Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([C:30]([NH:32][CH2:33][C:34]4[CH:35]=[C:36]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)[CH:42]=5)[C:37]([F:40])=[CH:38][CH:39]=4)=[O:31])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C)CC4)c3)c2)c1
Yield: 66.2 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-5-methyl-1,3-benzenedicarboxamide (30 mg, 0.044 mmol), 1-methylpiperazine (44.4 mg, 0.44 mmol, 10 eq) and acetic acid (2.54 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. The reaction mixture was then purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 22.15 mg (59.1%) of the title compound. LC-MS m/z 761 (M+H)+, 1.38 min (ret time).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCC(O)CC1
Reactant: C[C@@H]1CNC(=O)c2cc3cc(O)ccc3n21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Yield: 22 %

Procedure:
The title compound was synthesized in analogy to example 1, from (R)-8-hydroxy-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), tributylphosphine and 1,1′-(azodicarbonyl)dipiperidine, to give the desired product as a colorless gum (22%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)=[N+]=[N-].[F:19][C:20]([F:26])([F:25])[S:21]([OH:24])(=[O:23])=[O:22].FC(F)(F)C(O)=O.N>>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[C:7]([O:24][S:21]([C:20]([F:26])([F:25])[F:19])(=[O:23])=[O:22])=[CH:8][CH:9]=1
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: [N-]=[N+]=Nc1cccc(-c2nc3ccccc3s2)c1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2nc3ccccc3s2)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
2-(3-Azidophenyl)benzothiazole (1 g) was added in small portions (5×0.2 g) to a mixture of trifluoromethanesulphonic acid (4 ml), trifluoroacetic acid (5 ml) and triflucromethylacetic anhydride (1 ml) at 0° C. After evolution of nitrogen ceased, the mixture was stirred at 20° C. for 18 hours, basified with aqueous ammonia and the products extracted into ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated to give a gum which was separated on silica with hexane-ethyl acetate (6:4) as eluent. The product obtained was the title compound (70% yield). (Found: M+ 374. C14H9F3N2O3S2 requires MW 374). An in vitro assay of this compound against MCF-7 (wild type) cells gave an IC50 value of 50 nM which again indicates a useful level of activity.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>O1CCOCC1>[CH:15]1([NH:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH2:17][CH2:16]1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NC1CC1
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1NC1CC1
Reaction time: 24 h

Procedure:
2-Chloro-5-nitrobenzenesulphonamide (5 g) prepared in the Step above is introduced into a hermetically closed vessel containing a mixture of dioxane (70 mL) and cyclopropylamine (3.5 mL). The hermetically closed vessel is placed in an oven at 100° C. for 24 hours. After this time period, the solvent and the reagent are removed by concentrating under reduced pressure. The residue is taken up in methanol (20 mL) and the insoluble material, which contains the title product, is collected by filtration, washed with methanol and dried.
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:19])([F:18])[C:8]([C:14]([F:17])([F:16])[F:15])([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C1COCC1.C(OCC)C>[C:20]([O:12][CH2:11][CH2:10][CH2:9][C:8]([C:14]([F:15])([F:16])[F:17])([OH:13])[C:7]([F:18])([F:19])[F:6])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: OCCCC(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C(=O)OCCCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 78.8 %

