Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH2:32])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:33](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)C1C=CC=CC=1>>[CH2:17]([N:24]1[CH2:28][C@H:27]2[C@H:29]([NH:32][C:14](=[O:16])[C@@H:9]([N:8]([CH3:33])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][CH3:13])[CH2:30][CH2:31][C@H:26]2[CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Product: CCC[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N(C)C(=O)OC(C)(C)C

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step E of Example 16 for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5, temperature 90° C.) δ ppm 7.36-7.38 (m, 2H), 7.28-7.31 (m, 3H), 7.21 (t, J=7.2 Hz, 1H), 4.70-4.79 (m, 1H), 4.23-4.29 (m, 1H), 3.57 (d, J=13.2 Hz, 1H), 3.47 (d, J=13.2 Hz, 1H), 2.95 (s, 3H), 2.77-2.81 (m, 1H), 2.48-2.52 (m, 1H), 2.39-2.46 (m, 2H), 2.36 (dd, J=9.0, 2.9 Hz, 1H), 2.30 (t, J=8.0 Hz, 1H), 2.07 (dq, J=12.1, 6.1 Hz, 1H), 1.92-2.03 (m, 1H), 1.72-1.86 (m, 2H), 1.50-1.59 (m, 1H), 1.47 (s, 9H), 1.36-1.44 (m, 1H), 1.25-1.35 (m, 2H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 430 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[F:29][C:17]([F:16])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2)(=[O:25])=[O:26]
Reactant: CCOC(=O)c1cc2cccc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3C(F)(F)F)c2[nH]1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a mixture of ethyl 7-amino-1H-indole-2-carboxylate (4.1 g) and pyridine (60 mL) was added 2-trifluoromethylbenzenesulfonyl chloride (5.0 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 18 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The solution was washed with aqueous citric acid solution and saturated brine, and filtrated through silica gel. The eluate was concentrated under reduced pressure, and the obtained pale-brown oil was crystallized from ethyl acetate-hexane to give the title compound (7.3 g, yield 88%) as pale-brown crystals. MS: 413 (MH+). melting point: 138-139° C.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:1]1([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:40]3[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)[C:19]([C:24]([N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)=[O:25])=[CH:18]4)=[O:14])[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCCCC2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCCC2)CC1
Yield: 66 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-([1,4′]bipiperidinyl-1′-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 168), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a brown oil (66%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[CH3:20])=[CH:7][CH:6]=1)[CH3:2].O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:48](=[O:52])[CH:49]([CH3:51])[CH3:50].O>O1CCCC1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[C:9]2[C:8](=[CH:7][CH:6]=1)[NH:11][CH:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[CH3:20])[C:49]([CH3:51])([CH3:50])[CH:48]2[OH:52])=[O:21])[CH3:2]
Reactant: CC(C)C=O
Reactant: CCOC(=O)c1ccc(N=Cc2cc(F)ccc2C)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(F)ccc1C)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a mixture of 4-{[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (3.01 g, 10.6 mmol) and ytterbium(III) triflate hydrate (0.66 g, 1.06 mmol) in dry tetrahydrofuran (10 mL) at 25° C. was added isobutyraldehyde (0.96 mL, 10.6 mmol) and water (190 mg, 10.6 mmol) dropwise. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(5-fluoro-2-methyl-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethylester (3.78 g, 100%) as a light yellow oil: LC/MS m/e calcd for C21H24FNO3 M+: 357.4, observed: 340.3.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[CH2:20]([C:28]1[CH:29]=[N:30][C:31]([C:34]2[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=2)=[N:32][CH:33]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[OH-].[Na+].O>C(O)CCC.C(Cl)(Cl)Cl>[CH2:20]([C:28]1[CH:33]=[N:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:11][CH:12]([F:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:36][CH:35]=2)=[N:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCC(F)COS(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCCCO
Product: CCCCCCCCc1cnc(-c2ccc(OCC(F)CCCCC)cc2)nc1
Reaction time: 5.5 h

