Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:6]2[CH:12]=[N:11][NH:10][C:7]2=[N:8][CH:9]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:52]([O:56][C:57]([N:59]1[CH2:63][CH2:62][CH2:61][C@H:60]1[C@H:64]([C:68]1[CH:73]=[CH:72][C:71]([Cl:74])=[CH:70][CH:69]=1)[C:65](O)=[O:66])=[O:58])([CH3:55])([CH3:54])[CH3:53]>CN(C=O)C>[Cl:74][C:71]1[CH:70]=[CH:69][C:68]([C@@H:64]([C@@H:60]2[CH2:61][CH2:62][CH2:63][N:59]2[C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])[C:65]([N:16]2[CH2:15][CH2:14][N:13]([C:5]3[C:4]([CH3:3])=[CH:9][N:8]=[C:7]4[NH:10][N:11]=[CH:12][C:6]=34)[CH2:18][CH2:17]2)=[O:66])=[CH:73][CH:72]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: Cc1cnc2[nH]ncc2c1N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc2[nH]ncc2c1N1CCN(C(=O)[C@@H](c2ccc(Cl)cc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)CC1
Yield: 67 %

Procedure:
A solution of 5-methyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (75 mg, 0.194 mmol), diisopropylethylamine (135 μL, 0.775 mmol), HATU (73.7 mg, 0.194 mmol) and (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (79.0 mg, 0.233 mmol, see Example C) in DMF (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo. The resulting residue was redissolved in THF (5 mL) and treated with an aqueous solution of LiOH (2 mL, 0.5M) for 30 minutes. Next, the solvent was removed, and the resulting residue was suspended in EtOAc (50 mL) and washed with water (2×10 mL). The dried (MgSO4) organic phase was concentrated in vacuo, and the resulting residue was purified by reverse phase chromatography (Biotage, C-18 12M+) on Biotage SP4 unit using a gradient of 5-80% CH3CN/water to provide (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-(4-(5-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-2-oxoethyl)pyrrolidine-1-carboxylate (70 mg, 0.130 mmol, 67.0% yield) as a solid after drying under high vacuum. LCMS (APCI+) m/z 539.2, 541.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH2:28]Cl)=[O:22]>[I-].[K+].CC(=O)CC>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH2:28][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:7]=1)=[O:22]
Reactant: OCCCCc1ccc(O)cc1
Reactant: COC(=O)c1ccsc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1ccsc1COc1ccc(CCCCO)cc1
Yield: 65.4 %

Procedure:
To a stirred mixture of 8.31 g of 4-(4-hydroxyphenyl)butanol, 20.73 g of milled anhydrous potassium carbonate, 0.5 g of powdered potassium iodide and 200 ml of 2-butanone was added, over a few minutes, a solution of 9.45 g 2-chloromethyl-3-thiophenecarboxylic acid methyl ester and 20 ml of 2-butanone. The suspension was heated under reflux overnight, with stirring. The reaction mixture was filtered while hot, and the filter cake was washed with 2-butanone. The combined filtrate was concentrated. The residue was dissolved in 200 ml of dichloromethane, and the solution was washed with 200 ml of 5% sodium hydroxide solution, 200 ml of water and then saturated brine solution. The dried (over anhydrous sodium sulfate) organic phase was filtered and concentrated. The residue was purified by high-pressure liquid chromotography (Water Associates Prep LC/System 500; two silica gel columns; sample applied as a filtered solution in 200 ml of dichloromethane using a little pure dichloromethane to flush the material onto the column before elution; eluted with 10% (V/V) ethylacetate in dichloromethane; 150 ml/min. flow rate maintained until major component began to elute, then increased flow rate to 250 ml/min; U.V. and refractive index detectors used) to afford 10.38 g (65.3%) of product, m.p. 58°-60° C., after concentration and trituration of the eluents with hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][CH2:33]3)[CH:29]=[N:30][CH:31]=2)O1.C([O-])(=O)C.[K+]>C(#N)C.O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:26]3[CH:27]=[C:28]([N:32]4[CH2:33][CH2:34][CH:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:36][CH2:37]4)[CH:29]=[N:30][CH:31]=3)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3nn(C4CCCCO4)c4cnc(Br)cc34)c2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (0.0736 g, 0.180 mmol), tert-butyl 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperidin-4-ylcarbamate (0.080 g, 0.20 mmol) and 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (0.0221 g, 0.0270 mmol) were dissolved in Acetonitrile (3.00 mL), followed by the addition of 1.0 M of Potassium acetate in Water (0.270 mL) and 1.0 M of Sodium carbonate in Water (0.270 mL). The reaction was stirred at 80° C. for 1 h. After filtration, the crude was evaporated and purified by silica gel column using (EtOAc/Hep eluted at 75% EtOAc) to give tert-butyl 1-(5-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-3-yl)piperidin-4-ylcarbamate (45 mg, 45% yield). ESI MS m/z=558.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([CH3:24])=[C:2]([NH:1][C:32](=[O:33])[C:31]5[CH:30]=[CH:29][CH:28]=[N:27][C:26]=5[CH3:25])[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1NC(=O)c1cccnc1C
Yield: 31.7 %