Procedure:
To a 3-necked, 2-L round-bottomed flask equipped with an overhead stirrer, digital thermometer and a 1-L constant-pressure addition funnel with a nitrogen inlet was added 590 mL (0.944 mol) of n-butyllithium (1.6 M in hexane). The addition funnel was charged with a solution of 107 g (0.47 mol) of 1,1,1-trifluoro-2-trifluoromethyl-2,5-pentanediol in 300 mL of anhydrous THF. The flask was cooled and the diol was added dropwise with stirring while maintaining a temperature below 15° C. The resulting yellow-orange solution was stirred for an additional 2 hours at which time a solution of 54.5 g (0.52 mol) of methacryloyl chloride in 200 mL of anhydrous THF was added dropwise over 1 h at 10° C. The reaction mixture was allowed to reach room temperature overnight after which it was diluted with 500 mL of diethylether and washed with 2×500 mL of saturated ammonium chloride and brine, dried over MgSO4, evaporated and distilled at 74° C. at 1.0 mm Hg (0.5 g of phenothiazine was added to the pot prior to distillation) to yield 109 g (79%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:5]2[S:4][C:3]([CH2:2][N:18]3[CH2:24][CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[CH:8][C:6]=5[N:7]=4)[CH2:20][CH2:19]3)=[N:7][C:6]=2[CH:8]=1
Reactant: C1CNCCNC1
Reactant: COc1cc2nc(CCl)sc2c(OC)c1OC
Product: COc1cc2nc(CN3CCCN(Cc4nc5cc(OC)c(OC)c(OC)c5s4)CC3)sc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxybenzothiazole (200 mg) and homopiperazine (37 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH2:21][N:22]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-])=O)=[CH:43][CH:42]=2)[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][N:22]([CH2:21][C@@H:20]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:19])[NH:17]3)[O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:46][CH:45]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCCCc2ccc([N+](=O)[O-])cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Oc1ccc([C@H](CN(CCCCCCOCCCCc2ccc(N)cc2)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)c2ccc(=O)[nH]c12

