Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[C:19]=S.NC(N)=S>O1CCCC1>[Cl:12][C:11]1[C:2]2[N:1]=[C:19]([NH:18][C:21]3[C:22]([CH3:29])=[N:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[N:13]([CH2:14][CH2:15][CH2:16][OH:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COc1ccc(N=C=S)c(C)n1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Agent: NC(N)=S
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(OC)nc3C)n(CCCO)c12
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (2.00 g) in tetrahydrofuran (40.0 mL) was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 14 hrs. The starting material wasn't consumed completely. To the mixture was added 3-isothiocyanato-6-methoxy-2-methylpyridine (1.67 g, 9.277 mmol). The reaction mixture was stirred at 70° C. for 36 hrs. After cooling, the solvent was removed by concentration. The residue was purified by silica gel column chromatography eluting with a 30-80% ethyl acetate/n-hexane gradient mixture to give the mixture contained thiourea and title compound. The mixture was subject to next step without further purification. The mixture was dissolved into tetrahydrofuran (30 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (885.7 mg, 4.62 mmol) and triethylamine (0.71 mL, 5.08 mmol). The reaction mixture was stirred at 50° C. for 2 hrs. After cooling, the mixture was diluted with water, extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound as a colorless solid (1.50 g, 3.72 mmol, 48% (2 steps)).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[CH2:14][CH2:13][N:9]3[S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[H][H]>CO.[Pd]>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:28]=[CH:27][C:6]2[CH2:7][CH:8]3[CH2:16][NH:15][CH2:14][CH2:13][N:9]3[S:10](=[O:11])(=[O:12])[C:5]=2[CH:4]=1
Reactant: O=C(OCc1ccccc1)N1CCN2C(Cc3ccc(C(F)(F)F)cc3S2(=O)=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=S1(=O)c2cc(C(F)(F)F)ccc2CC2CNCCN21
Reaction time: 1 h

Procedure:
To a solution of phenylmethyl 3,4,11,11a-tetrahydro-8-(trifluoromethyl)pyrazino[1,2-b][1,2]benzothiazine-2(1H)-carboxylate 6,6-dioxide (59.0 mg, 0.134 mmol) in methanol (2 mL) under a nitrogen atmosphere was added 10% Pd-C (6 mg). The nitrogen atomosphere was exchanged for hydrogen (provided by a balloon) using 3 pump/purge cycles. The reaction was stirred for 1 h. The hydrogen atmosphere was exchanged for nitrogen and the reaction was filtered through Celite® AFA. The pad was rinsed with methanol (1 mL). The combined filtrates were concentrated in vacuo to provide the title compound: LCMS (pos. ion spectrum) m/z 307.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[NH:5][CH:6]([CH3:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17]#[N:18])[CH:16]=1)[N:13]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH2:12][CH2:11]2)[CH3:2].OO.[OH-].[Na+].C(O)(=[O:38])C>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:31])[NH:5][CH:6]([CH3:30])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([C:17](=[O:38])[NH2:18])[CH:16]=1)[N:13]([CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[CH2:12][CH2:11]2)[CH3:2]
Reactant: CCOC(=O)NC(C)Cc1cc(C#N)c2c(c1)CCN2CCCO[Si](C)(C)C(C)(C)C
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)NC(C)Cc1cc2c(c(C(N)=O)c1)N(CCCO[Si](C)(C)C(C)(C)C)CC2
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-{1-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-7-cyano-2,3-dihydro-1H-indol-5-yl}-1-methyl-ethyl)-carbamic acid ethyl ester compound (V) (6 g, 0.01 mole) in DMSO (100 ml) was added 30% H2O2 (15 ml) and the mixture was stirred at 25-30° C. for 15 min. To the reaction mixture was then added 5 N NaOH solution (15 ml) and the mixture was stirred at above temperature for further period of 3 h. Acetic acid (18 ml) was added and reaction mixture was diluted with water. The mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and the solvent was evaporated under reduced pressure to give 3.68 g of (VI) as pale yellow waxy solid.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[C:14]([O:15]C)=[N:13][C:12]2[C:7](=[CH:8][C:9]([N+:30]([O-:32])=[O:31])=[CH:10][C:11]=2[CH2:17][N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:19][C:20]([OH:22])=[O:21])[N:6]=1.[BrH:33]>C(O)(=O)C.C(OCC)C>[BrH:33].[BrH:33].[O:4]=[C:5]1[C:14](=[O:15])[NH:13][C:12]2[C:7](=[CH:8][C:9]([N+:30]([O-:32])=[O:31])=[CH:10][C:11]=2[CH2:17][N:18]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:19][C:20]([OH:22])=[O:21])[NH:6]1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CN(CC(=O)O)Cc3ccccn3)c2nc1OC
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)CN(Cc1ccccn1)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
49 mg (0.1 mmol) of N-(2,3-dimethoxy-7-nitro-quinoxalin-5-ylmethyl)-N-(2-pyridylmethyl)-glycine dihydrochloride are stirred in 2 ml of a 48% solution of hydrogen bromide in acetic acid for 18 hours at 70° C. The mixture is diluted with diethyl ether and the solid is filtered off, washed with diethyl ether and dried. The title compound is obtained in the form of a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH2:58])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1>[CH2:47]([O:54][C:55](=[O:59])[CH2:56][CH2:57][NH:58][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:10]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(=O)O)c1
Reactant: NCCC(=O)OCc1ccccc1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(C(=O)NCCC(=O)OCc2ccccc2)c1