Procedure:
Using N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (120 mg, 0.371 mmol), 2-methylpyridine-3-carboxylic acid (76 mg, 0.557 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (114 mg, 0.594 mmol), 1-hydroxybenzotriazole (81 mg, 0.600 mmol), triethylamine (0.09 mL, 0.631 mmol) and N,N-dimethylformamide (6.0 mL), and by a reaction in the same manner as in Example 187, the title compound (52 mg, 31%) was obtained as pale-pink crystals.
Reaction SMILES: [O:1]=[C:2]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[OH:19][CH:20]([CH3:40])[CH2:21]N1CCN(C(=O)COC2C=C(C=CC=2)C=O)CC1>>[OH:19][CH:20]([CH3:40])[CH2:21][N:16]1[CH2:17][CH2:18][N:13]([C:2](=[O:1])[CH2:3][O:4][C:5]2[CH:6]=[CH:7][C:8]([CH:9]=[O:10])=[CH:11][CH:12]=2)[CH2:14][CH2:15]1
Reactant: CC(O)CN1CCN(C(=O)COc2cccc(C=O)c2)CC1
Reactant: O=Cc1ccc(OCC(=O)N2CCNCC2)cc1
Product: CC(O)CN1CCN(C(=O)COc2ccc(C=O)cc2)CC1
Yield: 66 %

Procedure:
4-(2-oxo-2-(piperazin-1-yl)ethoxy)benzaldehyde (55) was treated in an analogous manner to compound 51 to yield the desired product (66%) as a colorless oil. LCMS: 96% (M++1).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4C(OC(C)(C)C)=O)([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(OCC(OC)=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.CO>Cl>[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[NH:7][C:8]([C:10]([C:21]3[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH3:32])=[C:26]4[C:22]=3[CH:23]=[CH:24][NH:25]4)([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:11]([F:12])([F:13])[F:14])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)COC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COC(=O)COC(c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Solvent: CO
Product: COC(=O)COC(c1nc2cc(C#N)ccc2[nH]1)(c1c(OC)cc(C)c2[nH]ccc12)C(F)(F)F
Temperature: 60 °C
Reaction time: 7 h

