Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:17]([O:24]C(CO)CO)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH:16]1[CH2:1][O:3][CH:4]([CH2:5][O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:14][CH2:15]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCC(CO)OCc1ccccc1
Reactant: CCOC(COCc1ccccc1)OCC
Product: c1ccc(COCC2OCC(OCc3ccccc3)CO2)cc1

Procedure:
Using the procedure of Example 47, benzyloxyacetaldehyde diethyl acetal and 2-benzyloxy-1,3-propanediol were reacted to give 5-benzyloxy-2-benzyloxymethyl-1,3-dioxane, nD25 1.5438. The ir spectrum was consistent with the assigned structure. The nmr spectrum indicated 28% cis isomer and 72% trans isomer.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]=O.[C:9](#[N:13])[CH2:10][C:11]#[N:12]>C(O)C.N1CCCCC1>[NH2:13][C:9]1[N:1]=[C:2]2[S:3][CH:4]=[CH:5][C:6]2=[CH:7][C:10]=1[C:11]#[N:12]
Reactant: N#CCC#N
Reactant: Nc1sccc1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: N#Cc1cc2ccsc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
2-Amino-thiophene-3-carbaldehyde described in Preparation Example T-4 (38 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol) were dissolved in ethanol (1 mL) to which piperidine (several drops) had been added, and the solution was stirred for 1 hour under reflux. The reaction solution was cooled to room temperature, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=10:1), and the title compound (50 mg, 0.29 mmol, 96%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.[Br:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[N:7]=[C:6]([C:8]3[S:9][C:10]([Cl:13])=[CH:11][CH:12]=3)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(Cl)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)s2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(5-chloro-thiophen-2-yl)-6-trifluoromethyl-pyrimidine (example A.1) (1.2 g, 4.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.88 g, 4.38 mmol) according to the general procedure IIb. Obtained as a white solid (0.73 g, 43%). MS (EI) 419.9 [(M)+]; mp 124° C.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].[B-](F)(F)(F)[F:40].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:40][C:22]1[CH:21]=[N:20][C:7]2[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:9]3[CH:10]=[N:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:6]=2[C:23]=1[N:24]1[CH2:28][CH2:27][C@H:26]([N:29]([CH2:37][CH3:38])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:25]1
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CCN(C(=O)OC(C)(C)C)[C@H]1CCN(c2c(F)cnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)pyrrolidin-3-yl(ethyl)carbamate (290 mg, 0.54 mmol) and Selectfluor™ (957 mg, 2.7 mmol) in acetonitrile (4.5 mL) was stirred at 0° C. for 5 minutes. The cooled reaction mixture was quenched with saturated aqueous sodium thiosulfate, diluted with ethyl acetate (50 mL), and washed with water (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as a pale yellow foam, which was used in the next step without any further purification (120 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].CS(C)=O.[CH2:26]1[O:34][CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[C:28]1([CH:27]([OH:34])[CH2:26][O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C2CO2)cc1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: OC(COCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer was separated and mixed with 10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a 2N-aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxy]ethanol (compound No. 144).