Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][NH2:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:40]4[CH2:39][C@H:35]5[CH2:36][CH2:37][CH2:38][N:34]5[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: NC[C@H]1CCCN1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Yield: 91.8 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (60 mg, 0.13 mmol) and [(2R)-2-pyrrolidinylmethyl]amine (100 mg, 1.0 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (60 mg, 91%). This material was hydrogenated in a second step as described in example Z-2 to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (21 mg, 42%) as a white solid. 1H NMR (CDCl3) δ 11.72 (m, 1H), 1.37 (m, 1H), 8.33 (s, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 4.57 (m, 2H), 4.52 (m, 1H), 4.24-4.19 (m, 2H), 3.87-8.76 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (m, 1H), 2.11-1.89 (m, 3H), 1.68 (m, 1H); ES+ MS: 413 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]([NH2:11])=[O:10])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:2]1[C:3]([C:9]([NH2:11])=[O:10])=[C:4]2[CH2:8][CH2:7][CH2:6][C:5]2=[N:1]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: NC(=O)c1n[nH]c2c1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1c2c(nn1Cc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.1 %

Procedure:
To a stirring solution of 1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (2.57 g, 17.0 mmol) in DMF (34 mL) at 25° C. was added K2CO3 (5.87 g, 42.5 mmol) followed by benzyl bromide (4.36 g g, 25.5 mmol). The reaction was stirred at ambient temperature for 16 h at which time the mixture was diluted with EtOAc (75 mL) and filtered. The filtrate was washed with H2O (100 mL) and the aqueous phase was back-extracted with EtOAc (75 mL) and CH2Cl2 (75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (50% EtOAc in hexanes gradient to 95% EtOAc in hexanes) gave 2-benzyl-2,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (739 mg, 3.07 mmol, 18% yield) isolated as a white solid followed by 1-benzyl-1,4,5,6-tetrahydro-cyclopentapyrazole-3-carboxylic acid amide (3.24 g, 13.4 mmol, 79% yield) isolated as a white solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C@@H:7]([CH2:10][CH:11]=[CH:12][CH3:13])[C@H:6]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][C:15]=3[O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:5]2)[O:3]C1.Cl>O1CCOCC1>[CH2:30]([O:29][C:15]1[CH:16]=[C:17]([C:20]([CH3:27])([CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:18]=[CH:19][C:14]=1[C@H:6]1[C@H:7]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:8][CH2:9][C:4](=[O:3])[CH2:5]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC=CC[C@@H]1CCC2(C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Product: CC=CC[C@@H]1CCC(=O)C[C@H]1c1ccc(C(C)(C)CCCCCC)cc1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of trans-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(2-butenyl)cyclohexanone ethylene ketal (700 mg, 1.38 mmole), dioxane (20 ml) and 2 N hydrochloric acid (20 ml) was heated at reflux for 1.5 hours. The reaction mixture was cooled, poured into ice water (500 ml) and extracted with ether (300 ml). The ether extract was washed with two 200 ml portions of saturated sodium bicarbonate, dried over magnesium sulfate and evaporated to give a quantitative yield of the title compound as an oil.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:14][C:13]=2[CH:37]=1)=[O:8].[BH4-].[Na+]>C1COCC1>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([CH2:18][CH3:19])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:14][C:13]=2[CH:37]=1)=[O:8]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)Nc3nn[nH]n3)ccc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2cc(C(=O)Nc3nn[nH]n3)ccc2o1
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
A solution of 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-5-carboxylic acid (2H-tetrazol-5-yl)-amide (90 mg, 0.179 mmol) in THF (5.0 mL) at RT is treated with NaBH4 (20 mg, 0.537 mmol). The resulting mixture is stirred for 30 min. The reaction is quenched with water (1.0 mL) and extracted with EtOAc (2×20 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (35 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:34]([C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH2:46])=[O:45])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[N:18]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH2:46])=[O:45])=[CH:41][CH:42]=3)(=[O:36])=[O:35])[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: NC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(NC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[[[3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) dissolved in 30 ml of dichloromethane and 0.4 ml of triethylamine was added to 128 mg of N-[4-(chlorosulfonyl)phenyl]urea. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and 0.1N sodium bicarbonate solution.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N+:30]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.[Pd]>[Si:1]([O:8][C@H:9]1[C@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@@H:13]([CH3:23])[CH2:12][N:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 14 h

