Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=4)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])(=[O:38])=[O:37])[CH:27]=3)[CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:13]([C:45](O)=[O:46])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:56][O:57][Si](C)(C)C.CO>C(Cl)Cl.CN(C=O)C>[OH:57][NH:56][C:45]([CH:13]1[CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:16][CH2:15][N:14]1[S:17]([N:20]1[CH2:21][CH2:22][CH:23]([C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([F:35])[CH:33]=3)[N:28]([S:36]([CH2:39][CH2:40][Si:41]([CH3:43])([CH3:44])[CH3:42])(=[O:37])=[O:38])[CH:27]=2)[CH2:24][CH2:25]1)(=[O:18])=[O:19])=[O:46]
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)O)CC2)c2cc(F)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)NO)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 86.3 %

Procedure:
To a solution of 4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)indol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxylic acid (288 mg, 0.40 mmol), [prepared as described in Step 6 above] in methylene chloride (5 ml) at 0° C. were added a few drops of DMF and oxalyl chloride (89 ml, 1.0 mmol). The reaction mixture was warmed to RT over 1 h, and stirring was continued for an additional 14 h. The reaction mixture was concentrated in vacuo, redissolved in methylene chloride (5 ml) and cooled to 0° C. N,O-bis-trimethylsilyl hydroxylamine (0.304 ml, 1.42 mmol) added, the reaction was warmed to RT, stirred for 3 h, and then recooled to 0° C. After adding methanol (3 ml), the mixture was stirred for an additional 30 min., and then concentrated in vacuo. The residue was partitioned between methylene chloride (50 ml) and aqueous 2.4 M HCl (10 ml), the organic layer was separated and washed with saturated aqueous sodium bicarbonate, dried over MgSO4, and concentrated in vacuo to afford N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide as a yellow foam (250 mg, 86%). The residue was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl.[C:22](N)(=[NH:24])[CH3:23].CC1NC=CN=1>C(Cl)(Cl)Cl>[NH2:24][C:22](=[N:13][NH:12][C:10]1[CH2:9][N:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:11]=1)[CH3:23]
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: CC(=N)N
Agent: Cc1ncc[nH]1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(N)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2.8 parts of 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine, 2.8 parts of acetamidine hydrochloride, 2.5 parts of 2-methylimidazole and 100 parts by volume of chloroform is stirred at room temperature for 24 hours. The chloroform layer is washed with water, dried over sodium sulfate and the solvent is evaporated. After treating the residue with diethyl ether, the resulting crystals are subjected to extraction with hot methanol. Evaporation of the methanol gives 2-(α-aminoethylidene) hydrazino-7-chloro-5-phenyl-3H-1,4-benzodiazepine as crystals. Recrystallization from acetone yields pale yellow needles melting at 203° C to 205° C (effervescence).
Reaction SMILES: FC(F)(F)C([O-])=O.[CH3:8][C:9]1[N:10]=[C:11]([NH2:27])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1.[CH:28]1[N:32]=[CH:31][N:30]([C:33](N2C=NC=C2)=[O:34])[CH:29]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:8][C:9]1[N:10]=[C:11]([NH:27][C:33]([N:30]2[CH:29]=[CH:28][N:32]=[CH:31]2)=[O:34])[S:12][C:13]=1[C:14]1[N:15]=[C:16]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[S:17][CH:18]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1csc(C(=O)N2CCOCC2)n1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1csc(C(=O)N2CCOCC2)n1
Temperature: 40 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
Trifluoroacetate salt of 4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-amine, prepared in Step II, described above (142.4 mg; 0.34 mmol; 1 eq.) is suspended in dry DCM (5 ml). CDI (108.8 mg; 0.68 mmol; 2 eq.) and triethylamine (511; 0.37 mmol; 1.10 eq.) are added. Some DMF (0.30 ml) is added to improve the solubility of the starting material. The mixture is stirred overnight at 40° C. A precipitate is formed. It is filtrated, washed with diethyl ether, affording N-[4′-methyl-2-(morpholin-4-ylcarbonyl)-4,5′-bi-1,3-thiazol-2′-yl]-1H-imidazole-1-carboxamide (107.1 mg; 79%) which is used as such in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].Br[CH2:19][CH2:20][CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]([F:15])([F:17])[F:16]
Reactant: Fc1ccc(N2CCNCC2)cc1C(F)(F)F
Reactant: CCCBr
Product: CCCN1CCN(c2ccc(F)c(C(F)(F)F)c2)CC1

