Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=2)[N:3]=1.CCN(CC)CC.[C:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][C:45]([O:47][CH3:48])=[O:46])#[CH:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:24]([O:23][C:22]([NH:21][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:37]#[C:36][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)[CH3:20])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: C#Cc1ccccc1CC(=O)OC
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)ncc1C(F)(F)F
Temperature: 120 °C

Procedure:
A suspension of tert-butyl 1-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)ethylcarbamate (A63) (487 mg, 1.17 mmol), Et3N (760 μL), methyl 2-(2-ethynylphenyl)acetate (K1) (244 mg, 1.40 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), CuI (22.0 mg, 0.117 mmol) and PPh3 (36.0 mg, 0.117 mmol) in DMF (4.6 mL) was heated under microwave irradiation at 120° C. for 15 minutes. The volatiles were evaporated in vacuo and the residue purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-25% EtOAc in cyclohexane) to give the title compound A64 as a yellow solid (400 mg, 62%); 1H NMR (300 MHz, CDCl3) δ 8.66 (s, 1H), 7.70 (dd, J=7.83, 1.17 Hz, 1H), 7.61 (d, J=8.61 Hz, 2H), 7.43 (m, 3H), 7.34 (d, J=8.40 Hz, 2H), 4.78 (m, 2H), 3.98 (s, 2H), 3.73 (s, 3H), 1.61 (s, 1H, peak obscured), 1.46 (m, 12H). LCMS-B: rt 8.90 min; m/z 555 [M+H]+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([CH2:27][N:28]2[CH2:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])[CH2:10]1)(C(C)(C)C)(C)C.Cl>CO>[O:34]=[C:29]1[NH:30][C:31](=[O:33])[CH2:32][N:28]1[CH2:27][C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CN2CC(=O)NC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Solvent: CO
Product: O=C1CN(C[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-(2,4-dioxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (4.78 g) in a mixture of methanol (100 ml) and concentrated hydrochloric acid (1.62 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was evaporated in vacuo. The resulting residue was dissolved in toluene (30 ml) and the solution was concentrated under reduced pressure to give a residue. The residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (2:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-2-(2,4-dioxoimidazolidin-1-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.27 g).
Reaction SMILES: C(O[Al])(CC)C.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3].[CH2:20]([C:22](=[CH:25][CH2:26][CH:27]1[CH2:31][CH:30]=[C:29]([CH3:32])[C:28]1([CH3:34])[CH3:33])[CH:23]=[O:24])[CH3:21]>>[CH2:20]([C:22](=[CH:25][CH2:26][CH:27]1[CH2:31][CH:30]=[C:29]([CH3:32])[C:28]1([CH3:33])[CH3:34])[CH2:23][OH:24])[CH3:21]
Reactant: CCC(C=O)=CCC1CC=C(C)C1(C)C
Agent: CC(C)[O-]
Agent: CCC(C)O[Al]
Agent: [Al+3]
Product: CCC(=CCC1CC=C(C)C1(C)C)CO
Reaction time: 5 h
Yield: 60 %

Procedure:
The reaction was carried out in the same manner as in Example 1, except that 2.18 g (10 mmol) of sec-butoxyaluminum diisopropylate was used instead of aluminum isopropylate, and 10.3 g (50 mmol) of 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al was used instead of 2-methyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-al. After 5 hours, according to GLC analysis, 60% of 2-ethyl-4-(2,2,3-trimethyl-3-cyclopenten-1-yl)-2-buten-1-ol was obtained (corresponding to 87% selectivity for conversion of the aldehyde as the starting material).
Reaction SMILES: CON(C)[C:4](=[O:16])[CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].[CH3:18][Mg]I>C1COCC1>[Cl:15][C:8]1[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([Cl:13])[C:7]=1[CH2:6][CH2:5][C:4](=[O:16])[CH3:18]
Reactant: C[Mg]I
Reactant: CON(C)C(=O)CCc1c(Cl)cc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(=O)CCc1c(Cl)cc(Cl)cc1Cl
Reaction time: 2 h
Yield: 59 %

