Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](NC)=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.Cl.Cl.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].Cl.C([O-])(O)=[O:39].[Na+]>C(O)(=O)C>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([OH:12])=[O:39])=[N:7][C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:30][C:24]=2[O:23][CH3:22])=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: O=C([O-])O
Reactant: COc1cc(N2CCOCC2)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc(Cl)c(Nc2ccccc2C(=O)O)n1
Temperature: 120 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
To a solution of 1.0 g (3.37 mmol) of 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide in 15 mL of acetic acid are added 2-methoxy-4-morpholinoaniline dihydrochloride (1.9 g, 6.73 mmol) and 6.0 mL of 1N ethanolic solution of hydrogen chloride (6.0 mmol). After the reaction mixture is stirred at 120° C. for 16 hours and cooled to room temperature, aqueous NaHCO3 solution is added to adjust the acidity between pH 5 and pH 6. The resulting precipitate is collected by a filtration and dried under reduced pressure to give 2-[5-chloro-2-(2-methoxy-4-morpholin-4-yl-phenyl-amino)-pyrimidin-4-ylamino]-benzoic acid (970 mg, 2.12 mmol, 63%) as ivory solid.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[C:9]=1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C.CO>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([I:17])[C:9]=1[C:10]([O:12][CH3:1])=[O:11]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cccc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (2.5 ml, 28.66 mmol, 1.5 eq.) was added at room temperature to a suspension of 2-fluoro-6-iodobenzoic acid (5.1 g, 19.17 mmol, 1 eq.) in 40 ml of dry DCM under nitrogen atmosphere. A few drops of dry DMF were added and the mixture was stirred at room temperature for 1 h. The solvent was removed by distillation. The obtained residue was taken up in acetonitrile, which was distilled again, to remove excess acidity. The resulting brown oil was dissolved in dry DCM and the resulting solution was dropwise added to a suspension of potassium carbonate (7 g, 50.6 mmol, 2.6 eq.) in 20 ml of dry methanol. The reaction mixture was then stirred at room temperature overnight.
Reaction SMILES: CC(C(N=NC1C=CC(Cl)=CC=1[N+]([O-])=O)C(N[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([NH:17][C:10]=2[CH:9]=1)=[O:16])=O)=O.N(CCO)(CCO)CCO>O>[N:14]1[C:15](=[O:16])[N:17]=[C:10]2[CH:9]=[CH:8][CH:13]=[CH:12][C:11]=12
Reactant: CC(=O)C(N=Nc1ccc(Cl)cc1[N+](=O)[O-])C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1
Solvent: O
Solvent: OCCN(CCO)CCO
Product: O=C1N=c2ccccc2=N1
Reaction time: 5 h

Procedure:
20 g of C.I. pigment orange 60 having an average primary particle diameter of 85 nm (in which the content as metal ions having a valence of at least 2 was 320 ppm), 1.6 g of the pigment derivative (a′) and 110 g of deionized water were mixed, triethanolamine was added so as to adjust pH of a mixture liquid to 9.0, and the mixture liquid was dispersed with a paint shaker in the presence of zirconia beads as media for approximately 5 hours, to obtain a pigment dispersion. The obtained water-based pigment dispersion was diluted so as to have a concentration of 3% by weight, and the diluted water-based pigment dispersion was dropped to NO.2 filter paper, to show no bleedings of the pigment derivative.