Procedure:
To a solution of 4-((3R,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylpiperidin-1-yl)-3-nitropyridine (1.0 equiv.) in ethanol, at a concentration of 0.05 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 14 hours. At this time the mixture was filtered through a pad of celite eluting with ethanol. The volatiles were removed in vacuo yielding 4-((3R,4R,5S)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylpiperidin-1-yl)pyridin-3-amine. LC/MS=452.4 (M+H), Rt=1.31 min.
Reaction SMILES: FC1C=CC2C(C3CCN([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[C:18]4=[O:25])CC3)=NOC=2C=1.[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1>>[F:28][C:29]1[CH:43]=[CH:42][C:32]2[C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[C:18]4=[O:25])[CH2:38][CH2:37]3)=[N:34][O:35][C:31]=2[CH:30]=1
Reactant: Fc1ccc2c(N3CCNCC3)noc2c1
Reactant: CC(C)N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O
Product: CC(C)N1CCN(CCN2CCN(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is prepared in the same manner as the compound of Example 1 but using 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperazine instead of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine in Step 1. The title compound so obtained melts at 125°-127° C.
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9][CH3:10])=[CH:7][CH:6]([O:11][CH3:12])[O:5]1)[CH3:3].C(O)=O.O>CO>[CH3:10][O:9][C:8]1[C:4](=[O:13])[CH:2]([CH3:3])[O:5][CH:6]([O:11][CH3:12])[CH:7]=1
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Solvent: O=CO
Solvent: CO
Solvent: O
Product: COC1=CC(OC)OC(C)C1=O
Reaction time: 0.08 h

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (8.4 g, 0.45 moles) in 3 ml methanol was added to 25 ml of formic acid and 1.2 ml methanol. After stirring for 5 minutes, the reaction was poured into 75 ml of water and extracted with chloroform. Concentration of the chloroform layer yielded a brown oil which solidified overnight. Recrystallization from hexane-ether yielded 4,6-dimethoxy-2-methyl-2H-pyran-3(6H)-one as white needles, mp 73°-74.5° C., NMR (CDCl3, δ) 5.75 (1H, d, J=4Hz), 5.3 (1H, d, J=4Hz), 4.62 (1H, q, J=7Hz), 3.68 (3H, s), 3.52 (3H, S), 1.2 (3H, t, J=7Hz).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[Cl:7][C:8]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:9]=1[O:10][C:11]1[CH:12]=[C:13]([S:20]Cl)[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1>CCOCC>[CH3:6][O:5][C:1]([CH2:2][S:3][S:20][C:13]1[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=[C:11]([O:10][C:9]2[CH:22]=[CH:23][C:24]([C:26]([F:27])([F:28])[F:29])=[CH:25][C:8]=2[Cl:7])[CH:12]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1SCl
Reactant: COC(=O)CS
Solvent: CCOCC
Product: COC(=O)CSSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 90 %

Procedure:
5.3 parts by weight of methyl thioglycolate were added dropwise to a solution of 19.2 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrobenzenesulfenyl chloride in 100 parts by volume of absolute ether at room temperature, the reaction mixture was stirred for a further two hours and then evaporated to dryness under reduced pressure, and the oily residue was crystallized using diisopropyl ether. 25 parts by weight (90% yield) of 3-(2'-chloro-4'-trifluoromethylphenoxy)-6-nitrophenyl methoxycarbonylmethyl disulfide of melting point 66°-68° C. were obtained (compound No. 3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:29])[CH:9]=2)[CH:7]=1.[NH2:32][C:33]1[CH:43]=[CH:42][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:35][CH:34]=1.CC(C)N=C=NC(C)C.C(#N)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:30]#[N:31])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24](=[O:28])(=[O:27])[CH2:23][CH2:22]3)[C:17]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:42][CH:43]=3)=[O:19])[C:10](=[O:29])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC2CCS(=O)(=O)CC2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1

