J2=2.4 Hz, 1 H), 7.01 (d, J=8.6 Hz, 1 H), 7.06 (d, J=2.4 Hz, 1 H), 7.12 (d, J=8.8 Hz, 1 H), 7.56 (dd, J1=8.5, J2=1.9 Hz, 1 H), 7.67 (d, J=1.9 Hz, 1 H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]1([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][CH2:34][OH:35])=[CH:28][CH:27]=4)[CH:23]=[N:22][C:21]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([CH2:32][CH2:33][CH:34]=[O:35])=[CH:30][CH:31]=4)[CH:23]=[N:22][C:21]=23)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: OCCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CCCc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Dimethylsulfoxide (0.862 mL, 12.2 mmol, 5.00 equiv) was added to a solution of oxalyl chloride (0.636 mL, 7.29 mmol, 3.00 equiv) in dichloromethane (10 mL) at −78° C. The mixture was stirred for 15 minutes before a solution of 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propan-1-ol (2-4, 0.800 g, 2.43 mmol, 1 equiv) in dichloromethane (100 mL) was added via cannula over 5 minutes. The resulting mixture was stirred at −78° C. for 1 hour. Triethylamine (3.50 mL, 25.1 mmol, 10.3 equiv) was added, and the mixture was then warmed to 0° C. and stirred for 30 minutes. The reaction mixture was partitioned between saturated sodium bicarbonate solution (100 mL) and additional dichloromethane (100 mL). The organic layer was dried over sodium sulfate and concentrated to give 3-[4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)phenyl]propanal (2-5) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ9.86 (t, 1H, J=1.2 Hz), 8.82 (d, 1H, J=2.4 Hz), 8.81 (d, 1H, J=2.4 Hz), 8.46 (s, 1H), 8.06 (br d, 2H, J=7.8 Hz), 7.54 (d, 2H, J=8.2 Hz), 7.47 (t, 2H, J=7.8 Hz), 7.37 (d, 2H, J=8.2 Hz), 7.29 (t, 1H, J=7.8 Hz), 3.05 (t, 2H, J=7.1 Hz), 2.86 (t, 2H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30]([CH3:32])=C)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1.CC[O:44]C(C)=O.CC(C)=O>O1CCOCC1.O.O=[Os](=O)(=O)=O>[CH3:1][C:2]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:33]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:40])([CH3:39])[CH3:41])[C:16]4=[N:17][CH:18]=[C:19]([N:21]([CH2:29][C:30](=[O:44])[CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[N:20]=[C:15]4[CH:14]=3)=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: CCOC(C)=O
Reactant: C=C(C)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Agent: O=[Os](=O)(=O)=O
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)CN(C(=O)OC(C)(C)C)c1cnc2c(cc(-c3ccc(C4(C)OCCO4)cc3)n2COCC[Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
tert-Butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-methylallyl)carbamate (0.55 g, 0.95 mmol) and NaIO4 (0.194 mL, 3.79 mmol) were combined in a mixture of 1,4-dioxane (14.0 mL) and water (4.9 mL). To the mixture was added OsO4 (2.5 wt % in t-BuOH, 0.475 mL, 0.038 mmol) and the mixture stirred for about 6 h at rt. EtOAc (50 mL) and water (30 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (40 g Redi-Sep™ silica gel) eluting with 50-100% EtOAc/heptane. The mixture was added to NaIO4 (0.194 mL, 3.79 mmol), acetone (14.0 mL) and water (4.9 mL). To the mixture was added OsO4 (2.5 wt % in t-BuOH, 0.475 mL, 0.038 mmol) and the mixture stirred for about 3 h at rt. EtOAc (50 mL) and water (30 mL) were added and the layers separated. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl 6-(4-(2-methyl-1,3-dioxolan-2-yl)phenyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl(2-oxopropyl)carbamate (0.473 g, 86%): LC/MS (Table 2, Method h) Rt=2.05 min.; MS m/z: 583 (M+H)+.