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[CH:11]=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=43)[C@@H:6]1[CH2:5][C@@H:4]([OH:20])[C@@H:3]2[OH:21].N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O>[Si:31]([O:20][C@@H:4]1[CH2:5][C@H:6]2[C@H:7]3[C@H:16]([CH2:17][CH2:18][C@:2]2([CH3:1])[C@H:3]1[OH:21])[C:15]1[CH:14]=[CH:13][C:12]([OH:19])=[CH:11][C:10]=1[CH2:9][CH2:8]3)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)[C@@H]2O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]2(C)[C@H]1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 11.52 g of 1,3,5(10)-estratriene-3,16α,17β-triol in 200 ml of dimethylformamide, cooled to -20° C., is combined, after adding 6.52 g of imidazole, dropwise with a solution of 13.24 g of tertbutyldimethylsilyl chloride in 100 ml of dimethylformamide. This reaction mixture is stirred for one hour with continued cooling and then poured into ice water. The resultant precipitate is filtered off, washed with water and dissolved in dichloromethane. The solution is dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica gel.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:8]([NH2:7])[CH2:9][CH3:10])[N:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:14]=2[CH:22]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (234 mg, 0.63 mmol) in DCM (3 mL) was added TFA (1.5 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM (20 mL) and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a colourless oil (42 mg, 25%). LCMS (Method B): RT 1.90 min [M−NH2]+ 253.0.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:22])([CH3:21])[CH:18]([CH3:20])[CH3:19])[C:7]=1[CH2:25][S:26][CH2:27][C@H:28]([NH2:35])[C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[CH:2]=[CH2:3].[C:37]([O:56][CH2:57][C:58](O)=[O:59])([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.Cl.CN(CCCN=C=NCC)C>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:4][C:5](=[O:36])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:16]([CH3:24])([CH3:23])[C:17]([CH3:21])([CH3:22])[CH:18]([CH3:19])[CH3:20])[C:7]=1[CH2:25][S:26][CH2:27][C@@H:28]([C:29]1[O:33][N:32]=[C:31]([CH3:34])[N:30]=1)[NH:35][C:58](=[O:59])[CH2:57][O:56][C:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH:2]=[CH2:3]
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](N)c1nc(C)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1CSC[C@H](NC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1nc(C)no1
Temperature: 0 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a suspension of 1.07 g of (R)-2-[2-amino-2-(3-methyl-1,2,4-oxadiazol-5-yl)-ethylsulfanylmethyl]-3-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-5-methoxy-6-methylbenzoic acid allyl ester and 0.96 g of trityloxy-acetic acid in 15 ml of acetonitrile, cooled to 0° C., were added 0.58 g of N-(dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride. The mixture was stirred at 0° C. for 4 h, then diluted with 30 ml of ethyl acetate, and washed successively with 0.5N hydrochloric acid, water, 5% sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 1.42 g of (R)-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-5-methoxy-6-methyl-2-[2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-(2-trityloxy-acetylamino]-ethylsulfanylmethyl]-benzoic acid allyl ester as a foam.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH2:36])=[S:35].[C:38]([O-])(=[O:40])C.[Na+]>>[C:27]1([CH3:37])[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:36][C:38]([NH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[O:40])=[S:35]
Reactant: NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(=O)[O-]
Reactant: Cc1ccccc1NC(N)=S
Agent: [Na+]
Product: Cc1ccccc1NC(=S)NC(=O)NCCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 63 using 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)propan-1-amine (C60) and 1-(o-tolyl)thiourea. Sodium acetate was used in place of sodium bicarbonate. The title compound was isolated as a white solid (0.061 g, 21%): 1H NMR (400 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.06 (s, 1H), 9.39 (s, 1H), 8.14-7.99 (m, 3H), 7.63 (dt, J=7.3, 1.3 Hz, 3H), 7.45-7.35 (m, 2H), 7.33-7.14 (m, 4H), 7.09 (t, J=5.6 Hz, 1H), 3.17 (q, J=6.6 Hz, 2H), 2.70 (t, J=7.6 Hz, 2H), 2.21 (s, 3H), 1.92-1.74 (m, 2H); 19F NMR (376 MHz, DMSO-d6) δ −56.97; ESIMS m/z 555 ([M+H]+), 553 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:44]([O:48][C:49](=[O:69])[NH:50][C@H:51]([CH2:67][NH2:68])[CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.CO>[C:44]([O:48][C:49](=[O:69])[NH:50][C@H:51]([CH2:67][NH:68][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])([CH3:47])([CH3:45])[CH3:46]
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (386 mg, 2.05 mmol) and HATU (781 mg, 2.05 mmol) in DMF (10 mL) is added N-methyl morpholine (831 mg, 8.22 mmol) followed by ((S)-1-aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester (prepared according to the procedure described in WO1997/01204 page 20) (750 mg, 2.05 mmol). The resulting solution is stirred at RT for 18 h and then concentrated in vacuo to afford an orange oil. The oil is dissolved in MeOH (10 mL) and allowed to stand at RT after which time a cream precipitate forms that is collected by filtration and dried under vacuum to yield the title compound. [M+H]+ 536.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13].FC1C=CC=C(F)C=1N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: N#CC(C#N)=NNc1c(F)cccc1F
Reactant: NN
Agent: Nc1c(F)cccc1F
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1c(F)cccc1F
Yield: 37 %

Procedure:
This compound was prepared using 103 mg (0.5 mmol) of 2-[(2,6-difluorophenyl)-hydrazono]malononitrile, which was derived from 2,6-difluoroaniline (108 μL, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube approximately 10 min after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 44 mg (37%) of the title compound as an orange solid.