Procedure:
768 mg (1.19 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoic acid (racemate, purity 72%), 786 mg (4.76 mmol) of ethyl 4-aminobenzoate, 67.6 mg (476 μmol) of Oxima and 741 μl (4.76 mmol) of DIC in 11.5 ml of dimethylformamide were reacted according to General Method 5B. Preparative HPLC (acetonitrile/water gradient) gave the title compound. Yield: 331 mg (45% of theory)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:36][CH2:37][O:38][C:39]2[CH:40]=[C:41]([CH:45]=[CH:46][CH:47]=2)[C:42](O)=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:42][C:41]1[CH:45]=[CH:46][CH:47]=[C:39]([O:38][CH2:37][CH2:36][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:40]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1cccc(OCCN2CCCCC2)c1
Agent: Cl
Product: CCN(Cc1cccc(OCCN2CCCCC2)c1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 86.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (60 mg) and 3-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (85 mg) according to an analogous synthetic method to Example 152, the title compound (70 mg) was obtained.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[NH:11][C:10](=[O:16])[CH2:9][CH2:8]2)(=O)C.[OH-].[Na+]>CO>[F:15][C:13]1[CH:14]=[C:5]([OH:4])[CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:16])[CH2:9][CH2:8]2
Reactant: CC(=O)Oc1cc(F)c2c(c1)CCC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2cc(O)cc(F)c2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 8-fluoro-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl acetate (1.3 g, 5.82 mmol) in MeOH (50 mL) at room temperature was added 1N NaOH (11.65 mL, 11.65 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated to a yellow oil. This was diluted with water and acidified with conc. HCl to pH 1. The precipitate was collected by filtration, washed with water, and recrystallized from MeOH/water to give 8-fluoro-6-hydroxy-3,4-dihydroquinolin-2(1H)-one as a white solid (0.46 g, 44%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 6.57-6.48 (m, 2H), 2.93 (s, 2H), 2.56 (dd, J=7.9, 6.9 Hz, 2H). LCMS: R.T.=1.125 min; [M+H]+=182.1.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:22])[CH2:21][CH2:20][CH:19]=[CH:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][C@@H:19]2[CH2:20][CH2:21][C:17](=[O:22])[C@@H:18]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=CCC1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A round bottom flask purged with argon was charged with N-benzyl-1-methoxy-N-(trimethylsilylmethyl)methanamine (31.2 g, 131.4 mmol) and cyclopent-2-ene-1-one (9.0 g, 9.2 mL, 109.5 mmol). The reaction mixture was cooled to 0° C. and a solution of trifluoroacetic acid (1.25 g, 847 μL, 11.0 mmol) in DCM (11 mL) was added to it. The reaction mixture was stirred at 0° C. for 4 h, warmed to room temperature and stirred for 18 h. The reaction was quenched by the addition of saturated sodium bicarbonate and the layers were separated. The aqueous layer was extracted with DCM and the combined organic layers was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified via silica gel column chromatography using 40 to 80% EtOAc in hexanes to obtain (3aR,6aS)-2-benzyl-1,3,3a,4,5,6a-hexahydrocyclopenta[c]pyrrol-6-one (19.8 g, 84%) as a light yellow oil.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[N:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[N:11]=1>C(OCC)C>[CH2:1]([NH:8][C:10]1[N:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(F)nc(F)n1
Reactant: NCc1ccccc1
Solvent: CCOCC
Product: Fc1cc(F)nc(NCc2ccccc2)n1
Reaction time: 1 h

Procedure:
23.5 g (0.22 mol) of benzylamine were added at -20 C. to a stirred mixture of 13.4 9 (0.1 mol) of 2,4,6-trifluoropyrimidine in 150 ml of diethyl ether within 15 min, and the mixture was stirred at this temperature for 1 hour. After a further hour at 25° C., working up was carried out as in Example 10. 21.4 g (98% of theory) of the title compound of melting point 70°-73° C. were obtained in this way.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][O:29]CC3C=CC=CC=3)[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16].B(F)(F)F.CCOCC.C(S)C>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH:21][S:22]([C:25]2([CH2:28][OH:29])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[C:12]2[O:20][CH2:19][CH2:18][N:13]2[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(COCc3ccccc3)CC2)c2n(c1=O)CCO2
Agent: FB(F)F
Solvent: CCS
Solvent: CCOCC
Product: Cc1c(Nc2ccc(I)cc2F)c(NS(=O)(=O)C2(CO)CC2)c2n(c1=O)CCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.8 %