Reaction SMILES: C(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)CCCC.I[C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=1.[C:32](=[O:35])([O-])[O-].[Na+].[Na+].Cl>C(O)C.C1(C)C=CC=CC=1>[CH2:32]([O:35][C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)=[CH:12][CH:11]=1)[CH2:12][CH2:7][CH2:8][CH3:9]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCCCOc1ccccc1-c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To a stirred mixture of 4-(4-n-pentoxyphenyl)phenylboronic acid (1.0 g, 3.52 mmol) and 4-iodobenzoic acid (874 mg, 3.52 mmol) in ethanol (11 ml) and toluene (30 ml) was added an aqueous solution of sodium carbonate (2M, 5.3 ml, 10.6 mmol) followed by tetrakis-(triphenylphosphine)palladium (204 mg, 5 mol %). The reaction mixture was heated at 100° C. under a nitrogen atmosphere for a period of 18 h. The cooled mixture was acidified to pH 3 (1N HCl) and partitioned between ethyl acetate and water. The organic phase was washed with water (3×) and brine, dried with magnesium sulfate, and filtered through a bed of Celite. The solvent was removed in vacuo to give crude product which was purified by flash silica gel chromatography to provide 4-(n-pentoxyphenyl)-4'-carboxybiphenyl (450 mg): 1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, 3), 1.37 (m, 4 ), 1.72 (m, 2), 3.98 (t, 2), 7.01 (d, 2).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[C:14](OC)[CH:13]=[C:12]([O:18]C)[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(OCC)(=O)C.[Cu](I)I>[CH2:22]([C:2]1[CH:21]=[CH:20][C:5]2[O:6][C:7]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:18])[C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1)[CH3:23]
Reactant: COc1cc(OC)c2c(c1)Oc1ccc(Br)cc1CC2=O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)CC(=O)c1c(O)cccc1O2
Temperature: 80 °C
Yield: 2664.1 %

Procedure:
2-Bromo-7,9-dimethoxy-10,11-dihydrodibenz[b,f]oxepin-10-one 500 mg (F. W. 349.18, 1.43 mmol) prepared in the first stage of Production Example 79, triphenylphosphine 75 mg (F. W. 262.29, 0.062 mmol), trisbenzyldene acetone dipalladium chloroform complex 74 mg (F. W. 1035.08, 0.015 mmol), diisopropylethylamine 575 μl (F. W. 98.22, d=0.742, 2.86 mmol), ethynyl trimethylsillane 350 μl (F. W. 98.22, d=0.742, 2.86 mmol) and copper iodide 27.5 mg (F. W. 190.44, 0.143 mmol) were dissolved in N-methyl-2-pyrrolidone (5 ml) and, after substituting with argon atmosphere, they were stirred with heating at 80° C. for one hour. The reaction mixture was diluted with ethyl acetate and washed with water and saturated sodium chloride solution. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography to give the title compound 420 mg (F. W. 367.419, 66%). The peaks of this compound in 1H-NMR (400 MHz, CDCl3) were as follows.
Reaction SMILES: [C:1]1([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[CH2:9]([C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=Cc1ccc(C=Cc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=Cc1ccc(CCc2ccccc2)cc1
Reaction time: 2 h
Yield: 50.5 %

Procedure:
To a solution of 4-stilbenecarboxaldehyde (5.14 g, 24.68 mmol) in 125 mL of ethyl acetate was added 0.13 g of 5% Pd/C catalyst. The reaction was stirred under hydrogen (1 atm) for 2 hours. An additional 0.14 g of 5% Pd/C catalyst was added and the reaction mixture was stirred under hydrogen (1 atm) again for 1 hour. The catalyst was removed by filtration through a pad of Celite. The residue was washed with ethyl acetate (2×30 mL) and the filtrate was concentrated on a rotavap. The residue oil was chromatographed with 15% ethyl acetate in hexanes on silica gel to give 2.62 g (50%) of the desired product as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][OH:19])[C@H:14]([OH:15])[C@H:12]([OH:13])[C@H:10]2[OH:11])[C@H:5]([OH:6])[C@H:3]1[OH:4].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:24]([O:1][C@H:2]1[O:21][C@H:20]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:7]([O:8][C@@H:9]2[O:17][C@H:16]([CH2:18][O:19][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:14]([O:15][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:12]([O:13][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:10]2[O:11][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:5]([O:6][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:3]1[O:4][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Solvent: c1ccncc1
Product: O=C(OC[C@H]1O[C@@H](O[C@H]2[C@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)O[C@@H]2COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
α-Lactose (2.3 g, 6.38 mmol) was dissolved in 30 ml of anhydrous pyridine, benzoyl chloride (8.9 ml, 76.6 mmol) was added thereto at 0° C., and the mixture was stirred for 8 hrs at room temperature. After the reaction was completed, the reaction mixture was extracted with ethyl acetate, and successively washed with 1 N HCl, saturated NaHCO3 and brine. The extract was dried over MgSO4, concentrated under a reduced pressure, and purified by column chromatography (ethyl acetate:n-hexane=1:3), to obtain the title compound as a white solid (7.19 g).
