Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O.Cl.Cl.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH2:29])[CH2:21]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1.CN(C)C=O>[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH:22]([CH2:28][NH:29][C:13]([C:7]1[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:17])[F:16])[CH:5]=3)[NH:9][N:8]=1)=[O:15])[CH2:21]2
Reactant: NCC1CN2CCC1CC2
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)(F)F)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC1CN2CCC1CC2)c1n[nH]c2ccc(OC(F)(F)F)cc12
Temperature: 60 °C
Yield: 20 %

Procedure:
To a solution of 5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.40 mmol) in tetrahydrofuran (5.0 mL) and N,N-dimethylformamide (5.0 mL) was added 1-(1-azabicyclo[2.2.2]oct-3-yl)methanamine dihydrochloride (0.40 mmol) and HATU (0.40 mmol). N,N-Diisopropylethylamine (10.0 mmol) was added and the reaction mixture was maintained for 16 h. The reaction mixture was heated at 60° C. for 1 h, and was filtered and concentrated. The residue was redissolved in methanol and loaded on a 5 g SCX column. The column was washed with methanol and the product was eluted with methanoudimethylethylamine (9/1) and concentrated. The residue was purified by preparative HPLC to produce the desired product in 20% yield. 1H NMR (CDCl3) δ 8.47 (s, 1 H), 8.10 (s, 1 H), 7.67 (d, J=9.1, 1H), 7.36 (d, J=9.1, 1H), 3.63-3.52 (m, 3 H), 3.48-3.23 (m, 4 H), 3.08-3.01 (m, 1 H), 2.66-2.44 (m, 1 H), 2.32-2.22 (m, 1 H), 2.14-2.08 (m, 1 H), 2.06-1.85 (m, 3 H); LC/MS (EI) tR 4.8 min, m/z 369 (M++1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]=[CH:6][C:5](=[O:8])[O:4]1.N1C=CN=C1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Si:18]([O:1][CH2:2][C@@H:3]1[CH:7]=[CH:6][C:5](=[O:8])[O:4]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1C=C[C@@H](CO)O1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@@H]1C=CC(=O)O1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of 2.25 g of (25)-2-(hydroxymethyl)-2H-furan-5-one (compound 40b, 2.11 g, 16.0 mmol) and imidazole (1.63 g, 24.0 mmol) in DCM was added tert-butyl(chloro)diphenylsilane (5.2 mL, 20.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with brine. The aqueous layer was extracted with DCM. The organic layers were combined, washed with 1N hydrochloric acid, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to afford 4.6 g of (25)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-2H-furan-5-one (compound 40c) as a white solid. MS obsd. (ESI+) [(M+H)+]: 353.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]([O:27]CC)=[O:26])=[CH:9]2.O1CCCC1.[OH-].[K+]>CO>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:17])=[O:18])[CH:14]=1)[NH:11][C:10]([C:25]([OH:27])=[O:26])=[CH:9]2
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(NS(=O)(=O)c3ccccn3)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCOc1cc(NS(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.1 %

Procedure:
To a mixture of ethyl 5-(2-methoxyethoxy)-7-[(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylate (5.40 g), tetrahydrofuran (50 mL) and methanol (50 mL) was added a 85% aqueous solution (30 mL) of potassium hydroxide (3.0 g), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated, aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and concentrated to give a white solid. The obtained solid was washed with a mixed solvent of ethyl acetate-hexane to give the title compound (4.24 g, yield 84%) as colorless crystals. melting point 230-232° C.
Reaction SMILES: [OH:1][CH:2]([C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6])[C:3]#[N:4].Cl.C[OH:21]>>[OH:1][CH:2]([C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:6])[C:3]([NH2:4])=[O:21]
Reactant: CO
Reactant: CC(c1ccccc1)(c1ccccc1)C(O)C#N
Agent: Cl
Product: CC(c1ccccc1)(c1ccccc1)C(O)C(N)=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
10.0 g (4.22 [sic] mmol) of 2-hydroxy-3,3-diphenylbutyronitrile were dissolved in 500 ml of methanol (abs.) and, at 5-10° C., HCl was passed in for 3 hours. The mixture was then stirred at 5° C. for 3 hours and at room temperature for 16 hours. Then 200 ml of 6 molar HCl were added and the mixture was evaporated to dryness under reduced pressure. The crude product was recrystallized from an ethyl acetate/heptane mixture. 2.5 g (23%) of 2-hydroxy-3,3-dihenylbutyramide were obtained as a white solid.
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([N:7]1[C:11]([CH:12]=O)=[CH:10][C:9]([N:14]([CH3:23])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:8]1)[CH3:6].[N:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N+]=[N-].[Cl-].[NH4+]>C(O)C>[CH2:5]([N:7]1[C:11]2[CH:12]=[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH:24][C:10]=2[C:9]([N:14]([CH3:23])[S:15]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])=[O:16])=[CH:8]1)[CH3:6]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: CCn1cc(N(C)S(=O)(=O)c2cccs2)cc1C=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cc2c([nH]1)c(N(C)S(=O)(=O)c1cccs1)cn2CC
Reaction time: 2 h
Yield: 10.3 %