Procedure:
For the preparation of the ester starting material, m-(1-t-butoxyformamido)benzoic acid in THF is activated (2 hours, 0° C.) with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine and reacted with β-alanine benzyl ester p-toluenesulphonate and N-methylmorpholine to give N-[m-(1-t-butoxyformamido)benzoyl]-β-alanine benzyl ester, m.p. 130°-131° C. Cleavage with trifluoroacetic acid gives N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate. Nα -Z-Nω -Nitro-L-arginine is activated (4 minutes, -10° C.) with isobutyl chloroformate and triethylamine in THF and coupled with N-(m-aminobenzoyl)-β-alanine benzyl ester trifluoroacetate and triethylamine to give the desired benzyl ester, m.p. 157°-160° C.
Reaction SMILES: [CH2:1]([N:3]([C:8]1[CH:13]=[C:12](F)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[S:4]([CH3:7])(=[O:6])=[O:5])[CH3:2].[N:18]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH2:1]([N:3]([S:4]([CH3:7])(=[O:6])=[O:5])[C:8]1[CH:13]=[C:12]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:20]2)[CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])[CH3:2]
Reactant: CCN(c1cc(F)ccc1[N+](=O)[O-])S(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCN(c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])S(C)(=O)=O

Procedure:
N-Ethyl-N-(5-fluoro-2-nitrophenyl)methanesulfonamide (3.2 g, 12.2 mmol), tert-butyl 1-homopiperazinecarboxylate (2.5 g) and potassium carbonate (2 g) were heated together in DMSO at 50° C. for 5 hours. The solution was allowed to cool and poured into 500 mL of water. The solid product was collected by filtration, washed with water and dried. The product was purified by flash chromatography (ethyl acetate:petrol 1:1). Yield 2.6 g (48%) 1H NMR (400 MHz, CDCl3) δ 1.16 (t, J=7.33 Hz, 3 H), 1.39 (s, 9 H), 2.0 (br, 2 H), 2.99 (s, 3 H), 3.2 (br, 2 H), 3.54-3.75 (br, 8 H), 6.65 (br d, J=9.3 Hz, 1 H), 6.67 (d, J=2.93 Hz, 1 H), 8.1 (d, J=9.3 Hz, 1 H); MS (ESI+) for C19H30N4O6S m/z 442 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([S:23][C:24]2[S:25][C:26]([NH2:29])=[N:27][N:28]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[Na].[C:34]([O:40][CH2:41]I)(=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36].O>CN(C=O)C>[CH3:36][C:35]([CH3:38])([CH3:37])[C:34]([O:40][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[S:23][C:24]1[S:25][C:26]([NH2:29])=[N:27][N:28]=1)[C@H:11]([NH:10][C:8](=[O:9])[C:7]([C:5]1[N:6]=[C:2]([NH2:1])[S:3][C:4]=1[Cl:32])=[N:30][OH:31])[C:18]2=[O:19])=[O:22])=[O:39]
Reactant: CC(C)(C)C(=O)OCI
Reactant: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)C1=C(Sc2nnc(N)s2)CSC2[C@H](NC(=O)C(=NO)c3nc(N)sc3Cl)C(=O)N12
Reaction time: 1 h

