Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([OH:20])=O)[N:4]=1.[C:21]1([S:27]([NH2:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N12CCCN=C1CCCCC2.Cl>O1CCCC1>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[C:18]([NH:30][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[O:20])[N:6]=1
Reactant: COc1cc(OC)nc(O[C@@H]2CCCC[C@H]2C(=O)O)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(O[C@@H]2CCCC[C@H]2C(=O)NS(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.7 %

Procedure:
trans-2-(4,6-Dimethoxypyrimidin-2-yl)oxycyclohexanecarboxylic acid (1.0 g), prepared as in Example 11, in dry tetrahydrofuran (10 ml) was added dropwise to a stirred solution of 1,1-carbonyldiimidazole (0.57 g) in dry tetrahydrofuran (10 ml) under nitrogen. The reaction mixture was stirred 30 minutes at ambient temperature, heated to reflux for 30 minutes and cooled to ambient temperature. Benzenesulphonamide (0.56 g) was added followed by dropwise addition of 1,8-diazabicyclo (5.4.0) undec-7-ene (0.54) in dry tetrahydrofuran (5 ml). The reaction mixture was stirred for 24 hours at ambient temperature, refluxed for 6 hours then poured into 1N hydrochloric acid (80 ml) and extracted with 3×100 ml portions of diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated. The residue was chromatographed on silica-gel, using a 2:1 dichloromethane/ethyl acetate eluant, to give 100 mg of the title compound, melting point 175° C.
Reaction SMILES: [CH2:1]([Si:4]([CH2:9][CH2:10][CH3:11])([CH2:6][CH2:7][CH3:8])Cl)[CH2:2][CH3:3].[C:12]([NH:20][CH:21]1[C:35](=[O:36])[N:23]2[C:24]([C:32]([OH:34])=[O:33])=[C:25]([CH2:30][Br:31])[CH:26]([Br:29])[S:27](=[O:28])[C@H:22]12)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCCl>[C:12]([NH:20][CH:21]1[C:35](=[O:36])[N:23]2[C:24]([C:32]([O:34][Si:4]([CH2:9][CH2:10][CH3:11])([CH2:6][CH2:7][CH3:8])[CH2:1][CH2:2][CH3:3])=[O:33])=[C:25]([CH2:30][Br:31])[CH:26]([Br:29])[S:27](=[O:28])[C@H:22]12)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Reactant: CCC[Si](Cl)(CCC)CCC
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC[Si](CCC)(CCC)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
123 mg of tri-n-propylchlorosilane were added to a suspension of 312 mg of 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylic acid-1-oxide (prepared by the process of Step D of Example 1) in 25 ml of 1,2-dichloroethane under a nitrogen atmosphere and then a solution of 64 mg of triethyl-amine in 4 ml of 1,2-dichloroethane was dropwise added over 15 minutes under cooling in an ice-bath. The clear, slightly yellow colored solution was stirred for two hours at room temperature and after removal of the solvent under vacuo, 7 ml of diethyl ether was added. The obtained suspension was centrifuged and the clear liquid layer was separated and evaporated to dryness under vacuo. The residue was kept at a pressure of 0.5 mm of mercury for half an hour to obtain 210 mg of tri-n-propylsilyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate-1-oxide having the following characteristics:
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([Li])[CH2:27]CC.IC>O1CCCC1>[C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([N:16]([CH2:26][CH3:27])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:6]=1[CH3:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]CCCC
Reactant: COc1ccc(Nc2cc3c(c(C(C)(C)C)c2C)OCC3(C)C)cc1
Solvent: C1CCOC1
Solvent: CI
Product: CCN(c1ccc(OC)cc1)c1cc2c(c(C(C)(C)C)c1C)OCC2(C)C
Yield: 92 %

