Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:30]([O:37][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccccc1
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C(NC(=O)c2ccc(OCc3ccccc3)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Temperature: 100 °C

Procedure:
4-Bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.4.AaBa, 1.00 g, 2.06 mmol) benzyl alcohol (3.1, 0.256 mL, 0.00247 mol) were dissolved in 10 mL dimethylformamide. The reaction was heated to 100° C. for 18 hours. Ethyl acetate (20 mL) was added and aqueous workup was performed. The organic layer was dried over magnesium sulfate evaporated and purified via SiO2 chromatography (16%-33% ethyl acetate/hexane) to yield 4-(benzyloxy)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2I) as a white solid. MS analysis (m+1)=513.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH:32]1([NH2:38])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1COCC1>[CH:32]1([NH:38][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NC2CCCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 18 h

Procedure:
The product of Example 48 (200 mg, 0.45 mmol) and cyclohexylamine (100 mg, 1 mmol) were combined in THF (10 mL) and stirred under Ar at 23° for 18 h. The solvents were removed in vacuo, and the residue was flash chromatographed with 50-100% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white-crystalline solid. mp 218-219° C., LC MS m/z=465 (MH+) Retention time=2.8 min.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][C@@H:12]2[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]2[CH2:10]1.[C:20]([O:24][C:25]([N:27]([CH3:36])[C@H:28]([C:33](O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])([CH3:23])([CH3:22])[CH3:21].O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:36][N:27]([C@@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:33](=[O:34])[NH:17][C@@H:14]1[C@@H:12]2[C@@H:11]([CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:1])([F:18])[F:19])[CH2:13]2)[CH2:16][CH2:15]1)[C:25](=[O:26])[O:24][C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](C(=O)N[C@H]1CC[C@@H]2CN(c3ccccc3C(F)(F)F)C[C@@H]21)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a 4 mL vial was added (3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-amine from Step 2 (21.6 mg, 0.080 mmol), N-(tert-butoxycarbonyl)-N-methyl-L-leucine (21.56 mg, 0.088 mmol), and 1-hydroxybenzotriazole hydrate (13.46 mg, 0.088 mmol) in dichloromethane (1 mL) to give a colorless solution. After 20 minutes, N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.016 mL, 0.088 mmol) was added. The reaction mixture was stirred at ambient temperature for 18 hours. The reaction was diluted with 1 mL of dichloromethane and quenched with 2 mL of water. The aqueous layer was extracted with more dichloromethane (2×2 mL), the solvent was removed in vacuo, and the crude material was applied to a 24 g silica gel cartridge and purified with 1-50% ethyl acetate/hexanes to give tert-butyl methyl((S)-4-methyl-1-oxo-1-((3aR,4S,6aS)-2-(2-(trifluoromethyl)phenyl)octahydrocyclopenta[c]pyrrol-4-ylamino)pentan-2-yl)carbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=6.8, 1H), 7.69-7.62 (m, 1H), 7.45 (t, J=7.4, 1H), 7.26 (d, J=8.2, 1H), 7.11 (t, J=7.6, 1H), 5.17 (s, 1H), 4.46 (s, 1H), 3.45 (d, J=8.8, 1H), 3.08 (d, J=24.1, 4H), 2.98-2.87 (m, 2H), 2.63 (s, 2H), 2.09 (s, 1H), 1.86 (ddd, J=23.7, 16.2, 10.4, 3H), 1.70-1.51 (m, 3H), 1.48 (s, 9H), 0.90 (d, J=6.5, 3H), 0.86 (d, J=6.5, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[N-:52]=[C:53]=[O:54]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:53]([NH2:52])=[O:54])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Agent: O=C([O-])C(F)(F)F
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CNC(N)=O)cc2)C1=O