Procedure:
Beginning with 1-(4-fluoro-3-trifluoromethyl-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. m.p. 238° C. (HCl); MS m/z (rel. intensity, 70 eV) 290 (M+, 17), 261 (70), 190 (34), 70 (bp), 56 (44).
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[CH2:40]([S:48](Cl)(=[O:50])=[O:49])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][N:37]([S:48]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])(=[O:50])=[O:49])[CH2:36][CH2:35]1
Reactant: CCCCCCCCS(=O)(=O)Cl
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CCCCCCCCS(=O)(=O)N1CCN(c2cc(F)c(OC)cc2F)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (456 mg) and 1-octanesulfonyl chloride (470 μL), respectively, to provide crude 4-(2,5-difluoro-4-methoxyphenyl)-1-(octylsulfonyl)piperazine (681 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:34](Cl)(=O)[O:35]C1C=CC([N+]([O-])=O)=CC=1.[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>ClCCl>[CH:47]1([CH2:50][NH:51][C:34]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:27])[F:28])[C:29]([F:32])([F:31])[F:30])=[CH:22][CH:23]=4)[CH2:13][CH2:12]3)=[CH:4][CH:3]=2)=[O:35])[CH2:49][CH2:48]1
Reactant: NCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc2cnn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc2cnn(C3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-(4-((4-(6-Amino-1H-indazol-1-yl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.212 mmol, 0.1 g) and 4-nitrophenyl carbonochloridate (0.212 mmol, 0.043 g) were combined and stirred in dichloromethane (2 mL) for 1 hour. Cyclopropylmethanamine (0.423 mmol, 0.037 mL, 0.030 g) was added and the reaction stirred at room temperature for 2 hours. The organic was washed with water and dried over sodium sulfate. The solvent was removed and the resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 6% methanol/dichloromethane) to afford the title compound (93 mg). MS (ESI) m/z 570.0 [M+H]+
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(C(F)(F)F)cc2)CC1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][OH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CC=CC=1.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[CH2:25]([O:24][C:22]([O:14][CH2:13][C@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[C:3]([O:2][CH3:1])=[O:15])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](COC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
A solution of N-(tert-butoxycarbonyl)-L-serine methyl ester (25.0 g, 114 mmol) in DCM (570 mL) was cooled to −50° C. Pyridine (23.0 mL, 285 mmol) was added. CBZ-Cl (18.9 mL, 125 mmol) was added dropwise over 1 hour. The reaction mixture was warmed to ambient temperature and stirred overnight. The reaction mixture was then diluted with DCM, washed with 10% citric acid and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexanes/EtOAc) to give (S)-methyl 3-(benzyloxycarbonyloxy)-2-(tert-butoxycarbonylamino)propanoate (36.0 g, 89%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22][CH3:23])=[O:21].N1C=CC=CC=1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:14][C:15]3[CH:19]=[CH:18][S:17][C:16]=3[C:20]([O:22][CH3:23])=[O:21])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCC2
Reactant: COC(=O)c1sccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
To a solution of 2,3-dihydro-1H-indene-5-sulfonyl chloride (0.5 g; 2.3 mmol) in dichloromethane (5 mL) at room temperature, methyl 3-aminothiophene-2-carboxylate (0.3 g; 1.9 mmol) was added followed by pyridine (0.32 g; 4.0 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and extracted with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude residue was recrystallized from acetonitrile to yield the title product as a white solid (0.3 g).
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]([C:9]([OH:11])=[O:10])=[CH:7][N:8]=1)[CH2:2][CH3:3].[CH:12]([NH:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]>CC(C)=O>[CH2:1]([C:4]1[S:5][C:6]([C:9]([O-:11])=[O:10])=[CH:7][N:8]=1)[CH2:2][CH3:3].[CH:12]([NH2+:15][CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13]
Reactant: CCCc1ncc(C(=O)O)s1
Reactant: CC(C)NC(C)C
Solvent: CC(C)=O
Product: CC(C)[NH2+]C(C)C
Product: CCCc1ncc(C(=O)[O-])s1
Yield: 90 %

Procedure:
4.45 Grams of 2-propyl-5-thiazolecarboxylic acid (obtained in Example II) are dissolved in 120 cc of acetone and 2.62 gm of diisopropylamine are added. The solvent is evaporated off under low pressure and the crystals thus obtained are recrystallized from isopropyl ether. The diisopropylammonium 2-propyl-5-thiazolecarboxylate is obtained in the form of colorless crystals, soluble in water and in alcohol, melting at 120° C. (Yield: 90%).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:26])[C:14]([CH3:25])([S:16]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH3:15])[O:9][N:8]=1)([CH3:6])[C:3](O)=[O:4].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(=O)(O)[O-].[NH4+].[N:47]1C=CC=CC=1>C(OCC)(=O)C.O1CCOCC1.CN(C=O)C>[CH3:15][C:14]([S:16]([CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18])([CH3:25])[C:13]([NH:12][C:10]1[O:9][N:8]=[C:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:47])=[O:4])[CH:11]=1)=[O:26]
Reactant: CC(C)(C(=O)O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Reactant: c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cc(NC(=O)C(C)(C)S(=O)(=O)C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.6 %