Procedure:
Following general procedure L and using 7-t-butyl-5-[(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 53), (0.12 g, 0.35 mmol), 1.6M solution of n-butyllithium in hexanes (0.442 mL, 0.7 mmol) and iodomethane (0.281 mL, 3.5 mmol) in 2 mL of anhydrous tetrahydrofuran, the title compound (0.11 9 g, 92%) was obtained as a brown oil. 1H NMR (300 MHz, CDCl3): δ 6.76 (d, 2H, J=9.0 Hz), 6.72 (s, 1H), 6.41 (d, 2H, J=9.0 Hz), 4.14 (s, 2H), 3.73 (s, 3H), 2.60 (s, 3H), 1.52 (s, 9H), 1.26 (s, 6H), 1.20 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][OH:10].[ClH:11]>>[ClH:11].[CH3:9][O:10][C:3]([C@H:4]1[CH2:7][C@@H:1]([NH2:2])[CH:6]=[CH:5]1)=[O:8]
Reactant: CO
Reactant: O=C1NC2C=CC1C2
Agent: Cl
Product: COC(=O)[C@@H]1C=C[C@H](N)C1
Temperature: 5 °C
Yield: 78.6 %

Procedure:
20.0 g (183.3 mmol) of 2-azabicyclo[2.2.1]hept-5-en-3-one and 400 mL (400 mmol) of a 1N-hydrogen chloride methanol solution were put into a four-necked flask (500 mL volume) equipped with a thermometer, and the mixture was heated and refluxed for 10 hours. The obtained reaction mixture was concentrated under reduced pressure. The residue was dissolved in 27 mL of diethyl ether, and then cooled to 5° C. The precipitated crystals were filtered off using a glass filter. The obtained crystals were dried under reduced pressure to give 25.6 g (144.1 mmol) of cis-4-amino-2-cyclopentene-1-carboxylic acid methyl ester hydrochloride. The yield was 78.6%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:21]2[SH:22])=[CH:16][CH:15]=1
Reactant: NCC(=O)c1ccc(F)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2cnc(S)n2-c2ccc(Cl)cc2)cc1
Temperature: 90 °C
Yield: 99.2 %

Procedure:
A mixture of 2-amino-1-(4-fluoro-phenyl)-ethanone hydrochloride (5.0 g, 26.5 mmol), 4-chlorophenyl isothiocyanate (4.49 g, 26.5 mmol) and sodium hydrogencarbonate (3.3 g, 39.7 mmol) in ethanol (100 mL) was heated at 90° C. for 2 hours. The solvent was removed under reduce pressure. The resulting residue was re-suspended in aqueous 1N sodium hydroxide (50 mL) and heated at 100° C. overnight. The hot mixture was filtered, cooled and carefully acidifed with aqueous 6N HCl. The resulting mixture was filtered to give 1-(4-chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazole-2-thiol (8.0 g, 26.3 mmol) as a yellow solid after drying.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:11]3[CH:12]=[CH:13][CH:14]=[C:10]3[O:9][C:8]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:20]I>C1C=CC=CC=1>[I:20][C:8]1([CH2:16][C:17]([OH:19])=[O:18])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[C:11]2[CH:12]=[CH:13][CH:14]=[C:10]2[O:9]1
Reactant: O=C(O)Cc1oc2cccc-2cc1-c1ccccc1
Reactant: II
Solvent: c1ccccc1
Product: O=C(O)CC1(I)OC2=CC=CC2=CC1c1ccccc1

Procedure:
To a solution of 2.08 g. (8.25 mmoles) of 3-phenyl-7-benzofuranacetic acid in 10 ml. of benzene at 60° C. is slowly added small portions of yellow mercuric oxide (1.45 g., 6.7 mmoles) and iodine (2.09 g., 8.25 mmoles). After about two hours the mixture is filtered, then the filtrate is evaporated to dryness to provide 2-iodo-3-phenyl-7-benzofuranacetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C.CCOC(C)=O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]3[CH3:14])[CH:7]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(C)n1-c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)n1-c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 30 %

Procedure:
To a stirred solution of 1-(5-chloro-2-nitro-phenyl)-2,5-dimethyl-1H-pyrrole (73 mg, 0.29 mmol, as prepared in the previous step) in DMF (2 mL) was added piperazine-1-carboxylic acid tert-butyl ester (542 mg, 2.9 mmol) and the result was heated to 90° C. for 18 h. The reaction a diluted with EtOAc (50 mL), washed with H2O (2×25 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromtographed on a SPE column (5 g, SiO2) to afford 35 mg (30%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 8.13 (d, 1H, J=9.3 Hz), 6.91-6.88 (m, 1H), 6.66 (s, 1H), 5.93 (s, 2H), 3.63-3.60 (m, 4H), 3.42-3.40 (m, 4H), 1.97 (s, 6H), 1.48 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C)=[O:30])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>C1COCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCCCCNC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)NCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
67 mg of methyl 8-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}-amino)octanoate Example 16 (0.15 mmol, 1 equivalent) were dissolved in 2.5 ml of THF, and 0.3 ml of 1 M lithium hydroxide solution in water (0.3 mmol, 2 equivalents) was added. The mixture was stirred at RT overnight and then acidified with 1 M aq. hydrochloric acid and concentrated. The residue was dissolved in methanol/acetonitrile and purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid). this gave 22 mg (34% of theory; purity: 100%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([O:52][CH3:53])[CH:48]=[CH:47][C:46]=1[F:54]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:54])=[CH:47][CH:48]=[C:49]([O:52][CH3:53])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(F)c(CBr)c1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccc(F)c(Cn2nc3nc(C(C)(C)C)nc(N4CCC(F)(F)C4)c3n2)c1Cl