Procedure:
0.43 g (1.5 mmol) of the thus obtained (+)-2-fluoroheptyl p-toluenesulfonate and 0.28 g (1.0 mmol) of 5-octyl-2-(4-hydroxyphenyl)pyrimidine were mixed with 0.2 ml of 1-butanol, followed by sufficient stirring. To the solution was quickly added a previously obtained alkaline solution of 0.048 g (1.2 mmol) of sodium hydroxide in 1.0 ml of 1-butanol, followed by 5.5 hours of heat-refluxing. After the reaction, 10 ml of distilled water was added, and the mixture was extracted respectively once with 10 ml of benzene and 5 ml of benzene, followed by drying with an appropriate amount of anhydrous sodium sulfate, distilling-off of the solvent and purification by silica gel column chromatography (eluent: chloroform to obtain 0.17 g (0.43 mmol) of objective (+)-5-octyl-2-[4-(2-fluoroheptyloxy)phenyl]pyrimidine.
Reaction SMILES: C([Li:5])CCC.[CH3:6][N:7]([CH3:15])[C:8]1[C:9]([CH3:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>CCCCCC.C(OCC)C>[CH3:6][N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Li:5]
Reactant: Cc1ccccc1N(C)C
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]Cc1ccccc1N(C)C

Procedure:
To a mixture of 23 ml of a 1.6 M solution of butyllithium in hexane and 10 ml of ethyl ether was added 5.0 g of N,N-dimethyl-o-toluidine with stirring. The mixture gradually became yellow and overnight a pale yellow solid was deposited. It was separated by filtration and dried, to give 2.0 g of 2-dimethylaminobenzyllithium.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:17].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)=[O:17]
Reactant: O=C(NC1CCNCC1)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: BrCc1ccccc1
Product: N
Product: O=C(NC1CCN(Cc2ccccc2)CC1)[C@@H]1CCCCN1c1nc2ccccc2o1

Procedure:
The title compound was prepared by a similar method to Example 6 from (2S)-1-(1,3-benzoxazol-2-yl)-N2-(4-piperidinyl)-2-piperidinecarboxamide [see Example 31] and benzyl bromide. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-(1-benzyl-4-piperidinyl)-2-piperidinecarboxamide as an oil.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[N:35]=[CH:34][C:33]([C:36](OC)=[O:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:36]([C:33]3[CH:34]=[N:35][C:30]([CH:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[N:31][CH:32]=3)=[O:37])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(C2CCN(C)CC2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(C4CCN(C)CC4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
Trimethylaluminium (2 M in toluene, 1.168 ml, 2.34 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (231 mg, 0.93 mmol) and methyl 2-(1-methylpiperidin-4-yl)pyrimidine-5-carboxylate (220 mg, 0.93 mmol) in anhydrous toluene (4.671 ml) at 25° C. The resulting solution was stirred at 60° C. for 2 h. The reaction mixture was poured into methanol (100 mL), acidified with 2M HCl and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (166 mg, 39%) as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[S:29][C:11]2[S:12][CH2:13][CH2:14][C:15]3[C:16](=[N:17][N:18]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:19](=[O:21])[CH:20]=3)[C:10]=2[CH:9]=1)=O)(=[O:3])[CH3:2].C([SiH](CC)CC)C.O>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:8]1[S:29][C:11]2[S:12][CH2:13][CH2:14][C:15]3[C:16](=[N:17][N:18]([C:22]4[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=4)[C:19](=[O:21])[CH:20]=3)[C:10]=2[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 36.9 %