Procedure:
A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(2-methoxy-2-oxoethoxy)ethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (510 mg, 0.711 mmol) was dissolved in 1.25 N HCl in MeOH (8.6 mL, 10.75 mmol), and stirred at 60° C. for 7 hours. The reaction mixture was then concentrated to dryness, dissolved in EtOAc, basified with a 15% aq. NH4OH solution at 0° C. and diluted with water. The organic layer was separated, dried over magnesium sulfate, filtered, concentrated and purified via FCC eluting with Heptane/EtOAc (0-60% of EtOAc) to provide the title compound. 1H NMR (400 MHz, Acetone) δ ppm 11.86 (br. s., 1H) 10.15 (br. s., 1H) 7.54-8.07 (m) 7.48 (d, J=8.08 Hz, 1H) 7.25 (t, J=2.91 Hz, 1H) 6.91-7.05 (m, 1H) 6.64 (s, 1H) 4.31 (m, 1H) 3.92-4.05 (m, 1H) 3.30-3.45 (s, 3H) 2.97-3.13 (s, 3H) 2.35-2.46 (s, 3H) HRMS calcd. for C23H19F3N4O4 (M+H)+ 473.1437. found 473.1438.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:15][CH2:16][CH2:17][N:18]([CH:30]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[C:36]([Br:40])[CH:37]=3)[O:32][CH2:31]2)[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[O:20])[CH2:10][C@@H:9]1[CH3:41])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[Br:40][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[O:32][CH2:31][CH:30]([N:18]([CH2:17][CH2:16][CH2:15][N:11]1[CH2:10][C@H:9]([CH3:41])[NH:8][CH2:13][C@H:12]1[CH3:14])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1)=[O:20])[CH2:39]2
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN[C@@H](C)CN1CCCN(C(=O)Nc1ccc(F)c(Cl)c1)C1COc2ccc(Br)cc2C1
Yield: 95.8 %

Procedure:
(2S,5R)-4-{3-[1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-ureido]-propyl}-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.053 g, 0.081 mmol) was treated with 20% TFA/CH2Cl2 (0.4 mL) at room temperature for 2 hours. The reaction mixture was diluted with toluene (4 mL) and concentrated in vacuo. Purification on reverse-phase HPLC gave 0.043 g (96%) of (2R,5S)-1-(6-bromo-chroman-3-yl)-3-(3-chloro-4-fluoro-phenyl)-1-[3-(2,5-dimethyi-pipe razin-1-yl)-propyl]-urea as a white solid. 1H NMR (300 MHz, CD3OD): □ 7.83 (dd, J=6.6, 2.4 Hz, 1H), 7.53 (m, 2H), 7.45 (dd, J=8.7, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 4.71 (m, 1H), 4.46 (m, 2H), 4.07 (m, 1H), 4.00-3.20 (m, 10H), 2.26 (m, 2H), 1.66 (d, J=6.2 Hz, 3H), 1.63 (d, J=6.6 Hz, 3H). MS-ESI: 553.0 (M+H+).
Reaction SMILES: C(N1C2C=C(F)C=C(O)C=2C(CCN2CC3C(=CC=CC=3)C2)=C1)C.C([O:32][C:33]1[CH:41]=[C:40]([F:42])[CH:39]=[C:38]2[C:34]=1[C:35]([CH2:45][CH2:46][OH:47])=[CH:36][N:37]2[CH2:43][CH3:44])C1C=CC=CC=1>>[CH2:43]([N:37]1[C:38]2[CH:39]=[C:40]([F:42])[CH:41]=[C:33]([OH:32])[C:34]=2[C:35]([CH2:45][CH2:46][OH:47])=[CH:36]1)[CH3:44]
Reactant: CCn1cc(CCO)c2c(OCc3ccccc3)cc(F)cc21
Agent: CCn1cc(CCN2Cc3ccccc3C2)c2c(O)cc(F)cc21
Product: CCn1cc(CCO)c2c(O)cc(F)cc21
Yield: 99 %

Procedure:
Following the procedure (step 3 scheme 31 used to prepare compound 31-4 compound 26-5 gave compound 39-2 (318 mg, 99%) as a light purple solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](O)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.S(Cl)([Cl:24])=O>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([Cl:24])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)O)c2nc1OC
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC