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1-fluoro-4-methoxybenzene and isolated as white solid. MS (m/e): 455.3 (MH+).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][S:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=3)[N:31]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C)C=O>[C:1]([S:3][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][S:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=3)[N:31]=2)[CH:17]=[CH:16][N:15]=1)(=[O:4])[CH3:2]
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)SCc1nccc(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A suspension of potassium thioacetate (0.44 g, 3.75 mmol) and potassium carbonate (0.87 g, 6.25 mmol) in 10 ml of dimethylformamide is stirred at room temperature for 30 min and then treated with a solution of 1.03 g (2.5 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine in 10 ml of dimethylformamide. The suspension is stirred at room temperature for a further 18 h. Water (100 ml) is then added, and the mixture is cooled to 0° C. and filtered. After drying the solid in vacuo at 40° C., it is additionally suspended in hot diisopropyl ether. After cooling to room temperature, the solid is again filtered and dried. 1.02 g (98%) of the title compound are isolated as a pale beige solid. M.p.: 138-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33](B(O)O)=[C:34]([CH3:37])[CH:35]=2)[CH:30]=[N:29]1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:33]5[CH:32]=[C:31]6[C:36](=[CH:35][C:34]=5[CH3:37])[N:28]([CH3:27])[N:29]=[CH:30]6)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1cc2c(cnn2C)cc1B(O)O
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5cc6cnn(C)c6cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 1,6-dimethyl-indazole-5-boronic acid following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.89 min; Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.[I:13]N1C(=O)CCC1=O.O>O1CCOCC1>[NH2:1][C:2]1[C:10]([I:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(N)ccc1C(=O)O
Reactant: O=C1CCC(=O)N1I
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(N)c(I)cc1C(=O)O
Yield: 49.1 %

Procedure:
To a stirred and heated (25° C.) solution of 5 g of 4-amino-2-methoxy benzoic acid in 75 ml of 1,4-dioxane were added 6.9 g of grinded 1-iodo-2,5-pyrrolidinedione. The mixture was stirred in an oil bath at 105° C. for 3 hours. After the addition of 300 ml of water, the crystallized product was filtered off and dried, yielding 4.3 g (48.9%) of 4-amino-5-iodo-2-methoxybenzoic acid; mp. 180.6° C. (interm. 5).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6](Cl)=[O:7])[CH3:2].C[O:11][C:12](=O)[CH2:13][C:14]1([NH2:17])[CH2:16][CH2:15]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([NH:17][C:14]1([CH2:13][CH:12]=[O:11])[CH2:16][CH2:15]1)=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)CC1(N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)NC1(CC=O)CC1
Yield: 40.3 %