Procedure:
To a solution (150 mL) of sodium ethoxide (8.3 g) in ethanol was added dropwise a mixture of N-(1-ethyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (8.5 g) and ethyl azidoacetate (16.5 g) under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was concentrated. The obtained residue was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, volume ratio). The obtained yellow oil was dissolved in toluene (50 mL), and the mixture was stirred at 110° C. for 1 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography to give ethyl 4-ethyl-6-[methyl(2-thienylsulfonyl)amino]-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylate (1.12 g, yield 32%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 122° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])/[C:2](=[CH:4]/[CH3:5])/[CH3:3]
Reactant: C/C=C(\C)C(=O)O
Reactant: CSCCl
Solvent: CCN(CC)CC
Product: C/C=C(\C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting tiglic acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 95° C./12 mm Hg, n20 1.4890.
Reaction SMILES: Cl.[Sn](Cl)Cl.[CH2:5]([N:7]([CH2:21][CH3:22])[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[N+:18]([O-])=O)[CH3:6].C(=O)([O-])O.[Na+]>CO>[NH2:18][C:9]1[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=1[N:7]([CH2:21][CH3:22])[CH2:5][CH3:6]
Reactant: CCN(CC)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCN(CC)c1ccc(C(F)(F)F)cc1N
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.8 %

Procedure:
Concentrated hydrochloric acid (1.00 ml, 12.0 mmol) and anhydrous tin dichloride (908 mg, 4.78 mmol) were sequentially added at 0° C. to a methanol (5 ml) solution of 1-diethylamino-2-nitro-4-(trifluoromethyl)benzene (251 mg, 0.957 mmol), obtained as described in Referential Example 6-1. The resulting mixture was warmed to room temperature and stirred for 22 hours. A saturated solution of sodium hydrogen carbonate was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=20/1-10/1). Thus, 2-amino-1-diethylamino-4-(trifluoromethyl)benzene (144 mg, 64.7%) was yielded as a colorless oily material.
Reaction SMILES: C1(CO)CC1.C[O-].[Na+].CS(Cl)(=O)=O.C(S(Cl)(=O)=O)C.[CH3:20][N:21]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[C:28]2[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=2[C:22]1=[O:40].[Br:41][C:42]1[C:43]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)=[CH:44][C:45]([F:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:47]=1>>[Br:41][C:42]1[C:43]([O:54][CH2:55][CH:56]2[CH2:58][CH2:57]2)=[CH:44][C:45]([F:53])=[C:46]([NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH:47]=1.[CH:56]1([CH2:55][O:54][C:43]2[C:42]([C:29]3[C:28]4[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=4[C:22](=[O:40])[N:21]([CH3:20])[CH:30]=3)=[CH:47][C:46]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])=[C:45]([F:53])[CH:44]=2)[CH2:57][CH2:58]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2c(c1=O)CCCC2
Agent: CCS(=O)(=O)Cl
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)Nc1cc(Br)c(OCC2CC2)cc1F
Product: Cn1cc(-c2cc(NS(C)(=O)=O)c(F)cc2OCC2CC2)c2c(c1=O)CCCC2

Procedure:
N-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyl]methanesulfonamide was prepared in 3 steps in a similar manner as Example 86 except that the alkoxide of cyclopropylmethanol was substituted for sodium methoxide in step 1 and methanesulfonylchloride was substituted for ethansulfonylchloride in step 3. The title compound of Example 163, step 3 and N-[5-bromo-4-(cyclopropylmethoxy)-2-fluorophenyl]methanesulfonamide were reacted in a similar manner as in Example 89, step 2 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 7.29 (d, J=9.2 Hz, 1H), 6.96 (s, 1H), 6.70 (d, J=12.0 Hz, 1H), 6.21 (s, 1H), 3.76-3.75 (m, 2H), 3.56 (s, 3H), 3.02 (s, 3H), 2.70-2.60 (m, 2H), 2.36-2.17 (m, 2H), 1.80-1.70 (m, 2H), 1.69-1.64 (m, 2H), 1.20-1.10 (m, 1H), 0.60-0.50 (m, 2H), 0.27-0.25 (m, 2H). LCMS: 421.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O:19]1[C:23]2[CH:24]=[CH:25][C:26](N)=[CH:27][C:22]=2[CH2:21][CH2:20]1.[K+].[Br-]>CCOC(C)=O>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:27][C:22]=2[CH2:21][CH2:20]1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2c(c1)CCO2
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)CCO5)c3c2s1
Yield: 95 %

