Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]2.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24]O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(Cl)[Cl:60]>>[ClH:60].[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[CH2:7][C@H:6]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:5]3)=[CH:20][CH:19]=1
Reactant: OCc1ccncc1
Reactant: ClCCl
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(OCc3ccncc3)cc2C1
Product: Cl
Temperature: 25 °C

Procedure:
A mixture of N-[(2S)-5-hydroxy-2,3-dihydro-1H-inden-2-yl]-2-propanesulfonamide (100 mg, 0.392 mmol, Description 3) and 4-pyridinylmethanol (42.7 mg, 0.392 mmol) in DCM (10 ml) were stirred under argon at room temperature. Triphenylphosphine (103 mg, 0.392 mmol) and diisopropyl azodicarboxylate (0.076 ml, 0.392 mmol) were then successively added. The resulting mixture was stirred at room temperature under argon for 16 hours. The reaction mixture was washed with water, dried over sodium sulphate, filtered and evaporated. The desired product was isolated by MDAP and concentrated to a small volume. The residual material was partitioned between dichloromethane and aqueous sodium bicarbonate solution, then the organic layer was separated and evaporated. The free base was dissolved in methanol and treated with ethereal hydrochloride to give the title compound as a hydrochloride salt (84 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=2)[NH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][N:25]2[S:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2](=[O:1])[C:10]3=[O:11])(=[O:14])=[O:13])[CH2:21][CH2:22]1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: CN1CCN(C[C@@H]2CCCN2)CC1
Product: CN1CCN(C[C@@H]2CCCN2S(=O)(=O)c2ccc3c(c2)C(=O)C(=O)N3)CC1

Procedure:
The title compound was prepared from 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonylchloride and 1-methyl-4-[(2S)-pyrrolidin-2-ylmethyl]piperazine according to a procedure similar to that of step 1 of Example 12. NMR (400 Mz, DMSO-d6): consistent.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:10])=[N:4][C:5]([NH2:9])=[N:6][C:7]=1Cl.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C([OH:19])C>>[F:1][C:2]1[C:3]([NH2:10])=[N+:4]([O-:19])[C:5]([NH2:9])=[N:6][C:7]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Nc1nc(N)c(F)c(Cl)n1
Reactant: CCO
Reactant: C1CCNCC1
Product: Nc1nc(N2CCCCC2)c(F)c(N)[n+]1[O-]

Procedure:
5-Fluoro-6-chloro-2,4-pyrimidinediamine, 3-oxide (6) (58 mg, 0.32 mmol), piperidine (112 mg, 1.3 mmol) and 95% ethanol (2.6 ml) were charged to a round bottom flask and refluxed for 2 days. The solution was concentrated and the residue was chromatographed on silica gel (elution with 15% methanol/chloroform+2% ammonium hydroxide), yielding 5fluoro-6-piperidinyl-2,4-pyrimidinediamine 3-oxide as a white solid. (51 mg, 69%): MS (70 eV, EI)m/z (relative intensity) 84 (100), 227 (M+, 98), 210 (55), 43 (30), 40 (24); 1H NMR (CD3OD)δ4.91 (s, 4H), 3.61 (mult., 4H), 1.67 (mult., 2H), 1.60 (mult., 4H); 13C NMR (CD3OD) ppm 150, 147.5, 147, 123, 49.86, 27.05, 25.82. Exact Mass Calcd for C9H4N5OF: 227.1182. Found: 227.1188. ##STR2##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].[CH3:41][S:42]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)(=[O:44])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:48]2[CH:49]=[CH:50][C:45]([S:42]([CH3:41])(=[O:44])=[O:43])=[CH:46][CH:47]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(S(C)(=O)=O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
Bring a mixture of trifluoro-methanesulfonic acid 3,5-dichloro-4-[(R)-2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-phenyl ester (0.14 g, 0.22 mmol), 4-methylsulfonylphenylboronic acid (0.06 g, 0.28 mmol), sodium carbonate (0.07 g, 0.67 mmol) in THF (26 mL) and water (13 mL) to 60° C. To the mixture at 60° C., add Pd(PPh3)4 (0.02 g, 0.01 mmol). Raise the reaction temperature to 80° C. and stir for 1 hour. Cool the reaction, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 25% to 50% ethyl acetate in hexanes gradient to afford 0.12 g of (R)-3-(3,5-Dichloro-4′-methanesulfonyl-biphenyl-4-ylmethyl)-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20]C(=O)C)[CH2:13][CH2:12]2)[CH:8]=[C:7]([CH:24]2[CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][OH:20])[CH2:15][CH2:16]2)[CH:8]=[C:7]([CH:24]2[CH2:26][CH2:25]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OCCCN1CCN(c2cc(C3CC3)nc(C(C)(C)C)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(C2CC2)cc(N2CCN(CCCO)CC2)n1
Yield: 30.8 %

