Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][C:11](=[O:12])[C:6]=2[N:5]=1)[CH3:3].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:22][C:17]1[CH:16]=[C:15]([CH2:14][N:5]2[C:6]3[C:11](=[O:12])[CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)c1nc2c([nH]1)CCC2=O
Reactant: Clc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.3 %

Procedure:
Tetrabutylammonium bromide (520 mg, 1.614 mmol) was added to a stirred mixture of Intermediate 17 (530 mg) and 4-(bromomethyl)-1,2-dichlorobenzene (852 mg) in sodium hydroxide 20% aq. (5.16 mL) and Toluene (6 mL). The RM was stirred at room temp for 3 hours. An excess of sat NH4Cl aq. solution was added and the mixture was extracted with EtOAc (3×30 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica (100 g) using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (660 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][CH:5]=[C:4]([Cl:16])[C:3]=1[NH:17][C:18]1[N:39]([CH3:40])[C:21]2=[N:22][C:23]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)=[C:24]([C:26](O)=[O:27])[CH:25]=[C:20]2[N:19]=1.ClC(N(C)C)=C(C)C.[F:49][C:50]([F:60])([F:59])[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[CH:54][CH:53]=1.N1C=CC=CC=1>CC#N.C(Cl)Cl>[F:49][C:50]([F:59])([F:60])[O:51][C:52]1[CH:53]=[CH:54][C:55]([NH:56][C:26]([C:24]2[CH:25]=[C:20]3[N:19]=[C:18]([NH:17][C:3]4[C:4]([Cl:16])=[CH:5][CH:6]=[C:7]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[CH3:12])[C:2]=4[Cl:1])[N:39]([CH3:40])[C:21]3=[N:22][C:23]=2[N:29]2[CH2:30][CH2:31][CH:32]([C:35]([F:36])([F:38])[F:37])[CH2:33][CH2:34]2)=[O:27])=[CH:57][CH:58]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)O)c(N3CCC(C(F)(F)F)CC3)nc21
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c(N3CCC(C(F)(F)F)CC3)nc21
Reaction time: 0.5 h

Procedure:
A mixture of 2-{2,6-dichloro-3-[(2,2-dimethyl-propionylamino)-methyl]-phenylamino}-5-[4-trifluoromethyl-piperidinyl]-3-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (54 mg, 0.090 mmol), (1-chloro-2-methyl-propenyl)-dimethylamine (0.026 mL, 0.20 mmol) and DCM (2 mL) is stirred for 30 min. This mixture is added to 4-trifluoromethoxyaniline (0.100 mmol) and pyridine (25 μL, 0.32 mmol) in MeCN (1 mL) and it is stirred for 2 h at 40° C. and overnight at 60° C. The mixture is concentrated and the residue is diluted with DMF/water 19/1 (2 mL) and purified via reverse phase HPLC. Yield: 18 mg. HPLC Rt=0.645 min (method G). MS m/z: 760 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]([CH3:17])([CH3:16])[C:8]2=[O:18])[CH2:4]1.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[CH:15][C:10]=3[C:9]([CH3:16])([CH3:17])[C:8]2=[O:18])[CH2:4]1
Reactant: Clc1nc2ccccc2s1
Reactant: CC1(C)C(=O)N([C@H]2C[C@H](N)C2)c2ncncc21
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC1(C)C(=O)N([C@H]2C[C@H](Nc3nc4ccccc4s3)C2)c2ncncc21
Temperature: 25 °C

Procedure:
A solution of 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, INTERMEDIATE 62, (0.100 g, 0.372 mmol), 2-chlorobenzothiazole (0.095 mL, 0.558 mmol), and N,N-diisopropylethylamine (0.194 mL, 1.116 mmol) in DMSO (0.4 mL) was stirred at 120° C. for 4 h. The reaction was allowed to cool to room temperature, diluted with water and extracted with EtOAc. EtOAc was concentrated and residue purified with ISCO using silica gel column eluting with 0-60% EtOAc/hexane to give the title compound 7-(trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.082 g, 0.224 mmol, 60.3% yield) as brown solid. m/z: 366.0 (M+1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.84 (s, 1 H), 8.33 (s, 1 H), 7.60 (dd, J=13.11, 7.82 Hz, 2 H), 7.23-7.39 (m, 1 H), 6.99-7.18 (m, 1 H), 6.26 (br. s., 1 H), 5.15-5.40 (m, 1 H), 4.53-4.70 (m, 1 H), 3.33-3.55 (m, 2 H), 2.41-2.58 (m, 2 H), 1.36-1.55 (m, 6 H).
Reaction SMILES: C([NH:20][CH:21]1[C:38](=[O:39])[N:23]2[C:24]([C:31]([O:33]C(C)(C)C)=[O:32])=[C:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][S:27][C@H:22]12)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>[N+](C)([O-])=O>[NH2:20][C@H:21]1[C:38](=[O:39])[N:23]2[C:24]([C:31]([OH:33])=[O:32])=[C:25]([CH:28]([CH3:30])[CH3:29])[CH2:26][S:27][C@H:22]12
Reactant: CC(C)C1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2SC1
Agent: Cl
Solvent: C[N+](=O)[O-]
Product: CC(C)C1=C(C(=O)O)N2C(=O)[C@H](N)[C@H]2SC1
Reaction time: 0.25 h
Yield: 84.2 %