Procedure:
To the stirred and cold solution (0° C.) of N-methoxy-N-methyl-3-(2,4,6-trichloro-phenyl)-propionamide (1 g, 3.37 mmol) in THF (15 ml) kept under nitrogen atmosphere, MeMgI (1.3 mL of 3M ether solution, 3.9 mmole) was added and stirring was continued at 0° C. for 2 hours. Reaction mixture was quenched with 5% of HCl (10 ml) at 0° C. and aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layer was washed with 20 ml of brine and dried over sodium sulfate; concentrated under vacuum to give off-white solid. The residue was purified by chromatography over silica gel. 0.50 g (60.0% of theory) of 4-(2,4,6-trichloro-phenyl)-butan-2-one was obtained in form of a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:17]=2[N+:26]([O-])=O)(=[O:15])=[O:14])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[Sn]Cl.CCO>C(Cl)Cl>[NH2:26][C:17]1[CH:18]=[C:19]([S:22]([CH3:25])(=[O:23])=[O:24])[CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)c3cccnc23)c(N)c1
Yield: 63 %

Procedure:
In the similar fashion using route 15 general procedure 29, N-(5-chloro-quinolin-8-yl)-4-methanesulfonyl-2-nitro-benzenesulfonamide (Intermediate 262 (350 mg, 0.79 mmol), SnCl2 (399 mg, 4.76 mmol) and EtOH (12 ml) gave the title compound (205 mg, 63%) after trituration from DCM: pentane
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.F[C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1>C1COCC1>[CH3:23][C:21]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=[C:17]([O:3][CH:4]2[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Cc1cc(F)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)C2)ncc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A suspension of sodium hydride (60% in oil, 11.54 mmol) in THF (2 mL) was added to tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.59 g, 8.46 mmol) in THF (15 mL) at 0° C. Once the bubbling had subsided, a solution of 2-fluoro-4-methyl-5-nitropyridine (1.2 g, 7.69 mmol) in THF (3 mL) was added over 5 minutes. After 1 h, more sodium hydride (60% in oil, 0.15 g) was added. After a further 1 h, the reaction was quenched with aqueous ammonium chloride solution and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give a yellow solid. Purification by column chromatography (silica gel: 100-200 mesh, 1:4 EtOAc:heptane) yielded the title compound (1.62 g, 65%) as a yellow solid. LCMS (ES+) 323.3 (M+H)+, RT 1.71 minutes (method 4).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].O.Br[CH2:12][C:13]([CH2:15][C:16]([NH:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]12)=[O:17])=O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:12]=[C:13]([CH2:15][C:16]([NH:18][CH:19]2[C:39](=[O:40])[N:21]3[C:22]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]23)=[O:17])[N:4]=1
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Thiourea (1.13 g), sodium bicarbonate (1.24 g) and water (20 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g) in tetrahydrofuran (60 ml), and stirred at room temperature for an hour. After concentrating the resultant solution under reduced pressure, the residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[C:17](O)(=O)[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[N:16][N:15]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccncc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccncc2)o1
Yield: 20 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using isonicotinic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:50:10:0 to 0:90:0:10, 57 mg, 20%) which was obtained as a white foam. MS: m/e=305.3 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:13]=2[N:12]=1)([CH3:3])[CH3:2].[N:23]1([CH2:29][CH2:30][NH:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH2:41])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[N:23]1([CH2:29][CH2:30][NH:31][C:32]2[C:40]3[C:35](=[CH:36][C:37]([NH:41][C:20]([C:18]4[CH:17]=[CH:16][C:14]5[N:15]=[C:11]([NH:10][C:5]6[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=6[CH:1]([CH3:3])[CH3:2])[NH:12][C:13]=5[CH:19]=4)=[O:22])=[CH:38][CH:39]=3)[NH:34][N:33]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CC(C)c1ccccc1Nc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: Nc1ccc2c(NCCN3CCOCC3)n[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(C(=O)Nc3ccc4c(NCCN5CCOCC5)n[nH]c4c3)cc2[nH]1