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10](Br)=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:8][C:7]=2[CH:20]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:26]([OH:28])=[O:27])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[S:8][C:7]=2[CH:20]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)O)cc1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-bromobenzo[b]thiophene (15.0 g, 42.9 mmol) was dissolved in 300 mL of anhydrous THF under N2 and cooled to −70° C. To this solution was added nBuLi (29.6 mL, 47.4 mmol, 1.6 M solution in hexanes) dropwise via syringe. After stirring at −70° C. for 20 min, a steady stream of CO2 (g) was introduced into the reaction mixture for 15 min. The mixture was allowed to gradually warm to 0° C. and then quenched by pouring the mixture into cold 1 N HCl (500 mL). The aqueous layer was extracted with EtOAc (3×300 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to a solid. The crude product was chromatographed (SiO2, 25% EtOAc/hexanes) to provide 9.35 g (69%) of 6-methoxy-2-(4-methoxyphenyl)-3-carboxybenzo[b]thiophene as a white solid. mp 166-170° C. 1H NMR (DMSO-d6) δ (doubling due to rotamers) 13.0-12.8 (bs), 8.10 and 7.68 (d, J=8.1 Hz, 1H), 7.63 and 7.47 (d, J=8.6 Hz, 2H), 7.59 and 7.54 (d, J=2.0 Hz, 1H), 7.10 and 6.97 (dd, J=8.1, 2.0 Hz, 1H), 7.02 (d, J=8.6 Hz, 2H), 3.83 and 3.79 (s, 3H), 3.82 and 3.80 (s, 3H). FD mass spec: 315. Anal. Calcd. for C17H14O4S: C, 64.95; H, 4.49. Found: C, 65.19; H, 4.32.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[NH:37][CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1.[C:48]([O:52][C:53]([N:55]1[CH2:58][CH2:57][C@H:56]1[C:59](O)=[O:60])=[O:54])([CH3:51])([CH3:50])[CH3:49].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:45][CH2:44][N:34]3[C:35]4[N:43]=[CH:42][CH:41]=[CH:40][C:36]=4[N:37]([C:59]([C@@H:56]4[CH2:57][CH2:58][N:55]4[C:53]([O:52][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:54])=[O:60])[CH2:38][CH2:39][CH:33]3[CH2:32]2)=[CH:28][CH:27]=1
Reactant: Fc1ccc(CN2CCN3c4ncccc4NCCC3C2)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)N1CCC2CN(Cc3ccc(F)cc3)CCN2c2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (177 mg, 0.465 mmol) was added to a mixture of the product of Example 64C (97 mg, 0.31 mmol) and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (94 mg, 0.465 mmol, prepared as described in J. Med. Chem. 2005, 48, 7637-7647) in CH2Cl2 (2.0 mL). Diisopropylethylamine (0.108 mL, 0.620 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The mixture was applied directly to a column of silica gel and eluted with 5% methanol-CH2Cl2 to provide the title compound: MS (DCI) m/z 496 (M+H)+.
Reaction SMILES: [AlH4-].[Li+].O1CCCC1.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](OCC)=O)[CH2:20][CH2:19]1.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:25][N:21]1[CH2:22][CH2:23][CH2:24][CH:18]([NH:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:19][CH2:20]1
Reactant: CCOC(=O)N1CCCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CN1CCCC(Nc2nc3ccccc3[nH]2)CC1
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred and heated (50° C.) mixture of 6.4 parts of lithium tetrahydroaluminate and 450 parts of tetrahydrofuran were added portionwise 23.5 parts of ethyl 4-(1H-benzimidazol-2-ylamino)hexahydro-1H-azepine-1-carboxylate under nitrogen atmosphere. Upon complete addition, stirring was continued for 2 hours at reflux temperature. The reaction mixture was decomposed with ethyl acetate, 30 parts of a sodium hydroxide solution and 30 parts of water. The whole was filtered over diatomaceous earth and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 10.5 parts (55.0%) of N-(hexahydro-1-methyl-1H-azepin-4-yl)-1H-benzimidazol-2-amine; mp. 168.3° C. (compound 213).
Reaction SMILES: C([NH:8][CH2:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]([O:15][CH:16]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:17]([O:19]C(C)(C)C)=[O:18])=[O:14])(OC(C)(C)C)=O.[BrH:31]>C(O)(=O)C>[BrH:31].[NH2:8][CH2:9][C:10](=[O:30])[CH2:11][CH2:12][C:13]([O:15][CH:16]([C:17]([OH:19])=[O:18])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OC(C(=O)OC(C)(C)C)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NCC(=O)CCC(=O)OC(C(=O)O)c1ccccc1
Yield: 71 %