Procedure:
A mixture of 541 mg of tert.butyl 7-tritylamino-3-isopropyl-3-cepheme-4-carboxylate in 11 ml of nitromethane was cooled on an ice bath and a current of gaseous hydrochloric acid was passed therethrough for 15 minutes. The mixture was evaporated to dryness and the residue was taken up in ether. The ether solution was vacuum filtered and the residue was washed with ether and dried. The residue was taken up in 1 ml of water and the pH was adjusted to 4 by addition of pyridine. The mixture was vacuum filtered and the crystals were washed with water, with acetone and then with ether and dried to obtain 204 mg of dl cis 7-amino-3-isopropyl-3-cepheme-4-carboxylic acid in the form of colorless crystals melting towards 230° C. with decomposition.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.B(OB=O)=O.[Cl:21][C:22]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:23]=1[CH:24]=O.B(OCCCC)(OCCCC)OCCCC.C(N)CCC.Cl.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Cl-].[Na+].O>[Cl:21][C:22]1[CH:29]=[C:28]([OH:30])[CH:27]=[CH:26][C:23]=1/[CH:24]=[CH:13]/[C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: CC(=O)CC(=O)CCc1ccc(O)cc1
Agent: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: O=BOB=O
Solvent: O
Solvent: CCCCN
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(O)cc1Cl)CC(=O)CCc1ccc(O)cc1
Reaction time: 1 h
Yield: 34.2 %

Procedure:
6-(4-Hydroxyphenyl)hexane-2,4-dione (18 mg, 87 μmol) and boron trioxide (22 mg, 0.32 mmol) was placed in a 20 mL reaction vessel, and dissolved in 0.4 mL of ethyl acetate. To the stirring solution at 80° C. were added 2-chloro-4-hydroxybenzaldehyde (12 mg, 78 μmol) and tri-n-butyl borate (50 μL, 0.19 mmol). After the reaction mixture was stirred for 2 h at the same temperature, n-butylamine (19 μL, 0.19 mmol) was added with additional stirring for 1 h. The reaction mixture was treated with a 1:1 solution (1 mL) of 1N HCl and brine, and was stirred at 50° C. for 5 min to 1 h (if necessary, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution). The organic layer was purified directly by silica gel column chromatography (eluting with hexane/ethyl acetate or chloroform/methanol) to obtain the title compound as a solid (9.2 mg, 34%) having the following characteristics.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH3:13])=[O:12])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:18][C:19]1[N:20]([CH3:24])[N:21]=[CH:22][CH:23]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>C(OCC)(=O)C.O>[OH:18][C:19]1[N:20]([CH3:24])[N:21]=[CH:22][C:23]=1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:14]([F:17])([F:16])[F:15])=[C:10]([S:11]([CH3:13])=[O:12])[C:2]=1[CH3:1])=[O:6]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Reactant: Cn1nccc1O
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)c2cnn(C)c2O)ccc(C(F)(F)F)c1S(C)=O
Temperature: 0 °C
Yield: 94.6 %

Procedure:
3.0 g of 2-methyl-3-methylsulfinyl-4-trifluoromethylbenzoic acid and 1.25 g of 3-hydroxy-2-methylpyrazole are suspended in 20 ml of ethyl acetate and 4.8 g of pyridine under an inert atmosphere and cooled to −25° C. with stirring. 1.51 g of thionyl chloride are then slowly added dropwise such that the temperature always remains below −20° C. Following the complete addition of the thionyl chloride, the mixture is stirred for a further 20 minutes. 40 μl of cold water, 10 ml of ethyl acetate and a further 10 ml of water are added, and the mixture is heated to 0° C. After separating the organic phase from the aqueous phase, the aqueous phase is extracted twice with 5 ml of ethyl acetate in each case. The combined organic phases are dried, giving 3.69 g of (5-hydroxy-1-methyl-1H-pyrazol-4-yl)[2-methyl-3-(methylsulfinyl)-4-(trifluoromethyl)phenyl]methanone (90.7% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.[C:24]1([S:30]([N:33]2[C:37]3=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=[C:36]3[C:35]([CH:43]=[O:44])=[CH:34]2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:43]([C:35]2[C:36]3[C:37](=[N:38][CH:39]=[C:40]([Cl:42])[CH:41]=3)[N:33]([S:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:32])=[O:31])[CH:34]=2)[OH:44])=[CH:6][CH:7]=1
Reactant: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Reactant: Nc1ccc(Br)cn1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.9 %