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]-methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and trimefflylsilyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 1.40 (s, 6H), 1.82 (m, 1H), 2.15-2.60 (m, 3H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.32 (d, 15 Hz, 1H), 7.05-7.43 (m, 17H). FAB-MS: calculated for C37H39N5O5 633; found 644(M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1.[N+:12]([O-])([OH:14])=[O:13]>C(O)(=O)C>[OH:11][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([O:2][CH3:1])=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(C=O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
To a solution of 5-methoxysalicylaldehyde (22.52 g; 148 mmol) in acetic acid (120 ml) was added dropwise over 1 hour a mixture of fuming nitric acid (7.1 ml) in acetic acid (25 ml). After complete addition the mixture was stirred at room temperature for 5 hours. The precipitate was removed by filtration, washed with ethanol and dried to give the title compound (20.3 g, 69%) as a bright yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15](I)[CH:16]=3)[CH:11]=[N:10]2)=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1CCCCC1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30]([OH:34])([C:32]#[CH:33])[CH3:31]>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.[Cu]I>[NH2:8][C:5]1[N:4]=[C:3]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:33]#[C:32][C:30]([C:26]4[S:25][CH:29]=[CH:28][N:27]=4)([OH:34])[CH3:31])[CH:16]=3)[CH:11]=[N:10]2)[C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1ncc(Cl)c(-n2ncc3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2cnn(-c3nc(N)ncc3Cl)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 5-chloro-4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (170 mg, 0.46 mmol) and piperidine (1.2 mL) was added tetrakis(triphenylphosphine)palladium (52.9 mg, 0.05 mmol), copper(I) iodide (8.7 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (140.2 mg, 0.92 mmol). The reaction was purged with N2 and stirred at RT for 20 min. The reaction mixture was concentrated in vacuo and the resultant residue purified by flash chromatography (Isolute column, 1% MeOH in DCM), followed by reverse phase preparative HPLC to give the title compound as a solid: 1H NMR (500 MHz, DMSO) δ 1.91 (3H, s), 7.09 (1H, s), 7.23-7.39 (3H, m), 7.69 (1H, d, J=3.36 Hz), 7.78 (1H, d, J=3.20 Hz), 7.90 (1H, d, J=8.24 Hz), 8.17 (1H, d, J=0.76 Hz), 8.43-8.53 (2H, m); LC-MS: m/z=+397.40 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][C@@H:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[C:10]1([C@H:9]([NH:16][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN[C@H](C)c1ccccc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
Ethyl bromoacetate (4.14 g; 24.8 mmol) was treated with (R)α-methylbenzylamine (3 g, 24.8 mmol) and ethyldiisopropylamine (3.2 g; 24.8 mmol) in toluene (100 mL). After heating at reflux for 18 hours, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 20% ethyl acetate/pentane) to provide the title compound (3.2 g, 63% yield). MS (DCI/NH3) m/z 208 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]([CH3:44])([CH:39](OC)[O:40]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(C)=O>[CH2:1]([S:8][C:9]([CH3:44])([CH:39]=[O:40])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][C:17]=2[N:28]([CH3:38])[S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)(=[O:30])=[O:31])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(SCc3ccccc3)C(OC)OC)cc2c1
Solvent: CC(C)=O
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(C)(C=O)SCc3ccccc3)cc2c1
Yield: 86.2 %

Procedure:
To a mixture of N-[2-(benzylthio)-3,3-dimethoxy-2-methylpropyl]-5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxamide (1.95 g), water (0.16 mL) and acetone (30 mL) was added Amberlyst (registered trade mark) 15 ion exchange resin (500 mg) at room temperature, and the mixture was added overnight at room temperature. The insoluble substance was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give the title compound (1.56 g, yield 87%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (9:1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[C:6]([NH2:11])[CH:5]=1.[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]([NH2:11])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(Br)c(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)c(N)c1
Temperature: 120 °C
Yield: 94 %

Procedure:
Add zinc cyanide (1.5 g, 12.77 mmol), palladium tetrakis (675 mg, 0.584 mmol), to 3-amino-4-bromo-benzoic acid methyl ester (1.328 g, 5.77 mmol) in anhydrous DMF (3 ml). Purge with nitrogen for few minutes and keep under nitrogen atmosphere while heating to 120° C. overnight. Cool the mixture to room temperature and add water. Extract the product with EtOAc (×2). Wash the combined organic layers with 2N ammonium hydroxide solution (×2), water (×2), saturated aq. sodium chloride and dry over anhydrous sodium sulfate, filter and concentrate to yield the crude product. Purification by flash chromatography (Silica gel-hexane/EtOAc) yields 3-amino-4-cyano-benzoic acid methyl ester (94%).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8](C)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.CI.[CH2:22](I)[CH3:23]>>[CH3:19][N:2]([CH3:1])[C:3](=[O:18])[C:4]([CH3:17])([C:23]1[CH:22]=[CH:9][CH:8]=[CH:7][CH:11]=1)[N:5]1[CH:9]=[CH:8][C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:6]1
Reactant: CCI
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Solvent: CI
Product: CN(C)C(=O)C(C)(c1ccccc1)n1ccc(-c2ccccc2)n1

Procedure:
Following the procedure of Example 95, but substituting N,N-dimethyl-α,3-diphenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and methyl iodide for ethyl iodide, there is obtained N,N,α-trimethyl-α,3-diphenylpyrazole-1-acetamide, m.p. 129°-131.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:15][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClCCOc1ccc2ccccc2c1
Reactant: CCCCCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octylamine (0.37 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-octyl)-2-(napthalen-2-yloxy)ethylamine, solid, m.p. 105° C., (yield 0.64 gm, 87.6%).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([C:21]2[N:26]=[C:25]([C:27]3[S:28][C:29]4[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=4[C:31](=[O:33])[N:32]=3)[CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:20])=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)c2cccc(-c3nc(=O)c4ccccc4s3)n2)cc1
Yield: 30.2 %