Procedure:
A suspension of Pd/C (10% w/w, 15 mg) and Intermediate 107 (0.25 g, 0.31 mmol) in MeOH (4 mL) was stirred under a balloon of hydrogen gas for 30 minutes, followed by filtration of the mixture through a pad of Celite diatomaceous earth, and concentration under reduced pressure. The title compound was provided as a white foam (0.13 g, 54%). ES/MS calcd. for C43H68N3O8Si+ 782.5. Found m/z=782.6 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[C:8]=1[O:23][CH3:24])[CH:2]=[CH2:3].C1C(=O)N(Br)C(=O)C1.[N:34]1([C:40](=[S:42])[NH2:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(Cl)Cl.CS(C)=O>[CH2:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[N:41]=[C:40]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[S:42][C:14]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[N:16]=2)[C:8]=1[O:23][CH3:24])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1OC
Reactant: NC(=S)N1CCOCC1
Agent: O=C1CCC(=O)N1Br
Solvent: CS(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
To a solution of 2-propen-1-yl[3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate (30 g, 82.9 mmol) in DCM (300 mL), NBS (14.8 g, 82.9 mmol) was added and the solution was allowed to stir at rt for 30 min. The reaction mixture was then concentrated on the rotovap and the resulting oil was diluted with DMSO (240 mL) and 4-morpholinecarbothioamide (14.8 g 101 mmol) was added at once. The reaction was complete after stirring 1 h at rt. The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product which was purified by column chromatography on silica gel (DCM:petroleum ether 2:1) to afford the product of Step A (40 g, 98.8% yield) which was used directly in the next step.
Reaction SMILES: C[O-].[Na+].C(O[C:9]([C:11]1[N:12]=[CH:13][C:14]2[C:19]([C:20]=1[OH:21])=[CH:18][CH:17]=[C:16]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])=[CH:25][CH:24]=1)[CH:15]=2)=[O:10])CCC.[NH2:40][CH2:41][C:42]([OH:44])=[O:43].Cl>CO>[OH:21][C:20]1[C:19]2[C:14](=[CH:15][C:16]([O:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])=[CH:27][CH:28]=3)=[CH:17][CH:18]=2)[CH:13]=[N:12][C:11]=1[C:9]([NH:40][CH2:41][C:42]([OH:44])=[O:43])=[O:10]
Reactant: CCCCOC(=O)c1ncc2cc(Oc3ccc(NS(=O)(=O)c4ccc(C)cc4)cc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc4c(O)c(C(=O)NCC(=O)O)ncc4c3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.85 ml of 0.5 M sodium methoxide in methanol was added 42 mg of 4-Hydroxy-7-[4-(toluene-4-sulfonylamino)-phenoxy]-isoquinoline-3-carboxylic acid butyl ester and 70 mg of glycine. The resultant mixture was heated at reflux temperature for 24 hours and then cooled to room temperature. The reaction was poured into a 0.2 N HCl aqueous solution and then extracted three times with ethyl acetate. The organic fractions were dried over anhydrous sodium sulfate and concentrated to 41 mg of a white solid; MS (+): m/z 508.10 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.Cl[CH2:14][N:15]1[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]1=[O:23].O>CN(C=O)C>[Cl:3][C:4]1[N:5]([CH2:14][N:15]2[CH2:19][CH:18]([CH2:20][CH2:21][CH3:22])[CH2:17][C:16]2=[O:23])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CCCC1CC(=O)N(CCl)C1
Reactant: Clc1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC1CC(=O)N(Cn2c(Cl)cc3ccccc32)C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
At −78° C., NaH (60% in mineral oil; 220 mg, 5.52 mmol, 1.1 eq) is added to a solution of 2-chloro-1H-indole x160 (0.76 g, 5.02 mmol, 1 eq) in dry DMF (50 ml). The temperature is raised to −20° C. during 20 minutes, then 1-(chloromethyl)-4-propylpyrrolidin-2-one x63 (0.76 g, 5.02 mmol, 1 eq) dissolved in DMF (10 ml) is added drop wise. After 2 hours at room temperature, water (50 ml) is added. The aqueous layer is extracted with CH2Cl2 (3×30 ml). The combined organic layers are dried on anhydrous MgSO4, filtered off and concentrated under reduced pressure to obtain a liquid that is purified on silicagel (AcOEt/Benzine 1/9) yielding 1-[(2-chloro-1H-indol-1-yl)methyl]-4-propylpyrrolidin-2-one 274 as a colorless liquid (605 mg).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][O:23][CH3:24].O>CN(C)C=O>[CH3:24][O:23][CH2:22][CH2:21][CH2:20][N:1]1[C:9]2[CH:8]=[C:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)c1cc2[nH]ccc2cn1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCn1ccc2cnc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
To a solution of tert-butyl 1H-pyrrolo[3,2-c]pyridine-6-carboxylate (2.0 g) in N,N-dimethylformamide (15 mL) was added drop by drop 60% oil-based sodium hydride (385 mg) under ice-cooling, and then the mixture was stirred at room temperature for 15 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (1.47 g) in N,N-dimethylformamide (5 mL) under ice-cooling, and then the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1) to give tert-butyl 1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(25-1)] (2.52 g) as a yellow oil.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:23]=[CH:22][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:22][CH:23]=1
Reactant: COC(=O)C(Oc1ccc(CN=[N+]=[N-])cc1)c1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(Oc1ccc(CN)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the product of Step E in dry tetrahydrofuran is treated protionwise with triphenylphosphine (1 equivalent). The solution is stirred under N2 at ambient temperature. After about 2 hours, when gas evolution has ceased, H2O (1 equivalent) is added, and the solution is concentrated in vacuo, and the residue is chromatographed on silica gel to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].CN(C1C=CC=CN=1)C.[C:23]([N:33]1[CH2:36][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([N:43]3[CH2:47][C@H:46]([CH2:48][NH2:49])[O:45][C:44]3=[O:50])=[CH:39][C:38]=2[F:51])[CH2:34]1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[F:51][C:38]1[CH:39]=[C:40]([N:43]2[CH2:47][C@H:46]([CH2:48][NH:49][C:7](=[O:9])[CH3:8])[O:45][C:44]2=[O:50])[CH:41]=[CH:42][C:37]=1[CH:35]1[CH2:36][N:33]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:34]1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4 dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].F[C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:32])[N:26]([CH3:31])[CH2:27][O:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:31][N:26]1[C:25](=[O:32])[C:24]2[C:29](=[CH:30][C:21]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:22][CH:23]=2)[O:28][CH2:27]1
Reactant: CN1COc2cc(F)ccc2C1=O
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (0.27 g, 1 mmol), 9-fluoro-4-methyl-2-oxa-4-azabicyclo[4.4.0]deca-6,8,10-trien-5-one (CAS no. 915771-24-3) (200 mg, 11 mol) and potassium carbonate (276 g, 2 mmol) in acetonitrile (20 mL) was heated in a microwave at 160° C. for 12 hours. The mixture was evaporated and the residue partitioned between ethyl acetate (40 mL) and water (40 mL). The organic phase was separated, washed with water (10 mL) and brine (20 mL), dried (MgSO4) and evaporated. The aqueous phase was acidified to pH 1 with 2N hydrochloric acid extracted with ethyl acetate (2×30 mL). The combined organic extracts were washed with water (2×20 mL), brine (20 mL), dried (MgSO4) and evaporated. The residue was dissolved in THF (2 mL) and methanol (1 mL) and treated with 2M TMS-diazomethane (0.14 mL) stirred for 30 minutes. The mixture was evaporated and the residue combined with that from the initial extraction and purified by flash chromatography on silica eluting with 0 to 100% ethyl acetate in isohexane to afford the product (232 mg, 54%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.25 (m, 1H), 2.53-2.66 (m, 1H), 2.93 (s, 3H), 3.09 (s, 3H), 3.32-3.58 (m, 2H), 3.89 (s, 3H), 4.91 (t, 1H), 5.17 (s, 2H), 6.51 (s, 1H), 6.72 (d, 1H), 6.97 (s, 1H), 7.34 (s, 1H), 7.52 (s, 1H), 7.93 (d, 1H); m/z 427 (M+H+).
Reaction SMILES: [C:1]1([C:7]([CH2:11][N:12]([CH3:14])[CH3:13])([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:27]Cl)[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[CH3:26][O:25][C:21]1[CH:20]=[C:19]([CH:18]=[C:17]([O:16][CH3:15])[C:22]=1[O:23][CH3:24])[CH2:27][O:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:8][CH3:9])[CH2:11][N:12]([CH3:14])[CH3:13]
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: CCC(O)(CN(C)C)c1ccccc1
Product: CCC(CN(C)C)(OCc1cc(OC)c(OC)c(OC)c1)c1ccccc1