Procedure:
To a stirring solution of (7R)-7-[2-(2-amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt (65 mg, 0.117 mmol) in DMF (0.3 mL) under nitrogen was added iodomethyl pivalate (31 mg, 0.128 mmol). After 1 h, water was added dropwise, and the precipitated product was removed by filtration to give 60.9 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[CH:43]=[C:42]([O:44][CH3:45])[N:41]=[C:40]([NH:46][C@@H:47]2[CH2:52][CH2:51][CH2:50][N:49]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:48]2)[N:39]=1
Reactant: COc1cc(Cl)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4c(F)cccc4F)cc23)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 90 °C
Yield: 62 %

Procedure:
To a solution of 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (600 mg, 1.17 mmol), and (R)-tert-butyl 3-((4-chloro-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (483 mg, 1.41 mmol) in DME (12 mL) and water (3 mL) was added Pd(PPh3)4 (270 mg, 0.234 mmol) and Na2CO3 (372 mg, 3.51 mmol) and argon gas was bubbled for 15 min. The above mixture was heated at 90° C. for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 30% EtOAc in petroleum ether) to give (R)-tert-butyl 3-((4-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)-6-methoxypyrimidin-2-yl)amino)piperidine-1-carboxylate (500 mg, 62.5%). MS (ESI, pos. ion) m/z: 690.2 (M+1); 1H-NMR (400 MHz CDCl3): δ ppm 8.16 (s, 1H), 8.09 (d, J=8 Hz, 1H), 7.84-7.90 (m, 3H), 7.26-7.46 (m, 6H), 7.02 (m, 2H), 6.41 (s, 1H), 5.07 (brs, 1H), 4.10-4.14 (m, 1H), 3.93 (s, 3H), 2.37 (s, 3H), 1.25-1.60 (m, 15H).
Reaction SMILES: [CH3:1][NH2:2].[CH:3]([C:6]1[C:7]([O:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([CH3:5])[CH3:4].[BH4-].[Na+]>CO>[CH:3]([C:6]1[C:7]([O:14][CH2:15][CH2:16][CH3:17])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][CH2:1][NH2:2])([CH3:5])[CH3:4]
Reactant: CCCOc1c(C=O)cccc1C(C)C
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(CCN)cccc1C(C)C
Reaction time: 72 h
Yield: 95 %

Procedure:
A solution of methylamine (30 mL of a 2.0 M solution in MeOH, 60 mmol) was added to 3-isopropyl-2-propoxybenzaldehyde (1.49 g, 7.22 mmol) and the mixture was stirred for 72 h. The solution was concentrated under reduced pressure. The resulting dark yellow oil was dissolved in EtOH (30 mL) and treated with NaBH4 (0.273 g, 7.22 mmol). After 18 h, the reaction mixture was concentrated under reduced pressure and dissolved in 1 N NaOH (30 mL). The mixture was extracted with Et2O (3×75 mL). The combined organics were dried (Na2SO4) and concentrated to yield the title compound (1.52 g, 95%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.21-7.14 (m, 2H), 7.04 (t, J=7.5 Hz, 1H), 3.70 (t, J=6.3 Hz, 2H), 3.63 (s, 2H), 3.32-3.23 (m, 1H), 2.28 (s, 3H), 1.78 (br s, 1H), 1.76-1.71 (m, 2H), 1.16 (d, J=6.9 Hz, 6H), 1.03 (t, J=7.3 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:11]1[O:13][CH2:12]1>CO>[OH:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: C1CO1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CO
Product: OCCN1CCC2(CC1)OCCO2
Temperature: -20 °C
Reaction time: 3 h

Procedure:
To 23 parts of 1,4-dioxa-8-azaspiro[4.5]decane in 300 parts by volume of methanol is added 15 parts of ethylene oxide in methanol. The mixture is stirred at -20° C. for 3 hours and allowed to warm to room temperature. The solvent is removed under reduced pressure and the residue distilled to afford N-hydroxyethyl-1,4-dioxa-8-azaspiro[4.5]-decane. The corresponding tosylate is formed by reacting 16 parts of the alcohol in 75 parts of dry pyridine with 21 parts of p-toluenesulfonylchloride. The mixture is stirred at 5° C. overnight and then poured into 300 parts by volume of ice water. The resulting solid is collected by filtration to afford the tosylate.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C[C@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Product: C[C@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (S)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described in Example 1. LC (method 2): tR=0.92 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])([CH3:28])[CH3:27].N1C=CN=C1.O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:18])([CH3:19])[CH3:20])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[C@@H:21]([OH:25])[CH2:22][CH2:23][O:24][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:32])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1[C@@H](O)CCO[Si](C)(C)C(C)(C)C
Yield: 92 %

