Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:31])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1B(O)O.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1B1OC(C)(C)C(C)(C)O1)(C)C>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C:13]2([CH3:31])[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:33]4[S:32][CH:36]=[CH:35][CH:34]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2(C)Cc3cc(Cl)cc(-c4cccs4)c3O2)cc1

Procedure:
Treatment of (±)-(5-chloro-2-methyl-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.90 g, 5.8 mmol), thiophene-2-boronic acid (1.11 g, 8.7 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.47 g, 0.58 mmol), and potassium carbonate (1.6 g, 11.6 mmol) generally according to the procedure described for Intermediate 35 gave (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (2.00 g, 30.7 mmol) generally according to the procedure described for Intermediate 98 provided (±)-2-(azidomethyl)-5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.250 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 0.58 g of (±)-(5-chloro-2-methyl-7-thien-2-yl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 251-252° C.; Anal. calcd. for C14H14ClNOSHCl: C, 53.17; H, 4.78; N, 4.43. Found: C, 51.17; H, 4.48; N, 4.32.
Reaction SMILES: OS(O)(=O)=O.N([O-])=[O:7].[Na+].N[C@@H:11]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:12]([OH:14])=[O:13].[Na+].[Cl-]>O>[OH:7][C@@H:11]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:12]([OH:14])=[O:13]
Reactant: N[C@@H](CC1CC1)C(=O)O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](O)CC1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
A 1 L, 3-neck flask was equipped with two dropping funnels, one containing 21.3 mL of 2.0 N H2SO4 and the other containing 21.3 mL of 2.0 N NaNO2. A mixture of 5.00 g (38.7 mmol) of 2-(S)-amino-3-cyclopropyl propanoic acid in 28 mL of H2O at 0° C. was treated with a sufficient amount of the acid solution to dissolve the solids. The remaining H2SO4 solution and the NaNO2 solution were added maintaing the internal temperature at less than 5° C. The resulting mixture was stirred cold for 3 h, then warmed to rt and stirred for 20 h. The reaction mixture was saturated with NaCl and extracted with 4×100 mL of EtOAc. The extracts were dried over MgSO4 and concentrated to afford 4.30 g (85%) of the title compound: 1H NMR (300 MHz): δ 0.13-0.18 (m, 2H), 0.48-0.54 (m, 2H), 0.89 (m, 1H), 1.67-1.76 (m, 2H), 4.37 (dd, J=6.4, 4.7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH:16]3[CH:12]([CH2:13][N:14](C(OC=C)=O)[CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1.C(OC(C)C)(C)C>[ClH:1].[Cl:29][C:25]1[CH:24]=[C:23]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(Cl)c3)(c3cccc(Cl)c3)C2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CNCC12
Temperature: 60 °C
Reaction time: 6 h
Yield: 144.6 %

Procedure:
(3aRS,7aRS)-7,7-bis-(3-chlorophenyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (1.5 g) is treated with a 6N solution (7.4 cc) of hydrochloric acid in dioxane for 2 hours at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is heated for 1 hour in solution in ethanol at 60° C. and then stirred for 6 hours at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the meringue obtained is solidified in isopropyl ether. The precipitate is drained and washed with isopropyl ether and then dried to give 7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone hydrochloride (1 g).
Reaction SMILES: Cl[C:2]([C:13]1[N:14]=[C:15]([CH3:31])[N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=2)[C:17]=1[CH3:18])=[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[CH:7]=1)C=O.CC(C)([O-])C.[K+].O>C1COCC1>[Cl:12][C:8]1[CH:7]=[C:6]([C:3]#[C:2][C:13]2[N:14]=[C:15]([CH3:31])[N:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:20]=3)[C:17]=2[CH3:18])[CH:11]=[CH:10][N:9]=1
Reactant: COc1ccc(-n2c(C)nc(C(Cl)=C(C=O)c3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2c(C)nc(C#Cc3ccnc(Cl)c3)c2C)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
A solution of 3-Chloro-2-(2-chloro-pyridin-4-yl)-3-[1-(4-methoxy-3-trifluoromethyl-phenyl)-2,5-dimethyl-1H-imidazol-4-yl]-propenal (0.9 g, 1.9 mmol) in 8 mL THF was dropped to a cold (0° C.) suspension of potassium tert-butoxide (0.47 g, 4.2 mmol) in 4 mL THF and water (0.04 mL, 2.1 mmol). The light brown reaction mixture was stirred at 0° C. for 1 hr. The reaction was extracted two times with ethyl acetate, saturated NaHCO3− solution, water and brine. The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (n-heptane/ethyl acetate 90:10→0:100) to obtain the desired product as a white solid (0.15 g, 19%), MS: m/e=406.2 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23]Br)=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].[P:25]([O:34]C(C)C)([O:30][CH:31]([CH3:33])[CH3:32])[O:26][CH:27]([CH3:29])[CH3:28]>>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:25]([O:30][CH:31]([CH3:33])[CH3:32])([O:26][CH:27]([CH3:29])[CH3:28])=[O:34])=[CH:8][CH:9]([NH:20][CH:21]=[O:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CBr
Reactant: CC(C)OP(OC(C)C)OC(C)C
Product: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Reaction time: 18 h