Procedure:
Chlorocarbonyl-acetic acid ethyl ester (2.75 ml; 22.1 mmol) is added dropwise under stirring and cooling to a solution of (1-amino-cyclopropyl)-acetic acid methyl ester (Chemstep Product List, 13926) (3.00 g; 23.2 mmol) in triethylamine (6.4 ml; 46.2 mmol) and CH2Cl2 (150 ml). After stirring at room temperature for 30 minutes, the reaction mixture is poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness. Purification via chromatography (SiO2; hexane/acetone 6:4) yield the title compound as crystalline light-yellow solid (1.9 g; 34%) 1H-NMR (400 MHz; DMSO-d6): 8.40 (s, 1H); 4.07 (q, 2H); 3.60 (s, 3H); 3.12 (s, 2H); 2.58 (s, 2H); 1.17 (t, 3H); 0.71 (m, 2H); 0.66 (m, 2H). MS (m/z) ES+: 244 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (100 mg), ethyl glycinate (50 mg) and acetic acid (5 mg) in DCM (15 mL) was added sodium triacetoxyborohydride (52 mg). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo to afford the crude product ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propyl}glycinate (D93) (100 mg), which was used directly in the next step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ncccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (more polar isomer) (22 mg, 0.091 mmol), 1-naphthalenesulfonyl chloride (38 mg, 0.18 mmol) and 1M NaN(TMS)2 (200 μL, 0.10 mmol) in THF (2.5 mL) at RT.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[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.[CH2:34]([O:36][CH2:37][CH2:38][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)[CH3:35]>>[CH3:1][O:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[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]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[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:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1cc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c(OC)cc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 7.6 using 1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl) pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give the title compound: Rf=0.42 (silica gel, 9/1/0/1 dichloromethane/methanol/concentrated aqueous ammonia).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:4]1[CH:3]=[CH:2][C:1]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:6][CH:5]=1)([O-:14])=[O:13]
Reactant: c1ccc(-c2nccs2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(-c2nccs2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A solution of 2-phenyl thiazole (200 mg, 1.24 mmol) in conc. sulphuric acid (0.5 ml) was cooled to 0° C. The nitrating mixture (made up of 0.5 ml of conc. nitric acid and 0.5 ml of conc. sulfuric acid) was added dropwise and stirred at 0° C. for 1 hr. The reaction was quenched with ice water and basified with sodium hydroxide solution. The resultant precipitate was filtered and washed with water. Purification by column chromatography over silica gel using EtOAc/pet ether gave 2-(4-nitrophenyl) thiazole (150 mg, 58.6%) as solid.
Reaction SMILES: [Na].[C:2]1([CH3:22])[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:9])=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][Cl:28]>C(O)C>[Cl:28][CH2:27][CH2:26][CH2:25][CH2:24][C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])([NH:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:22])=[CH:3][CH:4]=1)=[O:9])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: ClCCCCBr
Reactant: CCOC(=O)C(NC(=O)c1ccc(C)cc1)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(CCCCCl)(NC(=O)c1ccc(C)cc1)C(=O)OCC
Yield: 54.6 %

Procedure:
Sodium (6.42 g) was dissolved in 390 ml of ethanol at room temperature. To the solution was added 78.0 g of diethyl p-toluoylaminomalonate, and 47.9 g of 1-bromo-4-chlorobutane was added dropwise under heating to reflux. The mixture was heated to reflux for 20 hours. The reaction solution was concentrated. To the residue was added water, and the mixture was washed with ethyl acetate. After washing with 10% hydrochloric acid and water sequentially, the solution was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=9:1) to provide 55.7 g of the objective compound as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][C:12]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])[CH3:13]>>[C:12]([Si:15]([O:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:11]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cc(Br)cc1F

Procedure:
The title compound was prepared by reacting 4-bromo-2,6-difluoro-phenol (10.54 g, 50.4 mmol) with TBDMS-Cl (9.88 g, 150.7 mmol) according to method E to yield 14.61 g (90%) of a clear, colorless, oil: 1H NMR (CDCl3) δ 0.17 (6H, s), 0.99 (9H, s), 7.02 (H, d, J=7.13 Hz).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([CH3:7])[N:3]1[C:8]([C:10]1([NH:15]C(=O)OC(C)(C)C)[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9].[ClH:23]>O1CCOCC1>[ClH:23].[NH2:15][C:10]1([C:8]([N:3]2[C@@H:4]([CH3:7])[CH2:5][CH2:6][C@H:2]2[CH3:1])=[O:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C[C@@H]1CC[C@H](C)N1C(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CC[C@H](C)N1C(=O)C1(N)CCCC1
Temperature: 23 °C
Reaction time: 64 h

Procedure:
To tert-butyl 1-((2R,5S)-2,5-dimethylpyrrolidine-1-carbonyl)cyclopentylcarbamate (170 mg, 0.548 mmol) was added a 4.0 M dioxane solution of hydrogen chloride (0.137 mL, 0.548 mmol). The mixture was stirred at 23° C. for 64 h then concentrated. The residue was taken up in ether (10 mL). The precipitate was collected by filtration, rinsed with ether, and dried to provide the title compound as a white solid.