Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:21].[K+].O>O.C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:19])=[O:21])=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)Cc1cccnc1O2
Yield: 73.7 %

Procedure:
To 50 mg of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide was added 0.4 g of potassium hydroxide in 4 ml of water/ethanol (1:1), and the mixture was refluxed for 3 hours. After cooling, to this was added water, and the mixture was washed with ethyl acetate. The aqueous layer was acidified with acetic acid and extracted with ethyl acetate. The extract was washed with water and then a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a solid, which was recrystallized from acetone to give 37 mg (yield: 72%) of (5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetic acid as white needle crystals having a melting point of 181°-184° C.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]2>[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-].ClCCl>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[C:16]([Cl:1])=[C:15]([OH:20])[CH:14]=[CH:13]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2cc(Br)ccc2c1Cl
Temperature: 0 °C
Reaction time: 10 h
Yield: 95.4 %

Procedure:
The synthesis of (S1-2) was carried out following the method described in Synlett, No. 18, 2837 (2005), wherein 29.9 g of N-chlorosuccinimide and 600 ml of dichloromethane were added to a reactor in nitrogen atmosphere and cooled to 0° C., 2.6 g of zirconium (IV) chloride was added, and then 50 g of 6-bromo-2-naphthol (S1-1) was added slowly. The reaction solution was heated to room temperature and stirred for 10 hours, then washed with saturated sodium bicarbonate solution and water, dried over magnesium sulfate, and distilled under a reduced pressure to remove the solvent. Recrystallization was carried out using a mixed solvent of toluene/heptane=1/1 (volumetric ratio) to obtain 55 g of 6-bromo-1-chloro-2-naphthol (S1-2).
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li].BrC1C=CC=CC=1OC>CCOCC.CCCCCC>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccncc1)c1ccccc1
Reactant: [Li]c1ccccc1OC
Agent: COc1ccccc1Br
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccccc1C(Nc1ccncc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.5 %

Procedure:
2.98 Grams (0.016 mole) of 4-benzylideneaminopyridine in 50 milliliters of dry ether were added dropwise to a stirred solution of 2-methoxyphenyl lithium (prepared from 0.03 mole of butyl lithium and 5.61 grams [0.03 mole] of o-bromoanisole) in a mixture of ether and hexane at 0° C. under nitrogen. The mixture was stirred at room temperature for 2 hours and then poured onto ice. The organic layer was separated and extracted with acid and the acid extracts were combined with the aqueous layer. The combined aqueous medium was basified with 5 N sodium hydroxide and extracted into dichloromethane. After drying over magnesium sulphate, the solvent was removed to leave a solid which yielded 2.3 grams of title compound, m.p. 143°-5° C. The product was converted into its hydrobromide salt, m.p. 196°-198° C., by solution in 2-propanol and addition of hydrogen bromide in dry ether.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: CN(C)CC(=O)Nc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: CN(C)CC(=O)Nc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
55 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzenamine was reacted with N,N-dimethylglycine via General Procedure I to give N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide. 70 mg of the crude N-(3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl)-2-(dimethylamino)acetamide was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A. The product was purified by reverse phase HPLC to yield 3 mg of 152. MS (Q1) 514 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:20]I)[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:20][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH2:10][CH2:9][N:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(Cl)cc2)C1
Product: CCOC(=O)C1(COc2ccc(-c3ccc(C#N)cc3)cc2)CCN(C(=O)c2ccc(Cl)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 1-(4-chloro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 13) and 4′-hydroxy-4-biphenyl carbonitrile to afford the racemate as a white solid (181 mg, 79.6%)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:16]=1.CCO.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:16]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1ccc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
Methyl 2-hydroxy-5-nitrobenzoate (11.82 g, 60 mmol), triphenylphosphine (17.29 g, 66 mmol) and EtOH (3.03 g, 3.85 ml, 66 mmol) were taken up in THF (150 ml) and cooled in ice. Di-isopropyl-azodicarboxylate (8.31 g, 10 ml, 66 mmol) was added carefully, and the reaction was stirred at RT for 1 hr. The reaction was concentrated in vacuo, and the residue was triturated with EtOAc (50 ml). The solid thus formed was collected by filtration, washed with MTBE and dried in vacuo to give 12.2 g of crude methyl 2-ethoxy-5-nitrobenzoate. The filtrate was evaporated in vacuo, and the resulting residue was triturated with EtOAc (25 ml). The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give 6.31 g of a second crop of crude methyl 2-ethoxy-5-nitrobenzoate. The combined portions of methyl 2-ethoxy-5-nitrobenzoate were taken up in hot IPA (50 ml) and cooled to RT. The resulting solid was collected by filtration, washed with MTBE and dried in vacuo to give pure methyl 2-ethoxy-5-nitrobenzoate (5.49 g, 40.5%) as a yellow solid.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][N:13]=2)[CH:9]=[N:8][CH:7]=1.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[CH:7]1[N:8]=[CH:9][N:10]2[CH:11]([C:12]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][N:13]=3)[CH2:3][CH2:4][CH2:5][C:6]=12
Reactant: ClCCCc1cncn1Cc1noc2ccccc12
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc2c(C3CCCc4cncn43)noc2c1