Procedure:
A mixture of 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carboxylic acid (12) (500 mg, 1.70 mmol) in thionyl chloride (twice distilled over triphenyl phosphite) (25 mL) was heated at reflux for 20 hours. The reaction mixture was concentrated to an off-white solid which was purified by elution through a flash column (4:1 hexanes:ethyl acetate), 510 mg (96%), mp 162-164° C.; 1 H NMR (CDCl3): δ 8.35 (s, 1H), 4.15 (s, 3H), 4.03 (s, 3H), 2.55 (s, 3H); MS: m/z 312 (M+H). Anal Calcd. for C12H11ClN3O5: C, 46.24; H, 3.23; N, 13.48. Found: C, 46.38; H, 3.32; N, 13.28.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[Li+].[BH4-].O.Cl>C1COCC1.CO>[OH:1][C:2]1[C:3]([C:13]#[N:14])=[CH:4][C:5]2[CH:6]=[CH:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: N#Cc1cc2c(cc1O)CCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc2c(cc1O)CCC=C2
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To the suspension of 3-hydroxy-8-oxo-5,6,7,8-tetrahydronaphthalene-2-carbonitrile from (150 mg, 0.8 mmol) in 2 mL anhydrous THF was added 2M LiBH4 in THF (0.6 mL, 1.2 mmol, 1.5 eq) and 0.5 mL anhydrous methanol. The reaction was shaken at 40° C. for 2 h. To this was added 5 mL water and some 1N HCl until pH=2. The mixture was extracted with ethyl acetate 3 times and dried down with genavac at high temperature. The resulting dark liquid (about 100 mg) was used directly in the next step reaction.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C:4]1=[O:16].[Cl:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:17][C:3]1([S:2][CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C:4]1=[O:16]
Reactant: CSC1C(=O)Nc2ccc(C(F)(F)F)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CSC1(Cl)C(=O)Nc2ccc(C(F)(F)F)cc21

Procedure:
A solution of 3-methylthio-5-trifluoromethyloxindole (1.40 g, 0.0057 mol) and N-chlorosuccinimide (800 mg, 0.006 mol) in 100 ml of carbon tetrachloride was stirred at room temperature for 1 hour. The precipitated succinimide was removed by filtration, and the filtrate was evaporated to give 3-chloro-3-methylthio-5-trifluoromethyl oxindole as a yellow solid which was dissolved in 30 ml of tetrahydrofuran and added to a vigorously stirred slurry of red mercuric oxide (1.30 g, 5.8 mmol) and boron trifluoride etherate (860 mg, 5.8 mmol) in 100 ml of 20 percent aqueous tetrahydrofuran. The resulting mixture was stirred for 2 hours at room temperature, filtered through a pad of Celite and the filtrate was extracted with four 100-ml portions of methylene chloride. The methylene chloride extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated to give a residue which was chromatographed on silica gel. Elution with methylene chloride gave 5-trifluoromethylisatin as yellow needles (860 mg, 73%), mp 191°-193° (recrystallized from benzene); ir (KBr) 3200 (NH), 1750 (C=O), 1710 cm-1 (C=O); nmr (DMSO-d6), π-1.20 (b s, 1H, NH), 2.15 (d, 1H, H6), 2.30 (s, 1H, H4), 2.90 (d, 1H, J6,7 =8 Hz, H7); mass spectrum m/e obs. 215.0196 (calc. 215.0194).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(N2CCNCC2)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
A solution of t-butyl 4-(4-methoxyphenyl)piperazine-1-carboxylate (1.412 g, 4.84 mmol, 1.00 equiv) in dichloromethane (17 mL) and trifluoroacetic acid (6 mL) was placed in a 50-mL round bottom flask and stirred for 2 h at 20° C. in an oil bath. The pH of the solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The resulting mixture was concentrated under vacuum yielding 0.92 g (65%) of 1-(4-methoxyphenyl)piperazine as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][NH:5][CH:6]1[CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]([C:19](=[O:21])[NH2:20])[CH:8]=[C:7]1[CH2:22][C:23]([NH2:25])=[O:24])[CH:2]=[CH2:3].Cl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH2:1]([O:4][NH:5][CH:6]1[CH2:11][NH:10][C@@H:9]([C:19]([NH2:20])=[O:21])[CH:8]=[C:7]1[CH2:22][C:23]([NH2:25])=[O:24])[CH:2]=[CH2:3]
Reactant: C=CCONC1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1CC(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCONC1CN[C@@H](C(N)=O)C=C1CC(N)=O
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (2S)-tert-butyl 5-((allyloxy)amino)-4-(2-amino-2-oxoethyl)-2-carbamoyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 176, crude, 330 mg, 0.93 mmol) in DCM (5.0 mL) at 0° C. was added HCl (4.0M in dioxane, 0.233 mL, 0.93 mmol). The mixture was stirred from 0° C. to room temperature for 2 h. Then 0.233 mL more HCl was added to the mixture and stirred for 2 h. It was neutralized by K2CO3 and TEA, filtered and the solvent was removed under vacuum. The crude was subjected to silica column eluting with 0-50% MeOH/DCM to give the desired diastereomeric products as white solids. 100 mg, diastereomer 1. 32 mg, diastereomer 2. 56% yield.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[CH:7][S:8][CH:9]=2)[N:6]=1.C(=O)=O.[Br:13]N1C(=O)CCC1=O.[Cl-].[Na+]>O1CCCC1>[Br:13][C:9]1[S:8][CH:7]=[C:5]2[C:4]=1[O:3][C:2]([CH3:1])=[N:6]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cscc2o1
Agent: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc2csc(Br)c2o1