Procedure:
To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under an atmosphere of nitrogen at −78° C., a solution n-butyllithium (2.50 M in hexane, 7.10 mL) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed to warm to room temperature for 1 hour. The reaction was cooled to −78° C. followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture was stirred at −78° C. for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was cooled to −78° C., followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.50 mL) slowly. After 60 minutes, 1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (597, 1.90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound (598, 1.25 g, 50.9%). MS (ESI) [M+H+]+=415.2.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.CN(C)P(N(C)C)(N(C)C)=O.C(Cl)(Cl)Cl.CCO>O1CCOCC1.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>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:11]=2)[C:6](=[O:19])[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2cc(Br)ccc2c1=O
Reactant: C[Sn](C)(C)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Solvent: CCO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1cn(CC)c2cc(-c3cccnc3)ccc2c1=O
Yield: 56.3 %

Procedure:
A suspension of 10.0 g ethyl 7-bromo-1,4-dihydro-1-ethyl-4-oxo-3-quinolinecarboxylate (U.S. Pat. No. 3,753,993), 0.64 g dichlorobis(triphenylphosphine)palladium, 10.9 g 3-trimethylstannylpyridine and 6.5 ml hexamethylphosphoramide in 40 ml dioxane was heated at reflux under nitrogen for 48 hrs. The reaction mixture was filtered through neutral alumina, eluted with chloroform, washed with water, and dried over potassium carbonate. The solid product obtained by concentration in vacuo was subjected to chromatography (MPLC; 10:1 CHCl3/EtOH) to give 5.6 g of ethyl 1,4-dihydro-1-ethyl-7-(3-pyridinyl)4-oxo-3-quinolinecarboxylate, which was hydrolyzed by refluxing with 150 ml 3N hydrochloric acid for 1.5 hrs. The product which separated (3.9 g) was dried to give 1,4-dihydro-1-ethyl-7-(3-pyridinyl)-4-oxo-3-quinolinecarboxylic acid, m.p. 268-269° C.
Reaction SMILES: [O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([O-:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:6])([F:5])[F:4].O.C(=O)([O-])[O-].[K+].[K+].SCC(CO)O>CN(C=O)C>[O:1]=[C:2]([C:7]1[N:8]([C:12]2[N:13]=[C:14]([CH2:38][CH2:39][CH3:40])[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:16]=2[C:17]([OH:19])=[O:18])[CH:9]=[CH:10][CH:11]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: OCC(O)CS
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(-n2cccc2C(=O)C(F)(F)F)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.2 %

Procedure:
4-[2-(1-Oxo-2,2,2-trifluoroethyl)-1H-pyrrol-1-yl]-2-propyl-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (2.5 g) from Example 13 was dissolved in DMF (45 mL). Water (0.4 mL) followed by potassium carbonate (3.1 g) were added and the reaction mixture stirred at room temperature for 48 hours. Tlc of the reaction mixture showed the reaction to be incomplete. Additional potassium carbonate (0.6 g) and water (0.2 mL) were added and the reaction mixture stirred at room temperature for an another 18 hours. The insoluble materials were removed from the reaction mixture by filtration and washed with DMF A 10% citric acid solution (100 mL) was added slowly to the filtrate and the resulting mixture extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to afford 2.06 g (85% yield) of the title compound, mp 185°-188° C., MS (FAB, thioglycerol) 550.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:41])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccc2c(c1Nc1ccnc3[nH]c4c(c13)CNCC4)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(c1ccccc1)N1CCc2[nH]c3nccc(Nc4c(Cl)ccc5c4OCO5)c3c2C1
Temperature: 25 °C
Yield: 10 %

Procedure:
(5-Chloro-benzo[1,3]dioxol-4-yl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (100 mg, 0.29 mmol) and DIEA (0.15 mL, 0.88 mmol) were dissolved in 1,2-dichloroethane (2 mL) and stirred at room temperature. Benzoyl chloride (0.03 mL, 0.35 mmol) was added dropwise, and the reaction was stirred for 1 h at room temperature. The reaction solution was concentrated. The crude material was dissolved in DMSO (3 mL) and filtered. The filtrate was purified directly via prep-LC-MS to provide 67 (13 mg, 10% yield) as a white fluffy solid. LC-MS (M+H=447, obsd.=447).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1.C(OCC)(=O)C>CO.O.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: Nc1ccc(-c2ccc(Cl)cc2)cc1F
Temperature: 80 °C
Reaction time: 14 h