Procedure:
To a solution of (2S,4R)-1-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-1,3-dihydroxypropyl]pyrrolidine (16.95 g, 45.2 mmol) in methylene chloride (200 ml) were successively added tert-butylchlorodimethylsilane (6.81 g, 45.2 mmol), 4-N,N-dimethylaminopyridine (0.55 g, 4.5 mmol) and imidazole (3.08 g, 45.2 mmol) in a nitrogen atmosphere under cooling with ice under stirring. The mixture was stirred at room temperature for 1 h. Then, the reaction solution was poured into water (200 ml). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, heptane-ethyl acetate=9:1→4:1) to give (2S,4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-[(S)-3-tert-butyldimethylsiloxy-1-hydroxypropyl]pyrrolidine (20.36 g, yield: 92.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][NH:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.Br[CH2:37][C:38]([NH2:40])=[O:39]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C@@H:24]5[CH2:28][CH2:27][CH2:26][N:25]5[CH2:37][C:38]([NH2:40])=[O:39])[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:33])[F:34])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CCCN1
Reactant: NC(=O)CBr
Product: NC(=O)CN1CCC[C@H]1CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(2S)-2-{[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]methyl}pyrrolidin-1-yl]acetamide was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-pyrrolidin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 145) and 2-bromoacetamide following General Procedure H.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:30]=[N:29][NH:28][N:27]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([O:33]C(OC(OC3CCCCC3)=O)C)=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1.C(OC1NC2C(CC3C=CC(C4C=CC=CC=4C4NN=NN=4)=CC=3)=CC=C(C(O)=O)C=2N=1)C.[C:79](Cl)([C:92]1[CH:97]=[CH:96][CH:95]=[CH:94][CH:93]=1)([C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:2]([O:3][C:4]1[N:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[C:26]3[N:27]([C:79]([C:80]4[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=4)([C:92]4[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=4)[C:86]4[CH:87]=[CH:88][CH:89]=[CH:90][CH:91]=4)[N:28]=[N:29][N:30]=3)=[CH:18][CH:19]=2)[C:11]2[C:10]([C:31]([OH:33])=[O:32])=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1)[CH3:1]
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOc1nc2c(C(=O)O)ccc(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2[nH]1
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
U.S. Pat. No. 5,196,444 discloses Candesartan cilexetil and a process for its preparation by the reaction of 2-ethoxy-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid with trityl chloride in presence of triethyl amine in methylene chloride and purification by column chromatography gives 2-ethoxy-1-[[2′-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid, which upon condensation with cyclohexyl 1-iodoethyl carbonate in presence of potassium carbonate in DMF followed by purification with column chromatography gives a colorless powder which is recrystallized in ethanol yields ‘C’ type crystals of Candesartan cilexitil.
Reaction SMILES: [CH3:1][N:2]([N:4]=[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)[NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])=[CH:7][CH2:6]1)[CH3:3].N1CC[CH2:33][CH2:32]1.CC(O)=O>>[N:2]1([N:4]=[C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:30])[CH:13]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[NH:14][C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:16])=[CH:9][CH2:10]2)[CH2:1][CH2:33][CH2:32][CH2:3]1
Reactant: CN(C)N=C1C=CC(NC(=O)C(NC(=O)Nc2ccc(Cl)cc2)c2cccs2)=CC1
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Cl)cc1)NC(C(=O)NC1=CCC(=NN2CCCC2)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To the thioimidate solution in MeOH (4 mL, 0.24 mmol) from Example 19, a pre-mixed pyrrolidine (0.11 mL, 1.32 mmol) and HOAc (0.11 mL, 1.92 mmol) were added. The mixture was then stirred at room temperature overnight. After being concentrated in vacuo, the residue was purified by HPLC to give a white powder (24 mg). MS 482.1 and 484.1 (M+H, Cl pattern).