Procedure:
1 mmol of 2-methylthieno[3,4-d][1,3]oxazole was dissolved in 10 ml of tetrahydrofuran and the temperature was kept at −78° C. in a methanol bath cooled by dry ice. A solution in which 1.05 mmol of N-bromosuccinimide was dissolved in 5 ml of tetrahydrofuran was gradually added dropwise to carry out the reaction for 2 hours. Then an excess amount of saturated sodium chloride aqueous solution was added to stop the reaction. The reacted liquid was washed with water. Then the organic layer was recovered and dried under sodium sulfate. The solvent was evaporated out. The product was purified using column separation with the solvent of ethylacetate and hexane, obtaining 6-bromo-2-methylthieno[3,4-d][1,3]oxazole represented by formula (21).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:2]([NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
Ethylamine HCl (6.14 g, 75.376 mmol, 1.5 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1.0 eq) were dissolved in MeOH (200 ml); acetic acid (0.2 ml) was added and stirring was carried out for 2 hours at RT. NaBH3CN (6.3 g, 100.50 ml, 2.0 eq) was then added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated and the residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×400 ml). The combined org. phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 70% (8.0 g, 35.08 mmol)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(Cl)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 380 mg, 47%). mp 208-210° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.27 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H) 7.51 (d, J=9 Hz, 4H), 7.6 (t, 1H), 7.7 (m, 1H), 7.75 (d, J=9 Hz, 2H), 7.94 (dd, 1H), 8.25 (s, 1H). MS (DCI/NH3) m/z 474 (M+H)+, 491 (M+NH4)+. Anal. calc. for C22H14F2Cl2N3O3S.0.5H2O: C, 55.76; H, 2.98; N, 8.87. Found: C, 56.05; H, 3.42; N, 8.65.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.[C:13]1([CH2:19][CH2:20][CH:21]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO.O>[ClH:1].[CH3:12][O:11][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][CH2:21][CH2:20][CH2:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:10]
Reactant: O=CCCc1ccccc1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](NCCCc2ccccc2)CC1

Procedure:
A solution of 2 g of methyl trans-4-aminocyclohexane-carboxylate-hydrochloride, 1.5 ml of 3-phenylpropionaldehyde and 1.3 g of sodium cyanoborohydride in 40 ml of dry methanol is stirred for 20 hours at ambient temperature. The mixture is diluted with water and extracted with ethyl acetate. The combined ethyl acetate phases are dried, acidified with ethereal hydrochloric acid and the solvent is removed under reduced pressure. The residue is triturated with acetone, suction filtered and washed with acetone and then with ether. Yield: 1.9 g (59.1% of theory), Melting point: 258°-260° C.