Procedure:
Prepared according to the process described in Example 3 from 1-phenyl-1-dimethylaminomethyl-1-propanol and from 3,4,5-trimethoxy-α-chlorotoluene.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][CH2:18][CH2:19][C:20]3[CH:35]=[CH:34][C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]([O:32]C)=[O:31])=[CH:22][CH:21]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>CO>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]#[C:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]([OH:32])=[O:31])=[CH:34][CH:35]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1CCCN1Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCCN1Cc1ccc(CCC#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.5 mL 1 M NaOH solution are added to a solution of 33 mg (0.07 mmol) methyl 1-(4-{4-[5-(4-chloro-phenyl)-pyridin-2-yl]-but-3-ynyl}-benzyl)-pyrrolidine-2-carboxylate (Example 2.14) in 5 mL MeOH and the reaction mixture is stirred for 4 h at RT. The mixture is evaporated down i. vac., combined with 5 mL water, extracted with 10 mL EtOAc and the aqueous phase is saturated with NaCl, during which time the product is precipitated. It is evaporated down again i. vac., the residue is combined with EtOH, filtered and the solvent is eliminated.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)=[O:4].[CH:15]1([C:21](=O)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([C:21]2[O:4][C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=3)=[CH:2][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C(CCl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Product: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1C1CCCCC1
Yield: 42.1 %

Procedure:
An operation similar to that in Example 1 (1) was performed using 2-chloro-4′-(trifluoromethyl)acetophenone (13.4 g) and ethyl 3-cyclohexyl-3-oxopropanoate (9.9 g) to give the title compound (7.7 g, 40%) as a yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH2:28])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1>>[CH3:11][O:12][C:13](=[O:29])[C@@H:14]([NH:28][C:8]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][N:5]=1)=[O:10])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Cl)ccn1
Yield: 81.8 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(4-chloro-pyridine-2-carbonyl)-amino]-propionic acid methyl ester (1.26 g, 85%) was prepared by following general procedure A from commercially available 4-chloro picolinic acid (0.7 g, 4.4 mmol) and (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 3.9 mmol).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13]([CH:3]=[CH:2][CH2:1][NH2:4])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCN
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NCC=CC(=O)OCc1ccccc1

Procedure:
10.4 ml of allylamine and 19 ml of triethylamine are dissolved in 50 ml of absolute toluene. A 50% solution of benzyl chloroformate in toluene (46.8 ml) is added dropwise to the solution, which has been cooled in an icebath, while stirring. The mixture is stirred at room temperature for a further 1 hour in order to complete the reaction. A precipitate which has formed is filtered off. After that, the filtrate is concentrated and dried to constant weight under high vacuum (70° C., 0.5 mbar).