Procedure:
Prepared from VII and 2,3-dihydro-1-benzofuran-5-amine. Flash chromatography eluent (EtOAc). Yield: 95%; yellow solid; mp 216° C.; IR (KBr) νmax/cm−1 2894, 2853, 2228, 1643, 1609, 1579, 1484, 1467, 1376, 1353, 1306, 1269, 1219, 1192, 1164, 1123, 978, 941, 881, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H, J=8.7 Hz), 8.10 (s, 1H), 7.75 (d, 1H, J=8.7 Hz), 7.22 (m, 1H), 7.04 (s, 1H), 6.78 (m, 1H), 4.53 (t, 2H, J=8.7 Hz), 3.20 (t, 1H, J=8.7 Hz); HRMS calcd for C18H12N5OS (M+H+): 346.0763, found 346.0762.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[N:9]2)=[CH:5][CH:4]=1>O1CCCC1.NN.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:16][CH:17]=1
Reactant: COc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Agent: [Ni]
Agent: NN
Solvent: C1CCOC1
Product: COc1ccc(Cn2ccc(N)n2)cc1
Reaction time: 0.08 h

Procedure:
To a solution containing 1-(4-methoxy-benzyl)-3-nitro-1H-pyrazole (99 mg, 0.42 mmol) in tetrahydrofuran (2 mL), anhydrous hydrazine (100 μL) was added to the clear solution. Raney nickel (˜100 mg washed 3 times with 5 mL of anhydrous tetrahydrofuran) was then added in tetrahydrofuran (300 μL). Gas evolved from the mixture and the reaction was allowed to proceed for 5 min, after which time the raney nickel was removed by filtration through a celite plug. The solvent was removed in vacuo to afford 1-(4-methoxy-benzyl)-1H-pyrazol-3-ylamine which as a yellow oil was used in the following step with no further purification.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)([O:3]CC)=[O:2].[OH-].[Na+]>CO>[C:1]([CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCN(c2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
The product from Step C was dissolved in methanol and 5% aqueous sodium hydroxide added. After 1 h, methanol was removed in vacuo, and the residue partitioned between ethyl acetate and 10% aqueous HCl. The organic layer was washed with saturated brine, and dried over MgSO4. Filtration and concentration provided the title compound.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH3:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[CH3:27].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[CH3:27])[O:28][CH2:15][CH2:14][CH2:13][O:12][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([O:17][CH3:18])[C:3]([OH:2])=[O:19])[CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc(C)c(C)c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 3,4-dimethylphenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. 1H-NMR (CDCl3, 200.15 MHz): 7.18 (d, 1H, J=7.5), 7.02 (d, 1H, J=8.3), 6.84–6.62 (m, 5H), 4.14 (t, 2H, J=6.4), 4.12 (t, 2H, J=5.9), 4.02 (dd, 1H, J=7.3, 4.0), 3.39 (s, 3H), 3.13 (dd, 1H, J=14.2, 4.6), 2.97 (dd, 1H, J=14.0, 7.5), 2.23 (q, 1H, J=6.2.1), 2.22 (s, 3H), 2.18 (s, 3H). MS (ES) for C21H26O5 [M+Na]+: 381.2.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH3:13])[C:3]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C([O-])(=O)C.[Na+]>COCCO>[C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][C:3]2[C:4]([CH2:11][CH2:12][CH3:13])=[N:5][C:6]3[N:7]([N:8]=[CH:9][CH:10]=3)[CH:2]=2)=[CH:16][CH:17]=1)#[N:28]
Reactant: CCCc1nc2ccnn2c(Cl)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCCc1nc2ccnn2cc1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 81.3 %