Procedure:
3.7 g of acetic acid 3-[4-(2-tert-butyl-6-cyclopropyl-pyrimidin-4-yl)-piperazin-1-yl]-propyl ester (10.2 mmol) and 0.4 g of lithium hydroxide (16.7 mmol) were stirred overnight in 20 ml of tetrahydrofuran and 20 ml of water. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent was evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (0-8%) as eluent to yield 1.0 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.[O:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.[C:25](OC(C)(C)C)(=[O:30])[CH2:26][C:27]([O-])=[O:28].C(=O)(OC)OC(C)(C)C[N+]#[C-].CC(C)([O-])C.[Na+]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:21]([C:20]4[CH:23]=[CH:24][C:17]([CH:14]5[CH2:15][CH2:16][O:11][CH2:12][CH2:13]5)=[CH:18][CH:19]=4)[C:27](=[O:28])[CH2:26][C:25]3=[O:30])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Reactant: Nc1ccc2[nH]cnc2c1
Reactant: O=Cc1ccc(C2CCOCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [C-]#[N+]CC(C)(C)OC(=O)OC
Agent: [Na+]
Product: O=C1CC(=O)N(c2ccc3[nH]cnc3c2)C1c1ccc(C2CCOCC2)cc1

Procedure:
The compound was synthesized starting from 1H-benzo[d]imidazol-5-amine (1.04 g, 7.89 mmol), 4-(tetrahydro-2H-pyran-4-yl)benzaldehyde (1.0 g, 5.26 mmol), mono-tert-butyl malonate (0.84 g, 5.26 mmol), 1-isocyano-2-methylpropan-2-yl methyl carbonate (0.83 g, 5.26 mmol) and sodium tert.-butoxide (0.829 g, 7.39 mmol) according to method 5.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH3:17])=[N:5][C:6](S(C)(=O)=O)=[N:7][C:8]=1[CH2:9][CH3:10])#[N:2].[NH3:41]>O1CCOCC1.CCOC(C)=O>[NH2:41][C:6]1[N:5]=[C:4]([NH:15][C@H:16]([C:18]2[N:23]=[C:22]3[CH:24]=[CH:25][N:26]([CH3:27])[C:21]3=[CH:20][C:19]=2[N:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:30][CH2:29]2)[CH3:17])[C:3]([C:1]#[N:2])=[C:8]([CH2:9][CH3:10])[N:7]=1
Reactant: CCc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Reactant: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a 10 mL vial were added tert-butyl (S)-4-(5-(1-((5-cyano-6-ethyl-2-(methylsulfonyl)pyrimidin-4-yl)amino)ethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (32 mg, 0.056 mmol) in dioxane (2 mL) along with 0.5 M ammonia in dioxane (6.09 μL, 0.281 mmol) to give a yellow solution. The vial was sealed and the reaction mixture was stirred overnight at 75° C. The next day LCMS indicated the reaction was incomplete. Additional NH3 solution (2 eq) was added and the reaction mixture was allowed to stir for 6 hours at 75° C. LCMS showed the reaction was mostly complete. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography (ISCO 4 g, 50-100% EtOAc/hexane gradient) to give the title compound as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:4].[NH:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40].CCN(C(C)C)C(C)C>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[CH2:8][CH2:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=[O:40])([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=Cc1ncc[nH]1
Reactant: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)Cn1ccnc1C=O
Yield: 62.5 %