Procedure:
This compound was prepared from the product of 6b (2.75 g; 6.5 mmol) and 33% HBr in acetic acid (5 mL) as described in Example 1c. The crude product was purified by flash chromatography on a 40×55 mm silica gel 60 column eluted with 10% methanol in acetonitrile (400 mL) collecting 20×10 ml fractions. After evaporation of fractions 4-15 and vacuum-drying for 48 h at 40° C. and 0.01 mm Hg 1.60 g (71%) product was obtained (orange foam, mp 77-80° C.).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][C:12]3([C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[O:14]3)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.O>O1CCOCC1>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:15]([OH:22])=[O:14])[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC2(CC(c3cccc(C(F)(F)F)c3)=NO2)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccccc1-c1cc(-c2cccc(C(F)(F)F)c2)no1
Yield: 89 %

Procedure:
A mixture of 0.28 g. of 3'-(3-trifluoromethylphenyl)-spiro[isobenzofuran-1(3H), 5'(4'H)-isoxazol]-3-one, 0.5 ml. of concentrated HCl, 10 ml. of water and 6 ml. of dioxane was stirred at reflux for one hour. The mixture was cooled and filtered to give 0.25 g. of white solid; m.p. 176.5°-178° C. in 89% yield.
Reaction SMILES: O[C:2]1[CH:15]=[C:14](O)[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].OC1C=C(O)C=CC=1C(C1C=CC=CC=1O)=O.OC1C=C(O)C=CC=1C(C1C=CC(O)=CC=1O)=O>>[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:2]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Agent: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Agent: O=C(c1ccccc1O)c1ccc(O)cc1O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
2-hydrosybenzophenone, 2,4-dihydroxybenzophenone, 2,2′,4-trihydroxybenzophenone, 2,2′,4,4′-tetrahydroxy benzophenone, and 2,2′-dihydroxy-4-methoxy dibenzophenone.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH2:16][OH:17])[N:3]=1.[N+:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O-:20])=[O:19].C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:17][CH2:16][CH2:15][NH:14][C:4]1[N:5]=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[C:7]([C:8]#[N:9])=[C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N+:18]([O-:20])=[O:19])[CH2:28][CH2:29]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccccc1N1CCNCC1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCCO)nc1N1CCN(c2ccccc2[N+](=O)[O-])CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2,6-bis-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile was treated with 1-(2-nitro-phenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 60° C. to yield 2,4-bis-(2-hydroxy-ethylamino)-6-[4-(2-nitro-phenyl)-piperazin-1-yl]-pyrimidine-5-carbonitrile as a yellowish lyophilisate; MS: [M+H]+=429.
Reaction SMILES: C(N1CCCCC1)C.[C:9]([N:13]1[CH2:17][CH2:16][S:15][C:14]1=[S:18])(=[O:12])[CH2:10][CH3:11].C(O[C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1[C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH3:29])(=O)C.C(=O)(O)[O-].[Na+]>ClCCl.[Br-].[Zn+2].[Br-]>[Si:31]([O:30][C@@H:28]([C@@H:24]1[C@@H:23]([CH:10]([CH3:11])[C:9](=[O:12])[N:13]2[CH2:17][CH2:16][S:15][C:14]2=[S:18])[NH:26][C:25]1=[O:27])[CH3:29])([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:32])[CH3:33]
Reactant: CCC(=O)N1CCSC1=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCN1CCCCC1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: ClCCl
Product: CC(C(=O)N1CCSC1=S)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a suspension of stannous trifluoromethanesulfonate (1.63 g) and N-ethylpiperidine (0.827 ml) in dichloromethane (12 ml) was added dropwise a solution of 3-propionyl-2-thioxothiazolidine (1.07 g) in dichloromethane (9 ml) at -78° C. under nitrogen atmosphere. After stirring at -78° C. for 30 minutes, a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (0.876 g) and zinc bromide (1.37 g) in dichloromethane (3 ml) was added to the reaction mixture, and the reaction mixture was stirred at -20° C. for 15 hours. The reaction mixture was poured into aqueous sodium bicarbonate solution (30 ml) and the precipitated white mass was removed by passing through a layer of Celite. The organic layer was separated and washed with 10% aqueous sodium chloride solution (30 ml×2). The organic solution was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (21 g) eluting with a mixture of acetone and dichloromethane (2:98, V/V) to give (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(1RS)-1-methyl-2-oxo-2-(2-thioxothiazolidin-3-yl)ethyl]-2-azetidinone (878 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Br[CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:6]1([C@@H:2]([N:1]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]([OH:5])=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)[C@@H](c1ccccc1)N1CCCC1

Procedure:
To (R)-2-amino-2-phenylacetic acid (1.0 g, 6.62 mmol), 1,4-dibromobutane (1.57 g, 0.727 mmol) and sodium carbonate (2.103 g, 19.85 mmol) was added ethanol (40 mL) and the resultant mixture heated at 100° C. for 65 hours. After cooling, the resultant solid was removed by filtration and washed with ethanol. The filtrate was concentrated, and then dissolved in ethanol then a solution of 4N aqueous hydrochloric acid added until the pH of the solution was 3. The resultant solid was removed and discarded. The filtrate was concentrated and purified by reversed phase chromatography (C18), eluting with 10-100% acetonitrile in water (0.1% TFA) to give the title compound. MS (ESI) m/z 206 (M+H)+.
Reaction SMILES: [Cl-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([OH:17])=O)[C:12]([C:18]3[S:22][C:21]([CH3:23])=[N:20][CH:19]=3)=[N:11]2)=[N:8][CH:9]=1.[O-:24][N+:25]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[C:27]([C@H:35]([NH2:37])[CH3:36])[CH:26]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([NH:37][C@@H:35]([C:27]3[CH:26]=[N+:25]([O-:24])[C:30]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:28]=3)[CH3:36])=[O:17])[C:12]([C:18]3[S:22][C:21]([CH3:23])=[N:20][CH:19]=3)=[N:11]2)=[N:8][CH:9]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: Cc1ncc(-c2nn(-c3ccc(F)cn3)cc2C(=O)O)s1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ncc(-c2nn(-c3ccc(F)cn3)cc2C(=O)N[C@H](C)c2ccc(C(F)(F)F)[n+]([O-])c2)s1
Temperature: 50 °C
Reaction time: 2 h
Yield: 58.5 %

