Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH2:36]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:37][CH3:38].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH2:36]([N:39]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[CH:9]=1)[CH2:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=1)[CH2:37][CH3:38]
Reactant: CCCNc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C(=O)CCC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 18 h

Procedure:
A mixture consisting of 100 mg of 4-[N-methyl-N-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(naphth-2-yl)-pentanoic acid, 29.9 mg of N-propyl-aniline, 85.3 mg of propanephosphonic acid anhydride, 154 νl of triethylamine and 2 ml of methylene chloride is left to stand at room temperature for 18 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. Chromatography of the residue over silica gel with methylene chloride/methanol 19:1 yields the title compound in the form of a yellow foam. Rf value=0.63 (methylene chloride/methanol 19:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:32][C@@H:33]([C@@H:40]1[C@@:44]2([CH3:62])[CH2:45][CH2:46][CH:47]3[C@@:52]4([CH3:61])[CH2:53][CH2:54][CH:55]([O:57][C:58](Cl)=[O:59])[CH2:56][C:51]4=[CH:50][CH2:49][CH:48]3[CH:43]2[CH2:42][CH2:41]1)[CH2:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38].Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][N:7]([C:14](=[O:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:58]([O:57][CH:55]1[CH2:56][C:51]2[C:52]([CH3:61])([CH:47]3[CH:48]([CH2:49][CH:50]=2)[CH:43]2[C:44]([CH3:62])([CH:40]([CH:33]([CH3:32])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])[CH2:41][CH2:42]2)[CH2:45][CH2:46]3)[CH2:53][CH2:54]1)=[O:59])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CCC2C3CC=C4CC(OC(=O)Cl)CC[C@]4(C)C3CC[C@@]21C
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN(CC(=O)OCC)C(=O)CCCCCNC(=O)OC1CCC2(C)C(=CCC3C2CCC2(C)C(C(C)CCCC(C)C)CCC32)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The hydrochloride salt of 3-[(6-Amino-hexanoyl)-ethoxycarbonylmethyl-amino]-propionic acid ethyl ester AC (4.7 g, 14.8 mmol) is taken up in dichloromethane. The suspension is cooled to 0° C. on ice. To the suspension diisopropylethylamine (3.87 g, 5.2 mL, 30 mmol) is added. To the resulting solution cholesteryl chloroformate (6.675 g, 14.8 mmol) is added. The reaction mixture is stirred overnight. The reaction mixture is diluted with dichloromethane and ished with 10% hydrochloric acid. The product is purified by flash chromatography (10.3 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH:31]=[O:32])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
A solution of 0.41 g (1.07 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 6, intermediate) in 28 mL diethyl ether was cooled to −100° C. and treated with 0.80 mL (1.18 mmol) tert-butyl lithium (1.5M solution in n-pentane). After 15 min. 0.12 mL N,N-dimethylformamide was added and the temperature was raised to −78° C. After 45 min. the solution was poured into 10% aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was purified by column chromatography on silica gel (0.040–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to give the compound as a yellow foam (80.2%).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:22][C:23]1[C:24]([F:33])=[C:25]([S:29]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]2[S:8][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=3)=[CH:10][CH:11]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccc(Cl)c1F

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 3-chloro-2-fluorophenylsulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 3-chloro-2-fluoro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless oil. MS: 532.7 ([M+NH4]+)
Reaction SMILES: [CH3:1][O:2][C@@:3]1([NH:20][C:21]([CH2:23][C:24]2[S:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[C:6](=[O:7])[N:5]2[C:8]([C:17]([OH:19])=[O:18])=[C:9]([CH2:12][O:13][C:14]([NH2:16])=[O:15])[CH2:10][S:11][C@H:4]12.C([O-])(=O)C(C)O.[Na+:35]>CC(C)=O>[CH3:1][O:2][C@@:3]1([NH:20][C:21]([CH2:23][C:24]2[S:28][CH:27]=[CH:26][CH:25]=2)=[O:22])[C:6](=[O:7])[N:5]2[C:8]([C:17]([O-:19])=[O:18])=[C:9]([CH2:12][O:13][C:14]([NH2:16])=[O:15])[CH2:10][S:11][C@H:4]12.[Na+:35]
Reactant: CO[C@@]1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@@H]21
Agent: CC(O)C(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CO[C@@]1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@@H]21
Reaction time: 0.17 h