Procedure:
A solution of di-tert-butyl 4-(2-bromoacetamido)-4-(3-(tert-butoxy)-3-oxopropyl)heptanedioate (1.397 g, 2.61 mmol), 1H-imidazole-2-carbaldehyde (0.30 g, 3.13 mmol), DIPEA (2.0 mL), and KI (0.30 g) in DMF (5.0 mL) was stirred at 80° C. for 5 hrs. The solvent was evaporated under reduced pressure to afford a residue, which was purified by biotage eluting with 20% EtOAc in hexanes to 100% EtOAc to give di-tert-butyl 4-(3-(tert-butoxy)-3-oxopropyl)-4-(2-(2-formyl-1H-imidazol-1-yl)acetamido)heptanedioate (0.90 g, 63%). 1H NMR (400 MHz, CDCl3) 9.78 (s, 1H), 7.32 (s, 1H), 7.23 (s, 1H), 6.65 (s, 1H), 4.90 (s, 2H) 2.19 (t, J=7.8 Hz, 6H), 1.94 (t, J=7.8 Hz, 6H), 1.42 (s, 9H); MS (ESI), 552 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3([F:19])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[C:9]([F:20])[CH:8]=2)[CH2:5][C@H:4]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:3]1.Cl.CN(C)CCCN=C=NCC.[CH:38](O)=[O:39]>O1CCCC1.O.C(Cl)Cl>[CH:38]([N:16]1[CH2:17][CH2:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([N:6]3[CH2:5][C@H:4]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])[O:3][C:2]3=[O:1])=[CH:8][C:9]=2[F:20])([F:19])[CH2:14][CH2:15]1)=[O:39]
Reactant: O=CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3(F)CCNCC3)c(F)c2)C(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(F)CCN(C=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (S)-3-N-[[2-oxo-3-[4-(4-fluoro-4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 74, Step 5, 205 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (145 mg) and formic acid (28 μL) in dry tetrahydrofuran (11.6 mL) is diluted with water to solubilize all reactants and stirred at ambient temperature for 6 hrs. The reaction is then diluted with methylene chloride (30 mL), washed with water (20 mL) and saline (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is chromatographed on silica gel (230-400 mesh, 40 g), eluting with a gradient of methanol/methylene chloride (3/97-5/95). Those fractions with an Rf=0.40 by TLC (methanol/chloroform, 10/90) are pooled and concentrated and the residue is recrystallized from chloroform/diethyl ether to give the title compound, mp 180-181° C. (decomp.).
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([CH2:14][NH2:15])[CH2:6]1)=O.CC(C)([O-])C.[Na+]>CO>[O:2]=[C:3]1[NH:15][CH2:14][CH:7]2[CH2:6][CH:5]1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12
Reactant: COC(=O)C1CC(CN)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1NCC2CC1c1ccccc12
Temperature: 25 °C