Procedure:
11.1 g (27.9 mmol) of benzyl 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoate and 30.5 ml (111.5 mmol) of 90% triisopropyl phosphite are heated to 80° C. and the mixture is stirred for 18 hours under a pressure of 100-150 mbar. Excess triisopropyl phosphite is removed by distillation and the residue is purified by chromatography over silica gel with ethyl acetate/isopropanol (7:1), giving benzyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate as an orange oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.F[B-](F)(F)F.[CH2:16]([O+](CC)CC)[CH3:17]>C(Cl)Cl>[CH2:16]([O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1)[CH3:17]
Reactant: CC[O+](CC)CC
Reactant: COC(=O)c1cc(O)no1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1cc(C(=O)OC)on1
Reaction time: 8 h
Yield: 86 %

Procedure:
A stirred suspension of 3.53 g (24.67 mmole) of a commercial sample of methyl 3-hydroxy-5-isoxazolecarboxylate in 50 ml of methylene chloride was treated dropwise with a solution of triethyloxonium tetrafluoroborate (5.62 g, 29.60 mmole) dissolved in 30 ml of methylene chloride at room temperature. After stirring overnight the solution was washed with water (2×30 ml), 5% sodium bicarbonate (2×30 ml) and water once again. The organic layer was dried (magnesium sulfate) and evaporated in vacuo to furnish the title compound (3.61 g, 86% yield) as a light yellow solid, m.p. 77°-9° C. 1H-NMR (DMSO-d6)delta, 6.65 (1H, s), 3.93 (2H, q, J=7.4 Hz), 3.87 (3H, s) and 1.21 (3H, t, J=7.4 Hz); EIMS (m/z): 171 (M+, 48%), 56 (M+ --CH3, 4%), 143 (C5H 5 NO4, 31%), 112 (C4H2NO3, 12%) and 69 (C3H3NO, base); ir (potassium bromide): 3105, 1744, 1611, 1441, 1241, 1106, 974 and 797 cm-1.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(C)=O)cc3)ccn2c1=O

Procedure:
Methyl 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-acetamido-phenyl)-boronic acid (56 mg, 0.31 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 94:6) afforded the title compound 26 as a yellow solid (93 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)nc23)CC1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccccc4)nc23)CC1

Procedure:
Beginning with 0.015 gm (0.062 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.068 mMol) benzoyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])O1.Br[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>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.C(OCC)(=O)C.COCCOC.O>[C:24]([O:23][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:31]1[CH:43]=[CH:42][C:34]([C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])=[C:33]([N+:44]([O-:46])=[O:45])[CH:32]=1)=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Water (0.6 mL), sodium carbonate (0.16 g), tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenylcarbamate (0.19 g), and tetrakis(triphenylphosphine)palladium(0) (29 mg) were added to an ethylene glycol dimethyl ether (2.0 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (0.15 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate and a 10% aqueous solution of citric acid were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 91-80% hexane/ethyl acetate] to obtain 0.21 g of tert-butyl 4-(2-(tert-butoxycarbonylamino)phenyl)-2-nitrobenzoate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]1[O:10][CH2:9]1>>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][CH2:8][CH2:9][OH:10]
Reactant: C1CO1
Reactant: CN(C)CCCN
Product: CN(C)CCCNCCO
Temperature: 115 °C
Reaction time: 0.25 h