Reaction SMILES: [BH4-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]=[O:14]>C(O)C>[OH:14][CH2:13][CH:4]1[CH2:5][CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:3]1.[OH:14][CH2:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1
Reactant: O=Cc1ccc2ccccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC1CCc2ccccc2N1
Product: OCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (21.7 g, 0.57 mol) was added in portions to a solution of quinoline-2-carboxaldehyde (30 g, 0.191 mol) in ethanol (300 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred at room temperature for 2 hrs, and quenched by water. Volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate, washed with water and saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide the desired compound and 2-(hydroxymethyl)quinoline. A solution of the recovered 2-(hydroxymethyl)quinoline in ethanol (250 mL) and tetrahydrofuran (250 mL) was hydrogenated at 60 psi in the presence of 5% platinum on carbon at 40° C. for 48 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)=O.CC(C)=O.C([Li])CCC.CON(C)[C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]([C:28](=[O:37])[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Reactant: COc1ccc(C(=O)N(C)OC)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(=O)c2ccc(OC)cc2C(=O)O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
A solution of 18.5 g (80 mmol) of 2-bromo-5-methoxybenzoic acid in 150 mL of tetrahydrofuran is stirred under nitrogen at −78° C. in a bath of cardice/acetone. 100 mL (160 mmol) of a 1.6M solution of n-butyllithium in hexane are added dropwise over about 1 hour, while taking care to ensure that the temperature does not exceed −70° C. About half way through the introduction, the formation of a beige-coloured precipitate that corresponds to the formation of the lithium carboxylate is noted. After the addition, the mixture is stirred at −78° C. for 1 hour, and a solution of 15.9 g (80 mmol) of N,4-dimethoxy-N-methylbenzamide in 20 mL of THF is added dropwise. The reaction medium is stirred at −78° C. for 1 hour and the bath of cardice/acetone is then removed and the reaction medium is stirred, while allowing the temperature to return gradually to room temperature, for 18 hours. The mixture is hydrolysed with 100 mL of water, basified to pH=12 with 2N NaOH solution and then extracted with tert-butyl methyl ether. The aqueous phase containing the carboxylate is acidified with 5N HCl solution to pH 1 and extracted with dichloromethane. The dichloromethane phase is washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The product is crystallized from isopropyl ether; after filtering and drying, 14.6 g of white crystals are obtained (yield=64%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[NH2:30][C@@H:31]([CH:42]([CH3:44])[CH3:43])[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CN1CCOCC1>C(Cl)Cl>[CH2:35]([O:34][C:32](=[O:33])[C@@H:31]([NH:30][C:10](=[O:12])[C@@H:9]([N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH3:14])[CH3:13])[CH:42]([CH3:44])[CH3:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl(methyl)amino)propanoic acid (4.06 g, 20.0 mmol, Eq: 1), HOAT (4.08 g, 30.0 mmol, Eq: 1.5) and EDC (5.74 g, 30.0 mmol, Eq: 1.5) in DCM (200 mL), was added a solution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride (5.35 g, 22.0 mmol, Eq: 1.1) and N-methylmorpholine (4.45 g, 4.83 mL, 43.9 mmol, Eq: 2.2) in 50 mL of DCM. The reaction mixture was stirred at 23° C. for 3 h. The clear yellow solution was concentrated in vacuo. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3 (1×300 mL), 5% aqueous KHSO4 and brine (1×300 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 0% to 80% EtOAc in hexanes) to afford (S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyric acid benzyl ester as a colorless oil (7.02 g), m/z=393 (M+H).