Procedure:
A solution of 3-chloroperbenzoic acid (ca. 70%, 0.53 g, 2.1 mmol) in chloroform (10 ml) was added dropwise to a solution of 2-{6-[(4-methylphenyl)sulfinyl]-2-pyridyl}-4H-1,3-benzothiazine-4-one (0.35 g, 11.0 mmol) in chloroform (50 ml) with stirring. The reaction mixture was stirred at room temperature for 5 hrs and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) and recrystallized from ethanol to give the titled compound (0.25 g, 64%) as crystals.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][CH:11]=1>OS(O)(=O)=O>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[O:13])[S:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: O=Cc1cc(Br)cs1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=Cc1cc(Br)c([N+](=O)[O-])s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of KNO3 (3.38 g, 33.4 mmol) in 96% aqueous H2SO4 (30 ml) was added to a solution of 4-bromothiophene-2-carbaldehyde (5.8 g, 30.4 mmol) in 96% aqueous H2SO4 (60 ml) over 45 minutes, maintaining the temperature below 4° C. The resulting mixture was stirred at 0° C. for 2 hrs and then at RT overnight. The reaction was poured into ice (300 ml) and the resulting precipitate was filtered and washed with water and hexane to afford 4-bromo-5-nitrothiophene-2-carbaldehyde (Int. 65) (6.987 g, 29.6 mmol).
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(=O)C)(=O)C.[N+:31]([O-])([OH:33])=[O:32].Cl>C(O)(=O)C>[C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[C:22]([N+:31]([O-:33])=[O:32])[CH:23]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Reactant: O=[N+]([O-])O
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1[N+](=O)[O-]

Procedure:
5 g of 4-(2-benzenesulfonylaminoethyl)phenoxyacetic acid are added to 30 ml of acetic anhydride, and 3 ml of a mixture of conc. nitric acid and acetic acid (1:2) are added thereto under ice-cooling and stirring. After the mixture is reacted for 4 hours at room temperature, the mixture is poured into a mixture of diluted hydrochloric acid and ice, extracted with ethyl acetate, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform: ethanol=60:1) and recrystallized from a mixture of ethyl acetate and n-hexane. 3.70 g of 4-(2-benzenesulfonylaminoethyl)-2-nitrophenoxyacetic acid are obtained as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][CH2:10][OH:11]
Reactant: O=C(O)Cc1cc(F)ccc1Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a solution of (2-bromo-5-fluorophenyl)acetic acid (1.29 g, 5.54 mmol) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (210 mg, 5.54 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 3 h. After cooling to 0° C., the reaction mixture was quenched by the addition of 2N hydrochloric acid (30 mL), extracted with diethyl ether (200 mL). The organic layer was washed with water (50 mL) and brine (50 mL) dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluting with hexane/ethyl acetate (5/1) to afford 247 mg (20%) of the title compound as colorless oil:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH2:26][CH:27]([OH:32])[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(O)C(F)(F)F
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)NCC(O)C(F)(F)F)cn1
Yield: 76 %

Procedure:
As described for example 10b, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid (68 mg, 0.21 mmol) was converted, using 3-amino-1,1,1-trifluoro-2-propanol instead of 4-aminotetrahydropyran, to the title compound (69 mg, 76%) which was obtained as a white solid. MS: m/e=440.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[C:16][C:17]3[N:22]=[CH:21][C:20]([NH:23][C:31](=[O:33])[CH3:32])=[CH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-[4-(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)-1-butynyl]-3-pyridinamine (Example 13) (1.5 g, 0.005 mol), triethylamine (0.76 mL, 0.0054 mol) and N,N-dimethylaminopyridine (catalytic amount) in 50 mL of dichloromethane is cooled to 0° C. and acetyl chloride (0.42 mL, 0.006 mol) is added dropwise. The cold bath is removed and the solution is stirred at room temperature for 1 hour. The reaction is quenched with saturated aqueous sodium bicarbonate, the organic layer is washed with water and dried (sodium sulfate), and the solvent is removed under reduced pressure. The residue is chromatographed (silica gel, 2% methanol/98% dichloromethane) to give the title compound, containing 0.35 mol of water; mp 158.5°-159.5° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([OH:23])=[N:12][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:14][C:15]=1[Cl:16].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15]([Cl:16])=[N:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:21][CH2:22]2)=[N:12][C:11]=1[OH:23]
Reactant: Oc1nc(C2CCNCC2)nc(Cl)c1-c1nc2ccccc2s1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
Into a mixture of 5-(1,3-benzothiazol-2-yl)-6-chloro-2-(piperidin-4-yl)pyrimidin-4-ol (50 g, 144.16 mmol, 1.00 equiv) and triethylamine (36.5 g, 361.39 mmol, 2.51 equiv) in dichloromethane (300 ml) was added benzyl chloroformate (29.5 g, 172.93 mmol, 1.20 equiv) dropwise. The resulting solution was stirred overnight at room temperature. Upon concentrated under vacuum, the residue was purified by flash chromatography on a silica gel column eluting with petroleum ether/ethyl acetate (2:1) to give 3 g of benzyl 4-[5-(1,3-benzothiazol-2-yl)-4-chloro-6-hydroxypyrimidin-2-yl]piperidine-1-carboxylate as yellow solid. MS m/z [M+H]+ (ESI): 481.