Procedure:
To a solution of sodium chloride salt of 1-(5-fluoropyridin-2-yl)-3-(2-methyl-1,3-thiazol-5-yl)-1H-pyrazole-4-carboxylic acid (0.14 g, 0.25 mmol) in DMF (2.5 mL) was added (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (66.2 mg, 0.27 mmol), EDC (83.0 mg, 0.43 mmol), HOAT (16.9 mg, 0.12 mmol) and triethylamine (0.21 mL, 1.49 mmol). The mixture was stirred at 50° C. After 2 h, saturated aqueous NaHCO3 were added and the mixture was extracted with dichloromethane (3×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane 85% dichloromethane/methanol) gave the title compound (72 mg). HRMS 493.1070 (M+1). 1H NMR (500 MHz, DMSO): δ 9.41 (s, 1H); 8.61 (s, 1H); 8.56 (s, 1H); 8.48 (s, 1H); 8.04-8.02 (m, 2H); 7.94 (d, J=8.4 Hz, 1H); 7.56 (d, J=8.3 Hz, 1H); 5.17-5.14 (m, 1H); 2.67 (s, 3H); 1.51 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([O:38]CC)=[O:37])([CH3:35])[CH3:34])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:32][C:33]([C:36]([OH:38])=[O:37])([CH3:34])[CH3:35])=[C:6]([CH:8]2[C:13]3([C:21]4[C:16](=[CH:17][C:18]([Cl:22])=[CH:19][CH:20]=4)[NH:15][C:14]3=[O:23])[CH:12]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[CH2:11][C:10](=[O:31])[NH:9]2)[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(Br)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 60 °C
Yield: 91.3 %

Procedure:
To a mixture of racemic(2′R, 3R, 4′S)-2′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (700 mg, 1.08 mmol) in methanol (20 mL) was added a solution of NaOH (120 mg, 3 mmol) in water (10 mL). The mixture was heated at 60° C. for 1.5 h, evaporated to remove methanol, cooled to room temperature, and acidified to “pH” 2 with HCl aq. The precipitate was collected, washed with water and dried to give the title compound as a white solid (610 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([Br:21])(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Br
Reactant: OCc1cccc(OCc2ccccc2)c1
Solvent: ClCCl
Product: BrCc1cccc(OCc2ccccc2)c1

Procedure:
A solution of 3-benzyloxybenzyl alcohol (9.54 g) in methylene chloride (40 ml) with TMSBr (2.5 eq, 13 mL) was heated at reflux for 1 hr. After cooling, the reaction was concentrated and then reconcentrated 2 × with methylene chloride (40 ml). The residue was chromatographed on silica gel eluting first with hexane followed by 10% methylene chloride in hexane to afford 3-benzyloxybenzyl bromide which solidifies on cooling . 5.75 g m.p. 38°-40°.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C.C(Cl)Cl>[CH3:19][C:18]1[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)CCC(=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)ccc1-c1ccccc1
Temperature: 70 °C
Yield: 72.5 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (1.378 g, 9.87 mmol) was diluted with ethanol (50 ml) then charged with TEA (8 ml, 57.4 mmol). 1-Phenylpentane-1,4-dione (1.74 g, 9.87 mmol) was then added and reaction was heated at 70° C. overnight. The reaction mixture was then diluted with 100 mL DCM and washed with water (100 mL). The aqueous was back-extracted with DCM (50 mL×2), the organics were combined, dried (Na2SO4), filtered, and concentrated to yield a crude orange oil. This oil was loaded onto a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording 1.74 g (72.4% yield) of the desired ethyl 2-(2-methyl-5-phenyl-1H-pyrrol-1-yl)acetate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:24]=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[N:22]3[N:42]=[CH:43][C:44]([C:45]4[CH:46]=[N:47][C:48]5[C:53]([CH:54]=4)=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:21]3[N:20]=2)[CH2:15][CH2:14]1)=[O:12]>C(#N)C>[CH3:9][O:10][C:11]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:24]([Br:1])=[C:23]([N:25]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[N:22]3[N:42]=[CH:43][C:44]([C:45]4[CH:46]=[N:47][C:48]5[C:53]([CH:54]=4)=[CH:52][CH:51]=[CH:50][CH:49]=5)=[C:21]3[N:20]=2)[CH2:17][CH2:18]1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Solvent: CC#N
Product: COC(=O)C1CCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
N-bromosuccinimide (148 mg, 0.832 mmol) was added to a solution of 4-{7-[bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (500 mg, 0.756 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the resulting oil is then purified via silica gel chromatography (0% to 30% ethyl acetate in hexanes gradient) to yield the title compound (530 mg, 95% yield) as yellow oil. LC-MS: 740 [M+H].