Procedure:
To cefoxitin acid (11 g) in 12% aqueous acetone (88 ml), 60% aqueous sodium lactate (4.7 g) solution was added at 30° C. and stirred for 10 minutes, excess acetone was added (275 ml) to precipitate the product. The solid was filtered and dried under vacuum to yield the title compound in pure form (10 g)
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28].[CH3:11][O:10][C:8](=[O:9])[CH2:7][CH:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[N:14]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:26]1[C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cc(Cl)ccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CC1c2ccc(Cl)cc2N(S(=O)(=O)c2ccccc2)C1C(=O)c1cc(Cl)ccn1
Product: COC(=O)Cc1c(C(=O)c2cc(Cl)ccn2)[nH]c2cc(Cl)ccc12
Yield: 28 %
Yield: 27 %

Procedure:
A mixture of methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A, 675 mg, 1.92 mmol), 2-bromoacetyl-4-chloropyridine hydrobromide* (907 mg, 2.88 mmol), and potassium carbonate (2.65 g, 19.18 mmol) in acetone (20 ml) was heated at reflux temperature for 4 h. The mixture was cooled and concentrated. The residue was diluted with ethyl acetate (150 ml) and washed with water (70 ml×6). After drying (MgSO4) and removal of solvent, the crude product was purified by flash column chromatography eluting with ethyl acetate/hexane (1:6-1:3) to afford 195 mg (28%) of the title compound (yellow solids) along with 264 mg (27%) of methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1-(phenylsulfonyl)indolin-3-yl]acetate (brown crystals).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[H][H]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:11]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCO
Product: Cc1cc(N)ccc1F