Procedure:
To a one liter stirred autoclave was charged 500 g 3-dimethylaminopropyl amine. A nitrogen atmosphere was provided and the sealed autoclave was heated to 115°C. Ethylene oxide (140 g) was added incrementally over 3 hours. Heating was continued for 15 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH:36]=[CH:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:35][CH:36]=[CH:37][CH3:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: CC=CCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CC=CCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 47.3 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt)(0.74 g, 1.41 mmol) and 4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.66 g, 1.40 mmol) to give the title compound: Rf=0.37 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5](=[CH:7][CH:8]=[C:9]([Cl:11])[CH:10]=1)[NH2:6].N1C=CC=CC=1.Cl.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:20]1([S:26]([NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[C:3]([O:2][CH3:1])=[O:12])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)c1cc(Cl)ccc1N
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloroanthranilic acid methyl ester (400 mg; prepared in Reference Example 1) and pyridine (0.87 ml) in methylene chloride, benzenesulfonylchloride (0.33 ml) was added at 0° C. The solution was stirred overnight at room temperature. The reaction mixture was poured into diluted HCl and extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (hexane-AcOEt) to give the title compound (664 mg) having the following physical data.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Br[CH2:26][C:27]1[O:28][C:29](=[O:33])[O:30][C:31]=1[CH3:32].C(=O)(O)[O-].[K+]>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:26][C:27]5[O:28][C:29](=[O:33])[O:30][C:31]=5[CH3:32])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1oc(=O)oc1CBr
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reaction time: 48 h

Procedure:
1.15 g (3.5 mmoles) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid are stirred in 20 ml of dimethylformamide with 0.85 g (4.4 mmoles) of 4-bromomethyl-5-methyl-1,3-dioxol-2-one and 0.42 g (4.2 mmoles) of powdered potassium bicarbonate for 3 days, while cooling with ice. The mixture is concentrated in vacuo, the residue is stirred with 20 ml of water, the resulting greasy product is dissolved in methanol and the solution is filtered. The filtrate is left to stand at room temperature for 2 days and the colorless crystals which have precipitated are isolated.
Reaction SMILES: N[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.N([O-])=[O:28].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][OH:28])=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: O=N[O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CO)o2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in acetic acid/water (1:1 v/v, 3 ml) was cooled to 0° C. Sodium nitrite (68 mg) was added and the solution stirred 24 hours at room temperature. Concentrated sodium hydroxide solution was added to the reaction and the mixture extracted with ether (3×20 ml). The combined organic phases were treated with potassium hydroxide in methanol (5%, 3 ml) for 2 hours, washed with water, dried (sodium sulphate) and reduced to dryness under vacuum. The residue was dissolved in 5% potassium hydroxide in methanol and stirred at room temperature for 90 minutes. The methanol was removed in vacuo, the residue partitioned between ethyl acetate/chloroform (1:1)/water and the organic phase dried and reduced to dryness under vacuum. This material was purified by HPLC, to give, after evaporation of the solvent, N-cyclopropyl-4′-[5-(hydroxymethyl)-1,3,4-oxadiazol-2-yl]-6-methyl-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:16])[NH:10][C@@H:11]([CH3:15])[C:12]([NH2:14])=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([NH:19][NH2:20])=O>C(O)C.[Hg](Cl)Cl>[N:19]1[N:20]=[C:12]([C@@H:11]([NH:10][C:9](=[O:16])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:15])[NH:14][CH:17]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(N)=S
Reactant: NNC=O
Agent: Cl[Hg]Cl
Solvent: CCO
Product: C[C@H](NC(=O)OCc1ccccc1)c1nnc[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
To a solution of benzyl[(1S)-2-amino-1-methyl-2-thioxoethyl]carbamate (13.4 g, 56.2 mmol) in ethanol (1.125 L) was added formic acid hydrazide (20.26 g, 337 mmol) and mercury(II) chloride (19.85 g, 73.1 mmol). After 1 h the reaction was filtered and concentrated. Saturated aqueous sodium carbonate and ethyl acetate were added. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. A solution of the resulting residue in ethanol (1.125 L) was heated to 80° C. After 16 h, the reaction was concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol with 1% ammonium hydroxide) gave the title compound (8.7 g). MS 247.1 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH2:12][C:13]([CH:15]1[CH2:20][C:19](=[CH2:21])[CH2:18][CH2:17][CH:16]1[C:22]([OH:24])=[O:23])=[O:14])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[CH2:12][C:13]([CH:15]1[CH2:20][C:19](=[CH2:21])[CH2:18][CH2:17][CH:16]1[C:22]([O:24][CH3:25])=[O:23])=[O:14])[CH3:11]
Reactant: C=C1CCC(C(=O)O)C(C(=O)Cc2c(CC)cc(C)cc2CC)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: C=C1CCC(C(=O)OC)C(C(=O)Cc2c(CC)cc(C)cc2CC)C1
Yield: 66.6 %