Procedure:
Using the same reaction conditions and workup as described for the prepaqration of Example 7A, 1-benzyloxymethyl-cyclopropanesulfonic acid [7-(2-fluoro-4-iodo-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-oxazolo[3,2-a]pyridin-8-yl]-amide (0.27 g, 0.515 mmol) was reacted with BF3.OEt2(1.94 mL, 15.45 mmol) and ethane thiol (0.3 g, 5.15 mmol). The resulting mixture was stirred at room temperature for 3 days. Purification by preparative HPLC afforded 60 mg of the product (26% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[C:24]([O:30][CH2:31][CH:32]([F:34])[F:33])[C:25]([C:27]([OH:29])=O)=[CH:26][C:20]=2[N:19]=1.[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C1COCC1>CCOC(C)=O>[Br:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:27]([C:25]2[C:24]([O:30][CH2:31][CH:32]([F:33])[F:34])=[CH:23][C:21]3[NH:22][C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:14])[C:2]=4[Cl:1])=[N:19][C:20]=3[CH:26]=2)=[O:29])=[CH:38][CH:37]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)Nc4ccc(Br)cc4)c(OCC(F)F)cc3[nH]2)c1Cl

Procedure:
PPA (0.223 mL, 50% in EtOAc, ˜0.38 mmol) is slowly added to a mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-6-(2,2-difluoro-ethoxy)-1H-benzimidazole-5-carboxylic acid (0.150 g, 0.291 mmol), 4-bromoaniline (50 mg, 0.291 mmol), TEA (0.101 mL, 0.728 mmol) and THF (10 mL). The mixture is refluxed for 3 d, concentrated and purified via prep. HPLC (column: Zorbax stable bond C18, 5 μm, 30×100 mm, gradient: water+0.15% HCOOH/MeOH 95:5→10:90) to furnish the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([CH2:19][CH:20]([OH:23])[CH2:21][OH:22])=[C:12]([O:24][CH3:25])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[C:28](OC)([CH3:30])[CH3:29].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O>[C:4]([Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([O:24][CH3:25])[C:13]([CH2:19][CH:20]2[CH2:21][O:22][C:28]([CH3:30])([CH3:29])[O:23]2)=[CH:14][C:15]=1[N+:16]([O-:18])=[O:17])([CH3:2])[CH3:3])([CH3:5])([CH3:7])[CH3:6]
Reactant: COC(C)(C)OC
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC(O)CO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)c([N+](=O)[O-])cc1CC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 41 h
Yield: 82.9 %

Procedure:
390 mg of 3-(4-(t-butyldimethylsilyloxy-methyl)-2-methoxy-5-nitrophenyl)propane-1,2-diol was dissolved in 8 ml of acetone. Then, 0.33 g of dimethoxypropane and 26 mg of pyridinium p-toluenesulfonate were added to the reaction solution. The obtained mixture was then stirred at room temperature for 41 hours. Thereafter, the reaction solution was concentrated under a reduced pressure. The residue was diluted with ethyl acetate and then washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), so as to obtain 358 mg of the subject compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([C:13]2[C:21]([CH:22]=[CH:23][C:24]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]3[CH2:32][CH3:33])=[O:25])=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(N)c2)nn2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1CCCCN1C(=O)C=Cc1c(-c2cccc(NS(C)(=O)=O)c2)nn2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
Methanesulfonyl chloride (0.59 g) was added dropwise to a stirred solution of 1-[3-{2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]- 2-ethylpiperidine (trans isomer) (1.20 g) and triethylamine (0.52 g) in methylene chloride (7.2 ml) with ice-cooling. After being stirred at room temperature for 6 hours, the reaction mixture was washed twice with water and once with saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (22 g) with chloroform as an eluent. The fractions containing the objective compound were combined and evaporated in vacuo to give crystals of 1-[3-{2-(3-methanesulfonamidophenyl)pyrazolo[1,5-a]pyridin-3-yl}acryloyl]-2-ethylpiperidine (trans isomer) (0.36 g).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[CH:11]\[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:3]=1[CH2:20][C:21](OC)=[O:22].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.Cl>C1COCC1>[OH:22][CH2:21][CH2:20][C:3]1/[C:4](=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)/[C:5]2[C:10]([C:2]=1[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)CC1=C(C)c2ccccc2/C1=C\c1ccc(SC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(CCO)=C(C)c3ccccc32)cc1
Reaction time: 1 h

Procedure:
To a solution of the ester from Step 3 (270 mg, 0.83 mmol) in dry THF (5 mL) at 0° C. was added a solution of diisobutyl aluminum hydride (1M) in toluene (2.1 mL, 2.1 mmol, 3.5 eq). After 1 hour, the reaction mixture was added dropwise to a solution of 1N aqueous HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and evaporated to dryness. The crude product was chromatographed on silica gel eluting with a 1:3 mixture of ethyl acetate-hexane to afford pure title compound as a yellow oil.