Procedure:
To a solution of 20 g (129 mmol) of 2-fluoro-5-nitrotoluene in 400 mL of ethanol was added 2 g of 10% Pd--C. The mixture was shaken under 45 P.S.I. H2 until hydrogen uptake ceased. The catalyst was filtered away and washed with ethanol, then the combined filtrate and washings were concentrated to 15.2 g (94%) of a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1([C:14]([O:16]CC)=O)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1.O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:14](=[O:16])[C:11]3([CH2:10][NH:9][C:3]=2[CH:4]=1)[CH2:13][CH2:12]3
Reactant: CCOC(=O)C1(CNc2cc(Br)ccc2N)CC1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Br)cc2NCC12CC2
Temperature: 90 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
To a stirred solution of ethyl 1-((2-amino-5-bromophenylamino)methyl)cyclopropanecarboxylate (624 mg, 2.0 mmol) in toluene (15 mL) was added dropwise tetraisopropoxytitanium (1.2 g, 4.0 mmol). After addition was complete, the reaction was stirred for 12 hours at 90° C. The mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL). The organic layer was separated, dried by sodium sulfate, filtered and concentrated to give the crude 7-bromo-4,5-dihydrospiro[benzo[b][1,4]diazepine-3,1′-cyclopropan]-2(1H)-one (400 mg, 75%) as white solid, used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:11][C:12]([CH2:17][OH:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:11][C:12]([CH:17]=[O:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCc1ccc(OCc2cc(OC)c(CO)s2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)c(C=O)s2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-[[5-(hydroxymethyl)-4-methoxy-2-thienyl]methoxy]phenyl]propanoate (1.6 g, 4.3 mmol) in anhydrous dichloromethane (10 mL), cooled to 0° C., is added Dess-Martin periodinane (2.76 g, 6.5 mmol). The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction mixture is diluted with water (15 mL), extracted with ethyl acetate, washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (8.8:1.2) to give the title compound (0.8 g, 50%). ESI/MS m/z 367.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([C:11]3[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=3)=[CH:10][C:3]=12.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC.O.C(O)C>[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([C:11]4[CH2:12][CH2:13][N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:15][CH:16]=4)=[CH:10][C:3]=23)[CH:23]=1
Reactant: CC1(C)OB(c2cc(F)ccc2N)OC1(C)C
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(Br)ccnc3[nH]2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CS(=O)(=O)N1CC=C(c2cc3c(-c4cc(F)ccc4N)ccnc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a mixture of Example 5F (500 mg, 1.404 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (399 mg, 1.684 mmol) and dichlorobis(triphenylphosphine)palladium (II) (99 mg, 0.14 mmol) in 7:3:2 1,2-dimethoxyethane/water/ethanol (14 mL) was added 2.45 mL 2M aqueous sodium carbonate. The suspension was stirred at room temperature for a few seconds and then stirred in a microwave reactor (Biotage Initiator) at 150° C. for 30 minutes. The mixture was partitioned between ethyl acetate and brine and the organic phase was concentrated. The residue was stirred in 2% methanol in methylene chloride and the solid was collected by filtration to provide the title compound. The mother liquor was purified by flash chromatography on silica gel (Teledyne CombiFlash Rf, 0-15% methanol in dichloromethane) to provide additional title compound. MS (ESI+) m/z 387 (M+H)+.
Reaction SMILES: [Si]([O:18][C:19]1[CH:54]=[CH:53][C:22]([O:23][CH2:24][C@@H:25]([OH:52])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:51]=[CH:50][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][CH:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH:45]1([CH2:44][NH:43][C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:50]=[CH:51][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:52])[CH2:24][O:23][C:22]4[CH:21]=[CH:20][C:19]([OH:18])=[CH:54][CH:53]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCC4CCCC4)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCC1CCCC1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 58.1 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-(cyclopentylmethyl)-1-piperidinecarboxamide (0.24 g, 0.32 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.095 g, 0.186 mmol).
Reaction SMILES: [CH2:1]([C@:8]([OH:17])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:44]=[C:45]([Cl:50])[CH:46]=[CH:47][C:48]=1[NH2:49].CN(C=O)C>C(OCC)(=O)C.O>[Cl:50][C:45]1[CH:46]=[CH:47][C:48]2[N:49]=[C:9]([C@:8]([OH:17])([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:42][C:43]=2[CH:44]=1
Reactant: CCOC(=O)[C@@](O)(Cc1ccccc1)C(=O)O
Reactant: Nc1ccc(Cl)cc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@](O)(Cc1ccccc1)c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2R)-2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (320 mg), HATU (562 mg), 3,4-diamino-chlorobenzene (230 gm) was added 4 mL of DMF at rt. The mixture was stirred at rt overnight. To this mixture was added water and ethyl acetate. The organic layer was washed with water and then concentrated in vacuo after being dried with mangesium sulfate. The residue, without purification, was dissolved in 3 mL of acetic acid and heated at 75 degrees for 2 h. The mixture was then concentrated and purified by Biotage silica gel column chromatography (8-35% ethyl acetate in hexanes) to give the title product.
Reaction SMILES: CN(C)C=O.F[C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.[H-].[Na+]>O>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:8][CH:9]=1)#[N:14]
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2ccnc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1500 ml of dry dimethylformamide (DMF) are placed in a 1000 ml four-necked flask while passing nitrogen over it and 72.67 g (0.6 mol) of 4-fluorocyanobenzene and 61.2 g (0.9 mol) of imidazole and finally 21.6 g (0.9 mol) of sodium hydride are added. The reaction mixture is heated to 100° C., stirred at this temperature for 4 hours and subsequently overnight at room temperature. The reaction mixture is then poured into water and the resulting mixture is extracted a number of times with dichloromethane. The organic phase is dried, evaporated on a rotary evaporator and finally dried further at 60° C. under reduced pressure. The yield is 94 g (93% of theory).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4]1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([CH2:2][CH:3]2[CH2:7][S:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Yield: 62.7 %