Reaction SMILES: P(OCC)(OCC)OCC.[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[C:24](=[O:30])[N:23]([CH2:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:22]1[C:40]3[CH:41]=[C:42]4[O:50][CH2:49][O:48][C:43]4=[CH:44][C:45]=3[C:46](=[O:47])[C:21]2=1)=[N+]=[N-]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[NH2:11][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[O:28][CH3:29])[C:24](=[O:30])[N:23]([CH2:31][CH2:32][CH2:33][N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1)[C:22]1[C:40]3[CH:41]=[C:42]4[O:50][CH2:49][O:48][C:43]4=[CH:44][C:45]=3[C:46](=[O:47])[C:21]2=1
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN=[N+]=[N-])C(=O)c1cc2c(cc1-3)OCO2
Agent: CCOP(OCC)OCC
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCN)C(=O)c1cc2c(cc1-3)OCO2

Procedure:
Triethyl phosphite (0.022 mL, 0.183 mmol) was added to a solution of the compound 21 (0.040 g, 0.073 mmol) in benzene (4 mL), and the mixture was heated at reflux for 24 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl3, to yield the title compound as a solid. The solid (0.015 g, 0.023 mmol) was diluted with benzene (4 mL), and 2 M HCl in methanol (6 mL) was added to the solution. The mixture was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered to provide the desired compound 22 as a solid (0.007 g, 58%): mp>350° C. IR (film) 3413, 2346, 1751, 1651, 1559, 1437, 1309, 737 cm−1; 1H NMR (D2O) δ 6.77 (s, 1H), 6.62 (s, 1H), 6.56 (s, 1H), 6.16 (s, 1H), 5.96 (s, 2H), 4.86-4.82 (m, 2H), 4.01 (s, 6H), 3.78 (s, 2H), 3.67 (s, 3H), 3.32 (s, 4H), 3.24-3.19 (t, J=7.5 Hz, 2H), 2.19-2.17 (m, 4H); ESIMS m/z 522 (MH+); HRESIMS m/z 522.2249 (MH+), called for C28H32N3O7 522.2246; HPLC purity: 95.23% (C-18 reverse phase, MeOH—H2O, 85:15).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)[C:15]1=[O:33].[ClH:34].O1CCOCC1>C(Cl)Cl.CO>[ClH:34].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)[C:15]1=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](Nc3cc(F)c(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(F)c(N[C@H]2CCCN(C3CCNCC3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (4.6 g, 9.4 mmol) was dissolved in CH2Cl2 (100 mL) and methanol (10 mL). 4N HCl in dioxane (24 mL, 94 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to provide (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1,4′-bipiperidin-2-one hydrochloride, which was used directly in the next step without purification.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]([F:17])=[C:8](F)[C:7]=1[F:19]>CC(C)=O.O>[N:1]([C:8]1[C:7]([F:19])=[C:6]([F:5])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:16])[C:9]=1[F:17])=[N+:2]=[N-:3]
Reactant: COC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1c(F)c(F)c(N=[N+]=[N-])c(F)c1F
Yield: 94.3 %

Procedure:
All reaction steps were carried out with protection from light due to the sensitive nature of the azido group. First, a mixture of NaN3 (300 mg, 4.6 mmol) and methyl pentafluorobenzoate (0.972 g, 4.3 mmol) in acetone (8 mL) and water (3 mL) was refluxed for 8 hours. The mixture was cooled, diluted with 10 mL of water, and then extracted with diethyl ether (3×10 mL). The extract was dried (anhydrous Na2SO4) and evaporated to give methyl 4-azido-2,3,5,6-tetrafluorobenzoate (1.01 g, 94%), as off-white flakes, mp 53.6-54.3° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1([CH2:20][CH2:21][C:22](Cl)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>ClC(Cl)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:22](=[O:23])[CH2:21][CH2:20][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCOC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc(C(=O)CCC2CCCC2)c[nH]1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
Ethylpyrrole-2-carboxylate (1.8593 g, 13.36 mmol) in a minimal amount of dichloroethane was added to an ice cooled stirring mixture of aluminum chloride (3.5756 g, 26.82 mmol) and 3-cyclopentylpropionyl chloride (4.1 mL, 26.59 mmol) in dichloroethane (20 mL, 0.66 M) under N2. The ice bath was removed, and the reaction was stirred at room temperature for 4 h. 18.18 g (2.6 mMol/g) Polyamine resin HL (200-400 mesh) and dichloroethane (20 mL) were added, and the reaction was stirred for ˜60 min. The reaction was then filtered through a glass-fritted funnel directly into ice water. The resin was rinsed with CH2Cl2, then the organic layers were removed, dried with Na2SO4, filtered and concentrated. The crude product was recrystallized from Hexanes/Ethyl acetate. The crude was dissolved in a minimal amount of hot EtOAc, then allowed to slowly cool to room temperature. When no product crystallized, a small amount of hexanes was pipetted down the sides of the flask. Pure crystals of desired product (2.3068 g, 65.6%) were obtained after sitting overnight. 1H (CDCl3, 400 MHz): δ 10.04 (1H, broad s), 7.55 (1H, s), 7.29 (1H, s), 4.34 (2H, q, J=7.1 Hz), 2.77 (2H, t, J=7.6 Hz), 1.85-1.67 (5H, m), 1.64-1.46 (4H, m), 1.36 (3H, t, J=7.1 Hz), 1.78-1.06 (2H, m) ppm. 13C (CDCl3, 100 MHz): δ 196.38, 161.09, 127.03, 126.14, 124.05, 114.76, 60.91, 39.82, 39.06, 32.53, 30.82, 25.11, 14.31 ppm. DEPT (CDCl3, 100 MHz): CH3 carbons: 14.31; CH2 carbons: 60.91, 39.06, 32.53, 30.82, 25.1 1; CH carbons: 126.14, 114.76, 39.82 ppm. HPLC: 10.800 min.