Procedure:
To a solution of 2-methyl-2-{5-[2-methyl-2-(tetrahydro-pyran-4-sulfonyl)-propionylamino]-isoxazol-3-yl}-propionic acid (35 mg, 0.09 mmol), di-tert-butyl dicarbonate (26 mg, 0.12 mmol), and ammonium bicarbonate (14 mg, 0.18 mmol) in the mixture of DMF (0.035 mL) and 1,4-dioxane (0.5 mL) is added pyridine (0.022 mL, 0.27 mmol). The reaction mixture is stirred at room temperature for 1.5 h. After this time, the reaction mixture is diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by preparative HPLC provides 3.0 mg of the title compound. Yield: 9%; m/z 388 [M+H].
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1.[OH-].[NH4+:26].N>C(#N)C.CS(C)=O>[C:3]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[N:18][C:17]=23)=[O:12])=[C:6]([O:22][CH3:23])[CH:5]=1)(=[O:2])[NH2:26]
Reactant: COC(=O)c1ccc(NC(=O)c2cnn3cccnc23)c(OC)c1
Reactant: [NH4+]
Agent: N
Agent: [OH-]
Solvent: CC#N
Solvent: CS(C)=O
Product: COc1cc(C(N)=O)ccc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Yield: 35 %

Procedure:
A mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and an aqueous solution of ammonium hydroxide (concentrated, 1 mL) and a mixture of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (5 mg) and a solution of ammonia (2 M in MeOH, 1 mL) were stirred at room temperature for 2 days. The two mixtures were then combined and dimethyl sulfoxide (1 mL) was added followed by acetonitrile (1 mL). A solution of ammonia (2 M in MeOH, 1 mL) and an aqueous solution of ammonium hydroxide (concentrated, 2 mL) were then added and the resulting mixture was heated to 50° C. for 24 hours. A second portion of 3-methoxy-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-amino]-benzoic acid methyl ester (35 mg) was added followed by dimethyl sulfoxide (5 mL), acetonitrile (5 mL), a solution of ammonia (2 M in MeOH, 5 mL) and an aqueous solution of ammonium hydroxide (concentrated, 5 mL) and the resulting mixture was heated to 85° C. for 3 days. The white precipitate which formed was collected by filtration, washed with water, methanol and diethyl ether to afford after drying 15 mg (35% yield) of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (4-carbamoyl-2-methoxy-phenyl)-amide as light yellow solid. MS=312 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([OH:22])[C:19]([I:21])=[CH:20][C:15]=4[CH2:14][CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:24][O:25]CCl.O1CCC[CH2:29]1>>[O:1]1[C:5]2[C:6]([CH:10]3[C:16]4[CH:17]=[C:18]([O:22][CH3:29])[C:19]([I:21])=[CH:20][C:15]=4[CH:14]([O:25][CH3:24])[CH2:13][N:12]([CH3:23])[CH2:11]3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CN1CCc2cc(I)c(O)cc2C(c2cccc3c2OCC3)C1
Reactant: C1CCOC1
Reactant: COCCl
Product: COc1cc2c(cc1I)C(OC)CN(C)CC2c1cccc2c1OCC2
Reaction time: 3.5 h

Procedure:
(+)-5-(2,3-dihydrobenzofuran-7-yl)-8-iodo-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (126.0 mg, 3.0 mmol) and potassiumm-tert-butylate 37.0 mg, 3.3 mmol) are dissolved in dry tetrahydrofuran (10 ml) at 20° C. Chloromethyl methyl ether (30.0 mg, 3.8 mmol) is added. The reaction mixture is stirred for 3.5 hours then poured into 5% sodiumhydrogencarbonate (20 ml). The product is extracted into dichloromethane (2×15 ml). The organic phase is evaporated to dryness under reduced pressure.
Reaction SMILES: [CH3:1][C@:2]1([C:12]([OH:14])=[O:13])[CH2:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[C:3]1([CH3:11])[CH3:10].S(Cl)(Cl)=O.O.[OH-].[Na+].[CH3:22]O>>[CH3:22][O:8][C:7]([C@@H:4]1[CH2:5][CH2:6][C@:2]([CH3:1])([C:12]([OH:14])=[O:13])[C:3]1([CH3:10])[CH3:11])=[O:9]
Reactant: CC1(C)[C@H](C(=O)O)CC[C@]1(C)C(=O)O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)[C@@H]1CC[C@](C)(C(=O)O)C1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (1S,3R)-1,2,2-trimethylcyclopentane-1,3-dicarboxylic acid (5.1 g, 25.5 mmol) in methanol (63.7 ml) at −78° C. was added thionyl chloride (2.045 ml, 28.0 mmol). After stirring at −78° C. for 30 minutes, the reaction was allowed to warm to room temperature. Stirring was continued for 14 hrs. The reaction mixture was concentrated under reduced pressure, yielding a yellow oil. The oil was taken into water. The solution was adjusted to pH 12 with 1.0 N NaOH and was washed with ethyl acetate. The basic aqueous layer was acidified with 1.0 N HCl, and was extracted with ethyl acetate (3×, 100 ml). The ethyl acetate extracts were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to afford (1S,3R)-3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (5.35 g, 24.97 mmol, 98% yield) as a colorless oil. ESI-MS m/z 237.1 ([M+H]+).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([OH:19])=[C:10]([S:15]([Cl:18])(=[O:17])=[O:16])[CH:11]=[C:12]([Cl:14])[CH:13]=1.[C:20](Cl)(=[O:22])[CH3:21].S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:20]([O:19][C:9]1[C:8]([Cl:7])=[CH:13][C:12]([Cl:14])=[CH:11][C:10]=1[S:15]([Cl:18])(=[O:17])=[O:16])(=[O:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)Oc1c(Cl)cc(Cl)cc1S(=O)(=O)Cl