Procedure:
A solution of 5.4 g of the chlorinated compound prepared in Example 27 in 110 ml of 2-methoxyethanol containing 1.2 g of anhydrous sodium acetate is hydrogenated, at atmospheric pressure and ambient temperature, in the presence of 1.4 g of 5% Pd-on-charcoal. The system is purged with nitrogen. The catalyst is filtered off on Celite 545 and washed with 2-methoxyethanol. The filtrate is concentrated and taken up in ether to give 5.2 g of crude product. Purification by chromatography on silica gel (eluent: dichloromethane 90%/acetone 10%) gives 4 g of 6-[(2'-cyanobiphenyl-4yl)methyl]-5-propylpyrazolo[1,5-a]pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][C:37]1([CH2:43][NH2:44])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:29]([S:36][C:37]1([CH2:43][NH:44][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[O:27])[CH2:42][CH2:41][S:40][CH2:39][CH2:38]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCC1(SCc2ccccc2)CCSCC1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC3(SCc4ccccc4)CCSCC3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.9 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (1.60 g), 1-[4-(benzylthio)tetrahydro-2H-thiopyran-4-yl]methanamine (1.00 g), 1H-1,2,3-benzotriazol-1-ol (0.90 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.12 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 15 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (1.92 g, yield 77%) as a colorless amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.S(O)(O)(=O)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][NH2:37])=[CH:32][CH:31]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:36]([C:33]3[CH:34]=[CH:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[N:37]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2ccc(Cl)cc2)c1-c1ccccc1
Yield: 82.9 %

Procedure:
8.0 grams 3,3-dibenzoyl-propionic acid-ethyl ester, 5.9 grams p-chlorophenyl-hydrazine sulfate, 2.5 grams sodium acetate and 3.0 grams glacial acetic acid were reacted and the reaction product recovered by a procedure analogous to the method set out in Example (2a). 7.9 grams 3,5-diphenyl-1-(p-chlorophenyl)-pyrazol-4-acetic acid, melting at 193°-194° C. were obtained, representing a yield of 78%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]3[C:11]4[C:12]5[CH:25]=[CH:24][S:23][C:13]=5[C:14](=[O:22])[NH:15][C:16]=4[CH:17]=[CH:18][C:19]=3[O:20]C)[CH:8]=2)[CH:3]=[N:2]1.BrB(Br)Br>>[OH:20][C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:22])[C:13]3[S:23][CH:24]=[CH:25][C:12]=3[C:11]=2[C:10]=1[C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[N:2][NH:1]2)=[CH:5][CH:6]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc2cn[nH]c2c1
Agent: BrB(Br)Br
Product: O=c1[nH]c2ccc(O)c(-c3ccc4cn[nH]c4c3)c2c2ccsc12
Yield: 10.8 %

Procedure:
Following General Procedure F, 9-(1H-indazol-6-yl)-8-methoxythieno[2,3-c]quinolin-4(5H)-one (35 mg, 0.10 mmol) was reacted with tribromoborane (1.5 mL, 0.15 mmol) to afford the desired product (3.6 mg, 11%) as a light brown solid: 1H NMR (500 MHz, CD3OD) δ 8.17 (s, 1H), 7.75-7.73 (m, 2H), 7.48 (d, J=5.5 Hz, 1H), 7.42 (d, J=8.9 Hz, 1H), 7.34 (d, J=9.2 Hz, 1H), 7.19 (d, J=8.9 Hz, 1H), 5.91 (d, J=5.5 Hz, 1H); ESI MS m/z 334 [C18H11N3O2S+H]+; HPLC 96.3% (AUC), tR=9.20 min.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6R)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.1 g, 3.1 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.70 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([O:23]CC4C=CC([N+]([O-])=O)=CC=4)=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO>[C].[Pd].O1CCCC1>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:36][O:37][CH2:38][CH2:39][NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:10]([NH:12][CH:13]2[C:34](=[O:35])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Yield: 54.3 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 3.3 g.), 10% palladium-carbon (1.7 g.), methanol (65 ml.) and tetrahydrofuran (65 ml.) were treated in similar manner to that of Example 11-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.45 g.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].COC1C=[C:27]2C(C(=O)C=[CH:25][NH:26]2)=CC=1C(O)=O.C(N(C(C)C)CC)(C)C.O1CCCC1.CNC>O1CCCC1.O>[CH3:25][N:26]([CH3:27])[C:14]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[N:10]=[CH:9][CH:8]=[C:7]2[Cl:13])=[O:15]
Reactant: COc1cc2[nH]ccc(=O)c2cc1C(=O)O
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Cl)c2cc1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
After dissolving 7-methoxy-4-chloro-quinoline-6-carbonyl chloride synthesized by the method of Production Example 152-2 from 7-methoxy-4-oxo-1,4-dihydroquinoline-6-carboxylic acid (1.0 g) in tetrahydrofuran (60 ml), the solution was cooled to 0° C. Diisopropylethylamine (1.6 ml) and a 2.0 M dimethylamine tetrahydrofuran solution (3 ml) were added and the mixture was stirred overnight at room temperature. Water was added, extraction was performed 3 times with ethyl acetate, and the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and then dried under reduced pressure to obtain the title compound (933 mg).