Procedure:
The ester obtained as above was hydrolyzed using general procedure C to yield 2-(2-isopropylphenylamino)-1H-benzimidazole-5-carboxylic acid. The carboxylic acid (0.25 mmol) was coupled with 3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-ylamine (0.25 mmol) using HBTU employing general procedure D. The product, 2-(2-Isopropylphenylamino)-3H-benzimidazole-5-carboxylic acid [3-(2-morpholin-4-yl-ethylamino)-1H-indazol-6-yl]-amide, was obtained after purification by silica gel chromatography using DCM/methanol as eluent. MS: m/z 539 (M+H)+.
Reaction SMILES: CC(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH:11]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=1[C:27]#[N:28])[CH2:12][CH:13]([CH3:15])[CH3:14])(C)C.Cl.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].C(O)C>O1CCOCC1>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[NH2:7][CH2:8][CH2:9][CH2:10][CH:11]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:27]#[N:28])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)CC(CCCNC(=O)OC(C)(C)C)Nc1cc(C(F)(F)F)ccc1C#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)CC(CCCN)Nc1cc(C(F)(F)F)ccc1C#N

Procedure:
4-[[2-Cyano-5-(trifluoromethyl)phenyl]amino]-6-methylheptylcarbamic acid 1,1-dimethylethyl ester (250 mg, 0.6 mmol) was stirred in a 4M solution of hydrogen chloride in dioxan (15 ml) for 3 h. The mixture was then concentrated to dryness and the residue treated with saturated aqueous sodium carbonate (50 ml). The products were extracted into diethyl ether (100 ml), and the extract dried over magnesium sulphate. Concentration of the extract gave a gum that was purified on silica gel eluting with 10% methanolic ammonia (7N) in dichloromethane. The product from the column was converted into a fumarate salt by addition of one equivalent of fumaric acid in the minimum amount of ethanol. The title compound was isolated as a colourless solid (80 mg, 31%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1>CN(C=O)C.O>[O:18]=[C:16]([N:52]1[CH2:53][CH2:54][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:66])([F:67])[F:68])[CH2:56][CH2:57]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.0685 g, 0.00024 mol) in DMF (2 mL) was added DIPEA (0.173 g, 0.00134 mol), HOBt (0.045 g, 0.00034 mol) and EDCI.HCl (0.064 g, 0.00034 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.068 g, 0.00024 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (35% ethyl acetate in hexane) to afford 0.0684 g (60%) of 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide. LCMS: 473.17 (M+1)+, 97.41%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.94 (m, 2H), 7.52 (m, 3H), 7.38 (m, 3H), 6.98 (d, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:22][C:23]2[C:24]([C:28]#[N:29])=[CH:25][S:26][CH:27]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: N#Cc1cscc1CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cscc1C#N
Yield: 82.1 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.097 g, 0.37 mmol), 4-bromomethyl-thiophene-3-carbonitrile (0.168 g, 0.83 mmol) (Terpstra, J. W., et al., J. Org. Chem. (1986) 51:230-238), KI (21 mg, 0.13 mmol), and DIPEA (0.15 mL, 0.86 mmol) in DMF (3 mL) was heated at 60° C. for 21 hours. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2—CH3OH—NH4OH) provided 118 mg (84%) of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-thiophene-3-carbonitrile as a tan solid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[CH:13][CH:14]=2)[CH:9]1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1)(C)(C)C>Cl>[ClH:33].[NH2:7][CH:8]1[CH:9]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[C:10]2[CH:11]=[C:12]([CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:13]=[CH:14][C:15]=2[CH2:16][CH2:17]1
Reactant: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)OC(C)(C)C)CC2
Agent: Cl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(N)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl[1-(3,4-dichlorobenzyl)-7-{[(propylsulfonyl)amino]methyl}-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (120 mg, 0.222 mmol, cf. example 39) was dissolved in 5 N isopropanolic hydrochloric acid (2 mL). The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated and the product was dried in vacuo. Yield: 101 mg (0.211 mmol, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[CH:7]2.[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Cl>O1CCOCC1>[Cl-:12].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][N+:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[CH3:1])[CH:7]=1
Reactant: Cc1cccc2c1CCN=C2
Reactant: ClCc1ccccc1Cl
Solvent: C1COCCO1
Product: Cc1cccc2c1CC[N+](Cc1ccccc1Cl)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 5-methyl-3,4-dihydro-isoquinoline and 2-chlorobenzyl chloride in dioxan. Melting point: 166°-168° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[CH2:23][N:24]1[C@H:28]([CH3:29])[C@H:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C:25]1=[O:36].Cl.[CH3:38]O>>[CH3:38][O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]2[C@H:28]([CH3:29])[C@H:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C:25]2=[O:36])[CH:4]=1
Reactant: CO
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)O)ccc1O
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Oc2ccc(C(F)(F)F)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To {4-hydroxy-3-[2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid (1.5 g, 3.74 mmol) in MeOH was added hydrochloric acid (4N in 1,4-dioxane), and the reaction was stirred at 80° C. for 2 hours. The mixture was concentrated to dryness, and the residue was worked-up with EtOAc and saturated aqueous NaHCO3 to give the title compound.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[C@@:24]([CH3:26])([OH:25])[CH:23]=[CH:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:18][CH2:19][C@H:20]1[C@@:24]([CH3:26])([OH:25])[CH:23]=[CH:22][CH2:21]1
Reactant: CC(C)(C)[Si](OC[C@@H]1CC=C[C@]1(C)O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@]1(O)C=CC[C@H]1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
To a solution of (1S,5S)-5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-methylcyclopent-2-en-1-ol (560 mg, 1.53 mmol) in THF (29.5 mL) at 0° C. was added 1.00 M of tetra-n-butylammonium fluoride in THF (3.06 mL, 3.06 mmol). The mixture was stirred at rt for 2 h, at which point the solvent was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with a gradient of 50 to 100% EtOAc in hexanes to afford the title compound (181 mg, 92%). LC/MS: Rt=0.76 min, ES+ 129 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](N(OC)C)=[O:15])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26](=[O:33])(=[O:32])[N:27]=CN(C)C)=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:4][CH:3]=1.[CH2:35]1COC[CH2:36]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14](=[O:15])[CH2:35][CH3:36])=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:27])(=[O:32])=[O:33])=[CH:22][CH:21]=3)[C:9]=2[CH3:34])=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1c(-c2ccc(S(=O)(=O)N=CN(C)C)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: C1CCOC1
Product: CCC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 0 °C
Yield: 21.08 %