Procedure:
To a solution of 2.8 g of 9-acetyloxyacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one obtained in Example 51 in 40 ml of trifluoroacetic acid is added 3.0 ml of triethylsilane and the mixture is stirred for 5 hours at room temperature. After the completion of reaction, to the mixture is added water and the solution is extracted with chloroform. The extract is washed, dried and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform and methanol (99:1). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 1.0 g of 9-(2-acetoxyethyl)-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 115°-117° C.
Reaction SMILES: [Li]CCCC.C(N[CH:10]([CH3:12])[CH3:11])(C)C.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1.BrCC1C2C=CC(O[Si](C(C)(C)C)(C)C)=CC=2O[N:26]=1>O.C1COCC1>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:10]([CH3:11])[C:12]#[N:26])=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(CBr)noc2c1
Reactant: CC(C)NC(C)C
Reactant: COc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(C)C#N)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A solution of n-BuLi 2.0M in THF (9.7 mmoles) was slowly added to a solution of diisopropylamine (1.3 ml, 1.05 eq) and dry THF (10 ml) at −20° C. under N2. The mixture was stirred for 30 min at −20° C., then 4-methoxybenzonitrile (1.3 g, 8.8 mmoles) and dry THF (10 ml) were slowly added at −78° C. The mixture was stirred for 30 min at −78° C., then 3-(bromomethyl)-6-[(tert-butyl(dimethyl)silyl)oxy]-1,2-benzisoxazole (3 g, 8.8 mmoles) and dry THF (10 ml) were slowly added. The mixture was then stirred for 30 min at room temperature, poured into water, extracted with AcOEt, dried over Na2SO4, and purified by flash chromatography (AcOEt/Heptane 2/8 with 0.1% TEA) to give 3-(6-[(tert-butyl)dimethylsilyl)oxy]-1,2-benzisoxazol-3-yl)-2-(4-methoxyphenyl) propanenitrile (1 g, 28%).
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][C:6]=1OC.[OH-].[Na+]>CCO.O>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]=1
Reactant: COc1cccc(N)c1N
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Cyanogen bromide (7.05 mmol, 0.74 g) was added to a solution of 2,3-diaminoanisole (4.7 mmol, 0.65 g) in EtOH (10 mL) and the reaction was stirred at room temperature for 14 h. The reaction was diluted with H2O and then basified (pH>12) using 4 M NaOH. The aqueous layer was extracted with CH2Cl2. The organic phase was then separated and washed with brine and then dried over MgSO4 and then concentrated to provide 2-aminobenzimidazole 37b.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[CH:11]1[C:16]([CH:17]=O)=[CH:15][C:14]2[O:19][CH2:20][O:21][C:13]=2[CH:12]=1.[C:22](#[N:26])[CH2:23][C:24]#[N:25].N1CCCCC1>C(O)C>[NH2:26][C:22]1[O:9][C:5]2[C:6]([CH:17]([C:16]3[CH:11]=[CH:12][C:13]4[O:21][CH2:20][O:19][C:14]=4[CH:15]=3)[C:23]=1[C:24]#[N:25])=[CH:7][CH:8]=[C:3]([N:2]([CH3:10])[CH3:1])[CH:4]=2
Reactant: CN(C)c1cccc(O)c1
Reactant: N#CCC#N
Reactant: O=Cc1ccc2c(c1)OCO2
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc2c(c1)OC(N)=C(C#N)C2c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
To a mixture of 3-dimethylaminophenol (489 mg, 3.56 mmol), piperonal (535 mg, 3.56 mmol), and malononitrile (233 mg, 3.53 mmol) in ethanol (20 ml) was added piperidine (0.70 ml, 7.1 mmol). The mixture was stirred at room temperature for 2 h and the resulting solid was collected by filtration, washed with methanol and dried in vacuo to yield the title compound as a yellow solid (940 mg, 2.80 mmol, 79%). 1H NMR (DMSO-d6): 6.83-6.77 (m, 4H), 6.66-6.64 (m, 2H), 6.47-6.44 (m, 1H), 6.21 (s, 1H), 5.96 (s, 1H), 5.95 (s, 1H), 4.53 (s, 1H), 2.85 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OC[CH:22]([N:25]=[N+:26]=[N-:27])[CH2:23][CH3:24])(=O)=O.N([CH2:31]CN1C=CC=C(OC)C1=O)=[N+]=[N-]>>[N:25]([CH2:22][CH2:23][CH2:24][CH2:31][N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:10]1=[O:15])=[N+:26]=[N-:27]
Reactant: CCC(COS(C)(=O)=O)N=[N+]=[N-]
Reactant: O=c1[nH]cccc1OCc1ccccc1
Reactant: COc1cccn(CCN=[N+]=[N-])c1=O
Product: [N-]=[N+]=NCCCCn1cccc(OCc2ccccc2)c1=O
Yield: 62 %