Reaction SMILES: OC1C(C(C)(C)C)=CC(C=NO)=CC=1C(C)(C)C.Cl[C:20](=[N:33][OH:34])[C:21]1[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([Cl:32])[CH:22]=1.[CH2:35]([N:38]=[C:39]=[S:40])[CH:36]=[CH2:37]>>[Cl:32][C:23]1[CH:22]=[C:21]([C:20]2[CH2:37][CH:36]([CH2:35][N:38]=[C:39]=[S:40])[O:34][N:33]=2)[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]=1[OH:31]
Reactant: C=CCN=C=S
Reactant: CC(C)(C)c1cc(C(Cl)=NO)cc(Cl)c1O
Agent: CC(C)(C)c1cc(C=NO)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(C2=NOC(CN=C=S)C2)cc(Cl)c1O

Procedure:
A 25 g. portion of 4-hydroxy-3,5-bis(t-butyl)benzaldoxime was chlorinated as in Example 1 to produce 1 g. of α,3-dichloro-4-hydroxy-5-(t-butyl)benzaldoxime by chlorination and rearrangement. The intermediate was reacted with an excess of allylisothiocyanate to produce 1 g. of product, an oily liquid, NMR singlets at 1.41 and 6.18 ppm., multiplets at 2.92-3.93, 4.68-5.23 and 7.5-7.63 ppm.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:13]1[O:15][N:48]=[C:39]([C:40]2[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=2)[N:38]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: Nc1c(C(=O)O)cnn1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(-c2nc(-c3ccc(CO)cc3)no2)cnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid (1.8 g, 8.86 mmol), HOBt (1.357 g, 8.86 mmol) and EDCI (1.698 g, 8.86 mmol) were dissolved in DMF (12 mL) under nitrogen at room temperature. The resulting clear, pale yellow solution was stirred for 30 minutes then N-hydroxy-4-(hydroxymethyl)benzimidamide (1.472 g, 8.86 mmol) was added in several portions. The reaction was placed in an oil bath set to 130° C. After 4 hours, the solution was cooled to RT and then added to rapidly stirring water (50 mL). The initial precipitate was stirred and sonicated to give a yellow solid which was collected by filtration, washed with water, air dried and then dried under vacuum to afford (4-(5-(5-amino-1-phenyl-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (1.5 g 4.05 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1Cl)[CH2:5][N:6]1[CH2:11][CH2:10][S:9][CH2:8][C:7]1=[O:12].ClC1C=C(C=CC=1Cl)CBr.N1CCSCC1=O>>[CH2:5]([N:6]1[CH2:11][CH2:10][S:9][CH2:8][C:7]1=[O:12])[C:4]1[CH:3]=[CH:2][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CSCCN1Cc1ccc(Cl)c(Cl)c1
Agent: Clc1ccc(CBr)cc1Cl
Agent: O=C1CSCCN1
Product: O=C1CSCCN1Cc1ccccc1

Procedure:
In the same manner, 4-(3,4-dichlorobenzyl)-thiomorpholin-3-one was prepared in 89% yield from 3,4-dichlorobenzyl bromide and thiomorpholin-3-one as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:31][CH2:32][CH2:33][OH:34]>CN(C=O)C.O>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:31][CH2:32][CH2:33][OH:34])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.51 g) in DMF (14 mL) was added 1.39 g of Cs2CO3 and 142 μL of 3-bromo-1-propanol. The mixture was stirred at RT for 12 h and then was diluted with water. The aqueous layer was extracted with Et2O and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (2% 2 M NH3 in MeOH/CH2Cl2) afforded 0.15 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.16 g the corresponding HCl salt. MS (ESI): exact mass calculated for C23H25ClN2O, 380.17. found, m/z 381.2 [M+H]+, 383.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.15 (s, 2H), 4.47 (br s, 2H), 3.93-3.25 (m, 6H), 2.94-2.93 (m, 2H), 2.01-1.96 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([N:12]3[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]3=[O:24])[CH:10]=[CH:11][C:6]=2[S:5][N:4]=1.[CH3:25][N:26]([CH3:28])[CH3:27]>C1(C)C=CC=CC=1>[Br-:1].[CH3:23][N:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][C:17](=[O:18])[N:12]([C:9]2[CH:10]=[CH:11][C:6]3[S:5][N:4]=[C:3]([CH2:2][N+:26]([CH3:28])([CH3:27])[CH3:25])[C:7]=3[CH:8]=2)[C:13]1=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Reactant: CN(C)C
Solvent: Cc1ccccc1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C[N+](C)(C)C)c3c2)c1=O
Product: [Br-]