Procedure:
To a solution of 3-aminomethyl-indan-1-carboxylic acid methyl ester (assume 20.0 mmol, 1 equivalent) in 50 mL of methanol (this was the crude reaction mixture from the prior step, Example 60C) was added 3.84 g of sodium tert-butoxide (40.0 mmol, 2.0 equivalent). The reaction mixture was heated to a reflux for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between 60 mL of ethyl acetate and 40 mL of 5% aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice more with 50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to provide a solid material. Recrystallization of the solid from 10 mL of toluene provided white crystals of the title compound (1.78 g, 51%). mp=172-173° C.; 1H NMR (400 MHz, CDCl3): δ 7.33 (d, J=7.6 Hz, 1H), 7.31(d, J=7.6 Hz, 1H), 7.22 (t, J=7.6 Hz, 1H), 7.18 (t, J=7.6 Hz, 1H), 5.62 (s, 1H), 3.68 (dd, J=11.2, 4.1 Hz, 1H), 3.55 (d, J=3.7 Hz, 1H), 3.43-3.37 (m, 1H), 3.18 (d, J=11.2 Hz, 1H), 2.52-2.45 (m, 1H), 2.32 (d, J=11.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 173.6, 144.7, 144.6, 128.0, 127.7, 123.2, 122.9, 49.3, 47.9, 39.1, 38.4; IR (neat, cm−1): 3218, 2949, 2872, 1666, 1485, 1459, 1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104, 1045, 1004, 946, 910, 756, 730, 643, 613; Anal. Calcd for C11H121NO: C, 76.28; H, 6.40; N, 8.09; Found: C, 75.94; H, 6.27; N, 7.99.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].ClCCl.[C:8]([O:12][C:13]([NH:15][CH2:16][C:17]1[S:18][C:19]([CH2:22]O)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:1]([O:4][CH2:22][C:19]1[S:18][C:17]([CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[N:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ncc(CO)s1
Reactant: CC(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1cnc(CNC(=O)OC(C)(C)C)s1
Reaction time: 17 h

Procedure:
A 6 ml portion of anhydrous acetic acid was added to a mixed solution of 10 ml of dichloromethane and 20 ml of pyridine containing 2.17 g of 2-(N-t-butoxycarbonylamino)methyl-5-hydroxymethylthiazole, and the mixture was then allowed to stand at room temperature for 17 hours. Under reduced pressure, the solvent was distilled off, and the resulting residue was dissolved in 120 ml of chloroform. The solution was washed once with water and twice with a 10% saline solution, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 2.47 g of 5-acetoxymethyl-2-(N-t-butoxycarbonylamino)methylthiazole.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.NC1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]([C:45]1[S:49][N:48]=[C:47]([CH3:50])[N:46]=1)[C:42](O)=[O:43])[CH3:33].C(N(CC)CC)C>ClCCl>[CH2:32]([O:34][C:35](=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH:41]([C:45]1[S:49][N:48]=[C:47]([CH3:50])[N:46]=1)[C:42](=[O:43])[NH:8][C:12]1[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:33]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)CCCCCC(C(=O)O)c1nc(C)ns1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCC(C(=O)Nc1ccccc1)c1nc(C)ns1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a stirred mixture of O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.56 g, 1.48 mmol) and aniline (0.13 g, 1.35 mmol) in dichloromethane (10 mL) was added over 5 min the solution of crude 2-(3-methyl[1,2,4]thiadiazol-5-yl)octanedioic acid 8-ethyl ester (2021039) and triethylamine in dichloromethane. The resultant reaction mixture was then stirred at room temperature overnight before being quenched with citric acid (5 g) in water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1 hexane/ethyl acetate followed by 1:1 hexane/ethyl acetate) to afford 7-(3-methyl[1,2,4]thiadiazol-5-yl)-7-phenylcarbamoyl heptanoic acid ethyl ester (2021040) (310 mg, 52% over two steps) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:21]=1[S:27]([NH:1][C:2]1[C:3]([F:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: COC(=O)c1cccc(N)c1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2c(F)cccc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
In a 500 mL flask was placed methyl 3-amino-2-fluorobenzoate (5.5 g, 32.5 mmol) and DCM (100 mL), and pyridine (2.9 mL, 35.8 mmol) was added. 2,6-Difluorobenzenesulfonyl chloride (7.6 g, 35.8 mmol) in DCM (50 mL) was added dropwise via addition funnel and the reaction mixture was allowed to stir at rt overnight. The reaction mixture was stripped onto silica and column chromatographed on silica with 5% to 100% EtOAc:Hexane to give 9.75 g (87%) of the title compound of Step C. 1H-NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.64-7.82 (m, 3H), 7.46-7.61 (m, 1H), 7.29 (t, J=8.8 Hz, 2H), and 3.81 (s, 3H). MS (ESI): 346 [M+H]+.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([F:11])[C:5]=1[C:4]1[N:28]=[C:27]([C:26]2[CH:29]=[CH:30][C:31]([N+:33]([O-:35])=[O:34])=[CH:32][C:25]=2[Cl:24])[N:2]([CH3:1])[N:3]=1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc([N+](=O)[O-])cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 118.3 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (1.90 g), 2-chloro-4-nitrobenzonitrile (1.80 g), anhydrous iron (III) chloride (1.60 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (100 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 2.20 g of desired compound (melting point: 144.0°-148.0° C.).
Reaction SMILES: Cl[CH:2]([CH3:8])[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[C:9]1([C:15]2[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][NH:17][N:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:23]C1C(C2C=CC=CC=2)=NNC=1>>[CH2:8]([CH:2]([N:17]1[CH:18]=[C:19]([CH:20]([CH3:22])[CH3:21])[C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:16]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:23]
Reactant: CC(Cl)C(=O)N(C)C
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: CC(C)c1c[nH]nc1-c1ccccc1
Product: CCC(C(=O)N(C)C)n1cc(C(C)C)c(-c2ccccc2)n1