Procedure:
a solution of 0.8 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydrothiazol-2-yl]carbamate, 0.76 g of p-toluene-sulfonyl chloride and 0.56 cm3 of triethylamine in 25 cm3 of dichloromethane is stirred for 16 hours at a temperature in the region of 20° C. The solution obtained is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The evaporation residue obtained is purified by chromatography under atmospheric pressure on a column of silica gel (particle size 60-200μ; diameter 2 cm; height 25 cm), eluting with a mixture of cyclohexane/ethyl acetate (70/30 by volume) and collecting 30 cm3 fractions. The fractions containing the expected product are combined and then concentrated under the above conditions. 0.8 g of tert-butyl N-[(4RS)-4-p-toluenesulfonylmethyl-4,5-dihydrothiazol-2-yl]carbamate is obtained in the form of a white solid [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 1.48 (s: 9H); 2.46 (s: 3H); 3.10 (dd, J=11.5 and 5.5 Hz: 1H); 3.33 (dd, J=11.5 and 8.5 Hz: 1H); 3.97 (dd, J=9.5 and 8 Hz: 1H); 4.06 (dd, J=9.5 and 4.5 Hz: 1H); 4.43 (mt: 1H); 7.36 (d, J=8 Hz: 2H); 7.80 (d, J=8 Hz: 2H); from 8.50 to 9.40 (very broad unresolved complex: 1H)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[O:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(N(CC)C(C)C)(C)C.[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:21][O:22][CH3:23])[CH:9]=[O:10]
Reactant: COc1cc(C=O)ccc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1ccc(C=O)cc1OC
Temperature: 0 °C
Yield: 83 %

Procedure:
In 320 ml of dimethylformamide was dissolved 3.2 g of vaniline, and 44.8 g of N,N-diisopropylethylamine was added to the solution and the mixture was stirred. The liquid mixture was cooled to 0° C. and 18.1 ml of chloromethyl methyl ether was added to the liquid mixture. The temperature was elevated to room temperature and the mixture was stirred for 5 hours. After the reaction, a large quantity of water was added to the reaction mixture, and the mixture was extracted with diethyl ether and the solvent was removed from the extract by distillation. The obtained residue was allowed to stand under ice cooling, and the obtained solid was washed with petroleum ether and recovered by filtration to obtain 34.0 g (yield=83%) of intended 3-methoxy-4methoxymethoxybenzaldehyde.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH3:15])=[O:13])(OCC)=O)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=O)[CH:21]=[N:22][CH:23]=1.O>C1COCC1>[CH3:16][O:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])[CH:21]=[N:22][CH:23]=1
Reactant: COc1cncc(C=O)c1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)/C=C/c1cncc(OC)c1
Temperature: 0 °C
Yield: 13.9 %

Procedure:
To a suspension of 3.12 g (78.1 mmol) of sodium hydride (60% in oil) in 30 mL of anhydrous THF is added, over 45 minutes, under argon and at 0° C., 16.4 g (78.1 mmol) of methyl (diethoxyphosphoryl)acetate in 10 mL of THF. Stirring is maintained for 30 minutes at 0° C. and 5.1 g (37.2 mmol) of 5-methoxypyridine-3-carbaldehyde in 20 mL of anhydrous THF are then added dropwise at 0° C. After cooling to room temperature, the reaction mixture is treated with 150 mL of water and then extracted with EtOAc (3×100 mL). The organic phases are combined, washed successively with water (2×20 mL), dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAC gradient of 0 to 40% EtOAc. 1 g of methyl (2E)-3-(5-methoxypyridin-3-yl)prop-2-enoate is obtained in the form of a white powder.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:26][CH2:25][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:29][CH2:28]4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1.CN(C(ON1N=N[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.C(O)CCCCC>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:19]([N:21]3[CH2:22][CH2:23][CH:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:33][C:34]([O:36][CH2:64][CH2:65][CH2:60][CH2:61][CH2:62][CH3:63])=[O:35])[CH2:29][CH2:28]4)[CH2:25][CH2:26]3)=[O:20])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:47]=[CH:48][CH:49]=[CH:50][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc(C)c1O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCCCCCO
Product: CCCCCCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 80 mg (0.12 mmol) (R)-2-(1′-carboxymethyl-4,4′-bipiperidinyl-1-yl)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 45 mg (0.14 mmol) TBTU and 32 μL (0.23 mmol) triethylamine in 1.2 mL DMF was stirred for 1 h at RT. Then 29 μL (0.23 mmol) 1-hexanol were added and the reaction mixture was stirred for 4 days at RT. The mixture was evaporated down i.vac., the residue was taken up in 30 mL EtOAc, the organic phase was washed with 20 mL 5% NaHCO3 solution and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by chromatography (silica gel, gradient DCM/isopropanol 95:5 to DCM/isopropanol 90:10). The fractions containing the product were concentrated by evaporation i. vac., the residue was triturated with DIPE, suction filtered and dried.