Procedure:
5.45 g (17.33 mmol) of 2-[(2,6-diethyl-4-methylphenyl)acetyl]-4-methylidenecyclohexane-carboxylic acid (XIII-1), together with 2.38 g of potassium carbonate and 2.62 g (20.8 mmol) of dimethylsulphate, are boiled at reflux in 50 ml of acetone for 5 h, and after cooling, the reaction mixture is taken up in ethyl acetate, extracted with water and dried (magnesium sulphate), and the solvent is distilled off. Chromatography on silica gel using ethyl acetate/hexane (v/v=30:70) gives 3.93 g (69%) of methyl 2-[(2,6-diethyl-4-methylphenyl)acetyl]-4-methylidenecyclohexane-carboxylate of the formula (II-1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1[CH3:15])=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>CCCCCCC.C(Cl)(Cl)Cl>[OH:13][C:10]1[CH:11]=[C:12]2[C:7](=[C:8]([CH3:15])[CH:9]=1)[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: COc1ccc(NC(=O)CCCl)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1cc(O)cc2c1NC(=O)CC2
Temperature: 110 °C
Reaction time: 96 h
Yield: 42.7 %

Procedure:
A suspension of 3-chloro-N-(4-methoxy-2-methylphenyl)propaneamide (0.50 g, synthesized from 3-chlorobutyryl chloride and 4-methoxy-2-methylaniline) and aluminum chloride (1.4 g) in n-heptane (4.0 mL) was stirred at 110° C. for 4 days. The reaction mixture was diluted with chloroform, followed by addition of ice-cold water under ice cooling. After stirring at room temperature for 1 hour, the organic layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform/methanol=10/0 to 97/3) to give the titled compound (0.166 g, 39%) as a light-brown solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=O)=[C:6]2[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH2:34])[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26]>>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([NH:34][C:11]([C:10]2[CH:9]=[N:8][N:7]3[C:2]([CH3:1])=[CH:3][C:4]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)=[N:5][C:6]=23)=[O:13])[CH:31]=[CH:32][CH:33]=1)(=[O:26])=[O:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)O)cnn12
Reactant: CS(=O)(=O)c1cccc(N)c1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc2c(C(=O)Nc3cccc(S(C)(=O)=O)c3)cnn12

Procedure:
The title compound was prepared from 7-methyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.25) and 3-methanesulfonyl-phenylamine according to general procedure II. Pale-yellow solid. MS (ISP) 475.1 [(M+H)+]; mp 198-200° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:14]#[N:15])[S:12][CH:13]=2)[C:4]1=[O:16].[Cl:17][C:18]1[N:23]=[C:22]2[CH:24]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:26][C:21]2=[CH:20][CH:19]=1>>[C:14]([C:11]1[S:12][CH:13]=[C:9]([CH2:8][N:5]2[CH2:6][CH2:7][C@H:3]([NH:2][S:27]([C:25]3[S:26][C:21]4[C:22](=[N:23][C:18]([Cl:17])=[CH:19][CH:20]=4)[CH:24]=3)(=[O:28])=[O:29])[C:4]2=[O:16])[CH:10]=1)#[N:15]
Reactant: N#Cc1cc(CN2CC[C@H](N)C2=O)cs1
Reactant: O=S(=O)(Cl)c1cc2nc(Cl)ccc2s1
Agent: Cl
Product: N#Cc1cc(CN2CC[C@H](NS(=O)(=O)c3cc4nc(Cl)ccc4s3)C2=O)cs1

Procedure:
The title compound is prepared from 4-(3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-thiophene-2carbonitrile hydrochloride as described in EXAMPLE 1, Part E using 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride in place of benzo[b]thiophene-2-sulfonyl chloride. The product is triturated with Et2O/CH2Cl2 /hexanes to give a white solid.