Procedure:
Using the procedure of Example 1, but substituting 2-bromo-N,N-dimethylbutyramide for 2-chloro-N,N-dimethylpropionamide and 3-phenyl-4-isopropylpyrazole for 4-methyl-3-phenylpyrazole, there was obtained α-ethyl-N,N-dimethyl-3-phenyl-4-isopropylpyrazole-1-acetamide, m.p. 89°-90° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(OC([N:25]=[C:26]=S)=O)C.Cl.NO.CC[N:33](C(C)C)C(C)C>O1CCOCC1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([N:33]=[C:26]([NH2:25])[N:8]=2)[CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)N=C=S
Agent: Cl
Agent: NO
Solvent: C1COCCO1
Product: Cc1c(Br)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
5-Bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 12.0 g, 36.25 mmol) was stirred in dioxane (250 mL) at RT and ethoxycarbonyl isothiocyanate (4.27 mL, 36.25 mmol) was added dropwise. The reaction mixture was stirred for 18 hrs, then the solvent was evaporated in vacuo. The resultant residue was dissolved in MeOH/IMS (1:1, 460 mL) and hydroxylamine hydrochloride (12.58 g, 181 mmol) was added and the reaction mixture was heated to 60° C. DIPEA (18.6 mL, 109 mmol) was added, and the reaction mixture was heated for a further 4.5 rs before allowing to cool. The resultant precipitate was collected by filtration, washed with MeOH and dried to afford the title compound as a white solid (11.49 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].[CH3:16][N:17]=[C:18]=[S:19].CN(C)C=O.CC(C)([O-])C.[K+]>C(O)(=O)C>[CH3:16][NH:17][C:18]([C:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[C:9]=1[OH:14])=[S:19]
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Reactant: CN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C(C)(C)Oc2ccc(C#N)cc21
Temperature: 0 °C
Yield: 68.5 %

Procedure:
To a mixture of 1.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.6 g of methyl isothio-cyanate, and 15 ml of dried N,N-dimethylformamide was added 0.93 g of potassium t-butoxide with stirring under ice-cooling, followed by stirring for 4 hours under ice-cooling. Ice-water was added to the reaction mixture, and the mixture was made acidic with acetic acid and then extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. The ether layer was removed by distillation, and the residue was recrystallized from ethanol to yield 1.4 g of N-methyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbothioamide represented by formula shown below.