Procedure:
A pyridine solution (1.1 g of pyridine in 10 ml of methylene chloride) was added dropwise over 30 minutes to a solution of 3.37 g of 3,5-dichloro-2-hydroxybenzenesulfonyl chloride, 25 ml of methylene chloride and 1.1 g of acetyl chloride. After two hours of stirring at room temperature the starting sulfonyl chloride was no longer present and one major product had formed. The reaction was concentrated and used immediately.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:17]1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1>C(#N)C>[NH2:30][C:31]1[C:32]([C:38]([NH:1][C:2]2[CH:7]=[C:6]([C:8](=[O:15])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:5]=[CH:4][C:3]=2[N:16]2[CH2:21][CH2:20][CH2:19][CH:18]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:17]2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][N:36]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2N)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(C(=O)c3ccccc3)cc2NC(=O)c2nc(Br)cnc2N)C1
Yield: 30 %

Procedure:
Following method 11, tert-butyl 1-(2-amino-4-benzoylphenyl)piperidin-3-ylcarbamate was coupled to 3-amino-6-bromopyrazine-2-carboxylic acid with TEA (1.5 eq) in ACN at 55° C. for 48 hours. Concentrated, triturated in cold ACN, filtered, and dried in vacuo yielding tert-butyl 1-(2-(3-amino-6-bromopyrazine-2-carboxamido)-4-benzoylphenyl)piperidin-3-ylcarbamate (30%). LCMS (m/z): 595.1 (MH+); LC Rt=3.87 min.
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.CS(N)(=O)=O.[F:54][CH:55]1[CH2:58][N:57]([S:59]([NH2:62])(=[O:61])=[O:60])[CH2:56]1>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:47])([F:48])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:62][S:59]([N:57]2[CH2:58][CH:55]([F:54])[CH2:56]2)(=[O:61])=[O:60])=[O:35])[CH2:28][CH2:27]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Reactant: NS(=O)(=O)N1CC(F)C1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CC(F)C1)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.12 g, 43%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.77-8.64 (m, 1H), 7.64-7.55 (m, 1H), 6.62-6.53 (m, 1H), 5.43-5.13 (m, 1H), 4.57-4.31 (m, 4H), 3.94-3.86 (m, 2H), 2.27-2.11 (m, 2H), 2.09-1.68 (m, 6H), 1.61-1.43 (m, 2H), 0.99-0.90 (m, 2H), 0.71-0.63 (m, 2H); MS (ES+) m/z 465.0 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:5][CH2:4][CH2:3]1.Cl/[C:7](=[N:13]\[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:11]([O:10][C:8]([C:7]1[CH2:1][C:2]2([CH2:5][CH2:4][CH2:3]2)[O:14][N:13]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)/C(Cl)=N/O
Reactant: C=C1CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=NOC2(CCC2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of methylenecyclobutane (2 mL, 21.6 mmol) in ethyl acetate (125 mL) was added (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (6.55 g, 43.2 mmol) and solid sodium bicarbonate (16.3 g, 194 mmol). The reaction mixture was sealed and stirred at room temperature for 6 hours. More (Z)-ethyl 2-chloro-2-(hydroxyimino)acetate (4 g, 26.4 mmol) and sodium bicarbonate (8 g, 95.2 mmol) were added and the reaction was stirred at room temperature for an additional 12 hours. The reaction was diluted with ethyl acetate and washed successively with water and brine, dried (MgSO4) and concentrated to yield crude 5-oxa-6-aza-spiro[3.4]oct-6-ene-7-carboxylic acid ethyl ester, contaminated with (Z)-Ethyl 2-chloro-2-(hydroxyimino)acetate and related compounds.