Procedure:
Grignard reagent (ethyl magnesium bromide, 0.531 g, 3.98 ml, 1M soln. In THF, 3.98 mmol) was added dropwise under a nitrogen atmosphere to a stirred solution of 5-(4-chlorophenyl)-3-(4-(N-((dimethylamino)methylene)sulfamoyl)phenyl)-N-methoxy-N, 1,4-trimethyl-1H-pyrrole-2-carboxamide (compound 49ω, 0.400 g, 0.79 mmol) in anhydrous THF (15 ml) at 25° C., and the reaction mixture was then heated to about 70 to about 75° C. for 1 hr. The progress of the reaction was monitored by TLC. After cooling the reaction mixture to 0° C., the cooled reaction mixture was quenched by addition of saturated solution of ammonium chloride (10 ml). The mixture so formed was extracted with ethyl acetate (2×50 ml). The combined organic layer was dried over anhydrous Na2SO4. The solvent from the dried organic solution was evaporated under reduced pressure to obtain a crude product, which was then purified by preparative HPLC to obtain the title compound (0.070 g, 21.08%).
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:58])([CH3:57])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:40][C:41]2[CH:46]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:55][CH3:56])=[O:12])=[O:7])(C)(C)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>Cl.O1CCOCC1>[C:6]([C:8]([CH3:57])([CH3:58])[CH2:9][O:10][C:11]([N:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:25])([F:26])[F:24])=[CH:20][CH:21]=2)[C@@H:16]([N:27]([CH2:40][C:41]2[CH:46]=[C:45]([C:47]([F:48])([F:49])[F:50])[CH:44]=[C:43]([C:51]([F:54])([F:53])[F:52])[CH:42]=2)[C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][N:29]=2)[CH2:15][C@H:14]1[CH2:55][CH3:56])=[O:12])([OH:7])=[O:5]
Reactant: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(N3CCOCC3)cn2)c2cc(C(F)(F)F)ccc2N1C(=O)OCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound obtained in Example 10 above (178 mg) was dissolved in 4N—HCl/dioxane (2 ml) and stirred at room temperature for 2.5 hours. To the reaction mixture, were added a saturated sodium hydrogen carbonate aq. solution and ethyl acetate and the organic layer was separated, washed with a saturated brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel; chloroform:methanol=1:0→9:1) to give the titled compound (157 mg). MS (m/z): 777 [M+H]+.