Procedure:
1.95 g (12.47 mmol) of 4-chlorophenylboric acid, dissolved in 10 mL of methanol, and 3.9 g (36.79 mmol) of sodium carbonate, dissolved in 10 mL of water, are added successively to a reaction mixture of 2.28 g (12 mmol) of 4-bromo-2-fluoroaniline and 0.6 g (0.51 mmol) of tetrakistriphenylphosphine palladium in 90 mL of dioxane and stirred for 14 hours at 80° C. Then ethyl acetate is added and the reaction mixture is filtered. The filtrate is evaporated down and extracted with ethyl acetate and water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: cyclohexane/ethyl acetate (3:1)). Yield: 2 g (75.2% of theory); C12H9FN (M=221.66); calc.: molecular ion peak (M+H)+: 222; found: molecular ion peak (M+H)+: 222; Rf value: 0.41 (silica gel, cyclohexane/ethyl acetate (3:1)).
Reaction SMILES: [S:1]1[CH2:7][CH2:6][CH2:5][CH2:4][S:3][CH:2]1[CH2:8][NH:9][C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:31][CH2:32][C:33](Cl)=[O:34]>CCOCC.O>[Cl:31][CH2:32][C:33]([N:9]([CH2:8][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][CH2:7][S:1]1)[C:10]1[C:15]([CH2:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:18][CH3:19])=[O:34]
Reactant: CCc1cccc(CC)c1NCC1SCCCCS1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: O
Product: CCc1cccc(CC)c1N(CC1SCCCCS1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dithiepan-2-ylmethyl)-2,6-diethylaniline (15 grams), sodium bicarbonate (10 grams), dioxane (30 ml) and water (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0°C and chloroacetyl chloride (7 grams) is added, with stirring, over a period of about 15 minutes. After the addition is completed stirring is continued for a period of about 1 hour. After this time ether (100 ml) is added to the mixture and the resulting solution is washed with water. The washed solution is then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue is recrystallized to yield the desired product N-α-chloroacetyl-N-(1,3-dithiepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:24]([OH:26])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH:27][C:28]1[CH:36]=[CH:35][C:31]([C@@H:32]([NH2:34])[CH3:33])=[CH:30][CH:29]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(#N)C.C(#N)C.C(Cl)Cl.C(N(CC)CC)C>[C:1]([NH:8][C@H:9]([C:24]([NH:34][C@@H:32]([C:31]1[CH:35]=[CH:36][C:28]([OH:27])=[CH:29][CH:30]=1)[CH3:33])=[O:26])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C[C@H](N)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccc(O)cc1
Yield: 94.8 %

Procedure:
Prepared according to the method described in Example 1(a) above from Nα -Boc-Nδ -Cbz-(R)-ornithine (5.34 g; 14.56 mmol), (S)-4-hydroxy-α-methylbenzylamine (2.0 g; 14.56 mmol), BOP reagent (9.67 g; 21.9 mmol), triethylamine (2.5 mL; instead of DiPEA) in acetonitrile (100 mL; instead of acetonitrile:CH2Cl2 (1:1)) to yield the sub-title compound (6.7g) as a white foam. The crude 1H NMR was consistent with the structure.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([OH:19])=O)[O:14][N:13]=2)=[CH:8][CH:7]=1>CN(C)C=O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[C:15]([C:17]([Cl:3])=[O:19])[O:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2cc(C(=O)O)on2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)Cl)on2)cc1

Procedure:
Using 40 ml of thionyl chloride, 7.3 g (35.9 mmol) of 3-(4 -methylphenyl) isoxazole-5-carboxylic acid obtained above in the procedure (2) were refluxed for 4 hours in the presence of 0.1 ml of dimethylformamide. Thionyl chloride was distilled off under reduced pressure, followed by the addition of 100 ml of benzene. The resultant mixture was distilled under reduced pressure so that 3-(4-methylphenyl) isoxazole-5-carboxylic acid chloride was obtained as a solid. The solid was provided for the next step without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:15]([C:11]1([C:13]([OH:26])=[O:14])[CH2:12][CH:7]2[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]2[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(Cc3ccccc3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5-Benzyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14b (0.729 g, 2.43 mmol) was dissolved in the solvent mixture of 28 mL of tetrahydrofuran and 14 mL of water under nitrogen atmosphere, followed by addition of sodium dihydrogenphosphate dihydrate (1.14 g, 7.29 mmol), sodium chlorite (0.66 g, 7.29 mmol) and 2-methyl-2-butene (0.513 g, 7.32 mmol) upon cooling to 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.76 g, yield 98%) as a colorless oil.