Procedure:
Reaction of 3-benzyloxypyridine-2-one (0.40 g, 1.99 mmol) and 156c (0.58 g, 2.98 mmol) within 16 h as described for synthesis of 157a gave compound 157c (0.36 g, 62%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 5H), 6.78 (dd, J=6.9, 1.7 Hz, 1H), 6.54 (dd, J=7.4, 1.7 Hz, 1H), 5.91 (m, 1H), 4.96 (s, 2H), 3.85 (t, J=7.2 Hz, 2H), 3.17 (t, J=6.8 Hz, 2H), 1.71 (m, 2H), 1.48 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.52, 148.27, 135.78, 128.37, 127.98, 127.42, 126.82, 114.92, 104.32, 70.09, 50.43, 48.46, 25.83, 25.42. HRMS (EI) calcd for C16H18N4O2 [M]+ 298.1430. found 298.1446.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:22])[C:20]=1[CH3:21].[CH2:23]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:22])[C:20]=1/[CH:21]=[C:6](\[O:7][C:34](=[O:35])[C:33]1[CH:37]=[CH:38][CH:39]=[C:31]([O:30][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:32]=1)/[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: O=C(Cl)c1cccc(OCc2ccccc2)c1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)c2cccc(OCc3ccccc3)c2)cc1OC

Procedure:
The compound was obtained starting from 3,4-dimethoxy-benzoyl chloride, 3,5-dichloro-4-methylpyridine and 3-benzyloxy-benzoyl chloride, following the procedure of Example 24.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:28]([N:29]([CH:31]([CH3:33])[CH3:32])[CH3:30])=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:34]([O:36][CH3:37])=[O:35])[CH:25]=2)[N:20]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:31]([N:29]([CH3:30])[C:28]1[C:19]([C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)=[N:20][C:21]2[C:26]([N:27]=1)=[CH:25][C:24]([C:34]([O:36][CH3:37])=[O:35])=[CH:23][CH:22]=2)([CH3:32])[CH3:33]
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4n3C(=O)OC(C)(C)C)c(N(C)C(C)C)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2nc(-c3cc4cc(OC)ccc4[nH]3)c(N(C)C(C)C)nc2c1
Yield: 68.7 %

Procedure:
A solution of methyl 2-(1-(tert-butoxycarbonyl)-5-methoxy-1H-indol-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (180.0 mg, 0.36 mmol) in 20% TFA/DCM (30 mL) was stirred overnight at room temperature and then quenched by the addition of water (100 ml). The reaction mixture was adjusted to pH 7 with aq. sodium bicarbonate, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column with 0.1%-1% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)-2-(5-methoxy-1H-indol-2-yl)quinoxaline-6-carboxylate as a light yellow solid (100.0 mg, 69%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[CH:7]=1.Br[CH2:37][CH2:38][CH2:39][NH:40]C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:27]([OH:29])=[O:28].[NH2:40][CH2:39][CH2:38][CH2:37][NH:1][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]3([C:27]([OH:29])=[O:28])[CH2:26][CH2:25]3)/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[CH:7]=1
Reactant: NCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NCCCNCc1cn(C[C@@H]2[C@H](NC(=O)/C(=N\OC3(C(=O)O)CC3)c3csc(N)n3)C(=O)N2S(=O)(=O)O)nn1
Product: O=CO