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (20.0 g, 0.0480 mol) and toluene is heated to 90° C., cooled to room temperature, treated with liquid trimethylamine (8.60 g, 0.145 mol), stirred at room temperature for 90 minutes, and filtered to obtain a solid. The solid is washed with toluene and dried in a vacuum oven at 45-50° C. to give the title product as a white solid which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([O:39]C)=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>CO>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:43]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:50])[F:51])[CH:45]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([CH2:41][CH3:42])[C:32]1[O:33][CH2:34][C@@H:35]([C:37]([OH:39])=[O:38])[N:36]=1)[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(C1=N[C@H](C(=O)OC)CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(C1=N[C@H](C(=O)O)CO1)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Methyl (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylate (190 mg) is dissolved in methanol (4 ml) and thereto is added a 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→4:1) to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg). The resulting (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid (130 mg) is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (180 μl) and concentrated under reduced pressure to give (S)-2-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethyl-amino]-4,5-dihydro-oxazole-4-carboxylic acid sodium salt (120 mg). MS (m/z): 729 [M−Na]−
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.ClC(Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CO>[CH2:1]([N:5]1[C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11](=[O:12])[O:13][C:14]1=[O:21])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccsc1NCC(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC(C)Cn1c(=O)oc(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A mixture of methyl 2-(isobutylamino)thiophene-3-carboxylate (2.1 g, 9.9 mmol), sodium hydroxide (0.39 g, 9.8 mmol), water (20 mL) and methanol (10 mL) was heated at reflux for 2 h and cooled to room temperature. Methanol was removed under reduced pressure; the residue was diluted with dichloromethane (10 mL) and cooled to 0° C. Triphosgene (5.85 g, 19.7 mmol) was added portionwise; the reaction mixture was stirred for 18 h and diluted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide the crude product as a light brown solid (2.0 g). This material was used in the next step (Step D) without any purification. 1H NMR (400 MHz, CDCl3): δ 7.25 (d, 1H), 6.95 (d, 1H), 3.79 (d, 2H), 2.40-2.36 (m, 1H), 1.02 (d, 6H).
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[CH:11]1[C:16]([C:17](CBr)=[O:18])=[CH:15][CH:14]=[C:13]([F:21])[CH:12]=1.[ClH:22]>C(Cl)(Cl)Cl.CCO>[ClH:22].[NH2:4][CH2:10][C:17]([C:16]1[CH:15]=[CH:14][C:13]([F:21])=[CH:12][CH:11]=1)=[O:18]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Hexamethylenetetramine (1.42 g, 10.1 mmol) was added dropwise over 30 min to a solution of 2-bromo-4-fluoroacetophenone (2.0 g, 9.2 mmol) in dry CHCl3 (40 mL) at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 16 h. After completion of the reaction the solid precipitate formed was collected by filtration and washed with CHCl3. The solid obtained was suspended in EtOH (40 mL) and conc. HCl (4 mL) was added. The mixture was heated to 80° C. for 3 h, cooled to room temperature, and the solid formed was filtered off. The clear filtrate was concentrated to afford 2-amino-1-(4-fluorophenyl)ethanone hydrochloride (1.5 g, crude) as yellow solid. MS (ESI) m/z: Calculated for C8H8FNO: 153.06. found: 153.9 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([O:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:33](=[O:35])[CH3:34])[CH3:20])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(Oc2ncc(-c3ccc(C(C)N)cc3)s2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Oc2ncc(-c3ccc(C(C)NC(C)=O)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of Example 11D ((110 mg, 0.337 mmol) and diisopropylethylamine (0.5 mL) in methylene chloride (1 mL) cooled to 0° C. was added acetic anhydride (100 μL, 1.06 mmol, 3.1 eq.). The mixture was stirred at room temperature overnight. The reaction mixture was purified directly on silica gel eluting with ethyl acetate:hexane gradient (0-80%) to give the title compound (109 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.30 (d, J=8.09 Hz, 1 H), 7.66 (s, 1 H), 7.45-7.54 (m, 2 H), 7.33-7.40 (m, 2 H), 7.27-7.32 (m, Hz, 2 H), 6.99-7.10 (m, 2 H), 4.77-4.96 (m, 1 H), 3.79 (s, 3 H), 1.83 (s, 3 H), 1.32 (d, J=6.99 Hz, 3 H); MS (DCl) m/e 369 (M+H).