Procedure:
Prepared in analogous manner to example 28, using 1-(((Z)-(2-(((2R,3S)-2-((4-(aminomethyl)-1H-1,2,3-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylic acid (20 mg, 0.038 mmol), tert-butyl (3 bromopropyl)carbamate (60 mg, 0.252 mmol), DIPEA (0.1 mL, 0.572 mmol), and DMF (0.5 mL). The crude residue was purified by reverse phase prep HPLC (Xselect CSH, 19×100 mm, 5 μM, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min). LCMS: Rt=0.29 min, m/z=587.1 (M+1) Method 2m_acidic. 1H NMR (500 MHz, D2O) δ 8.31 (s, 1H), 8.14 (s, 1H), 6.93 (s, 1H), 5.32 (d, J=5.1 Hz, 1H), 4.86-4.78 (m, 2H), 4.73-4.66 (m, 1H assumed; obscured by solvent residual peak), 4.29 (s, 2H), 3.04-3.01 (m, 2H), 2.97-2.92 (m, 2H), 1.96 (p, J=7.9 Hz, 2H), 1.22-1.11 (m, 2H), 1.10-0.96 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[C:7]([CH3:21])=[C:6]2[CH2:22][C:23]([OH:25])=[O:24].[CH2:26](OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)[CH3:27].[H-].[Na+].COC1C=CC=CC=1CCl>>[CH2:26]([O:24][C:23](=[O:25])[CH2:22][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:7]=1[CH3:21])[CH3:27]
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1ccccc1OC
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(Cc2ccccc2OC)c2ccc(OC)cc12
Yield: 52 %

Procedure:
5-Methoxy-1-[(2-methoxyphenyl)methyl]-2-methyl-1H-indole-3-acetic acid. Using the procedure described in Example 1, Part F, 2.0 g (8.12 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 325 mg (8.12 mmol) of 60% NaH/mineral oil and 1.272 g (8.12 mmol) of ortho-methoxybenzylchloride and after chromatography on silica (eluting with 25% EtOAc/hexane) there was obtained 1.74 g (52%) of 5-methoxy-1-[(2-methoxyphenyl)methyl]-2-methyl-1H-indole-3-acetic acid ethyl ester as an oil. This oil (1.74 g) in 30 mL of MeOH and 15 mL of 1N NaOH was heated to maintain reflux for 20 hours. The mixture was diluted with water, extracted with EtOAc, then the EtOAc solution was dried (Na2SO4), the solvent removed at reduced pressure and the residue crystallized from MeOH to give 1.1 g (68% yield) of 5-methoxy-1-[(2-methoxyphenyl)methyl]-2-methyl-1H-indole-3-acetic acid, mp 176°-180° C.
Reaction SMILES: [C:1](NC1C=CC(S(N=[N+]=[N-])(=O)=O)=CC=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].O=C(C)CP(=O)(OC)OC.[CH3:33][C:34]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=1)[C:41]([O:43][CH3:44])=[O:42])([CH3:37])[CH:35]=O>C(#N)C.CO>[CH3:33][C:34]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=1)[C:41]([O:43][CH3:44])=[O:42])([CH3:37])[C:35]#[CH:1]
Reactant: COC(=O)c1cccc(C(C)(C)C=O)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: COP(=O)(CC(C)=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: C#CC(C)(C)c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a suspension of p-acetamidobenzenesulfonyl azide (5.25 g, 21.9 mmol) and potassium carbonate (7.55 g, 54.6 mmol) in acetonitrile (100 mL) was added dimethyl (2-oxopropyl)phosphonate (3.00 mL, 21.9 mmol), and the mixture was stirred at room temperature for 2 hr. Then, to the reaction mixture was added a solution of methyl 3-(1,1-dimethyl-2-oxoethyl)benzoate in methanol (20 mL), and the mixture was stirred at room temperature for 16 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution (70 mL), and the mixture was extracted with ethyl acetate (100 mL). The combined organic layer was washed with saturated brine (20 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=100/0→90/10), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (2.26 g, 61%) as a colorless oil.