Procedure:
A suspension of 3-[(5-(3-chloropropyl)-1H-imidazol-1-yl)methyl]-1,2-benzisoxazole hydrochloride (1.9 g, 0.006 mole) in anhydrous tetrahydrofuran (25 mL) is stirred under an atmosphere of nitrogen and cooled in an ice bath during the portionwise addition of solid potassium t-butoxide (1.7 g, 0.015 mole). The reaction mixture is stirred at 0°-5° C. for 3 hours and then acidified by addition of glacial acetic acid (0.5 mL). The solvent is evaporated and the residue is taken up in methylene chloride (20 mL) and washed with saturated sodium bicarbonate (10 mL) and water (10 mL). The solution is dried over anhydrous sodium sulfate, filtered and evaporated to give crude 3-(5,6,7,8-tetrahydroimidazo-[1,5-a]-pyridin-5-yl)-1,2-benzisoxazole which is converted to the hydrochloride salt, m.p. 250°-252° C., when its solution in isopropanol is treated with ethereal hydrogen chloride.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[N+:7]([C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1)([O-])=O.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CC#N>[N:23]1([CH2:22][CH2:21][N:16]2[C:17]3[C:13](=[CH:12][CH:11]=[C:10]([NH2:7])[CH:18]=3)[CH:14]=[CH:15]2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2ccn(CCN3CCOCC3)c2c1
Temperature: 25 °C

Procedure:
K2CO3 (5.08 g, 36.726 mmol) was added to a slurry of 6-nitroindole (1.985 g, 12.242 mmol), 4-(2-chloroethyl)morpholine hydrochloride (2.278 g, 12.242 mmol), and CH3CN (100 ml). The mix was heated to reflux for 18 h, then cooled to RT, filtered, and concentrated in vacuo. The crude was eluted through a silica gel column with a gradient of 3:97 to 5:95 and finally 8:92 MeOH/CH2Cl2, to yield upon drying the desired intermediate which was hydrogenated under conditions previously described.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:36]([NH:43][CH:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][O:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][C@@:9]([CH3:31])([C:27]([O:29][CH3:30])=[O:28])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@](C)(Cc1cccc(OCC(=O)c2ccccc2)c1)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)[C@](C)(Cc1cccc(OCC(NCc2ccccc2)c2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-alpha-methyl-3-(2-oxo-2-phenylethoxy)phenylalaninate (0.600 g, 1.40 mmol), 4 A sieves (spatula tip), acetic acid (0.089 mL, 1.54 mmol), and benzylamine (0.184 mL, 1.68 mmol) in 10.0 mL dichloroethane was added sodium triacetoxyborohydride (0.357 g, 1.68 mmol). After 16 hr, additional benzylamine (0.092 mL, 0.840 mmol), sodium triacetoxyborohydride (0.178 g, 0.840 mmol), and acetic acid (0.045 mL, 0.770 mmol) were added. After an additional 16 hr, the temperature was raised to 50° C. for 30 hr., and additional amounts of 4 A sieves, acetic acid, benzylamine, and sodium triacetoxyborohydride were added over 72 hr to achieve full conversion. The reaction was quenched with bicarb. and filtered, washing with water and EtOAc. The layers of the filtrate were separated, and the aqueous layer was back extracted with EtOAc. The organic layers were combined, washed with bicarb. and brine (×2), dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography (90 g silica, 0-30% EtOAc in hexanes) gave methyl 3-[2-(benzylamino)-2-phenylethoxy]-N-(tert-butoxycarbonyl)-alpha-methylphenylalaninate as a yellow foam.
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:1]([N:11]1[CH2:18][CH2:17][CH2:16][CH:12]1[C:13]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH2:29])(=[O:27])=[O:28])=[CH:22][CH:21]=1)=[O:15])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(NC(=O)C2CCCN2C(=O)OCc2ccccc2)cc1

Procedure:
The reaction and recovery procedures of Example I are observed while reacting N-carbobenzyloxy-DL-proline with 4-aminobenzenesulfonamide to yield the desired product, 4-(N-carbobenzyloxy-DL-prolylamino)benzenesulfonamide, having a mp. of 144°-150° C.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH2:19][C:20]#[N:21])[CH3:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-:27].[K+].[K+].OO.O>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:23]=[CH:22][C:11]([O:12][CH2:13]/[CH:14]=[CH:15]/[CH2:16][N:17]([CH3:18])[CH2:19][C:20]([NH2:21])=[O:27])=[CH:10][CH:9]=2)=[O:7])=[CH:24][CH:25]=1
Reactant: O=C([O-])[O-]
Reactant: CN(CC#N)C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C/C=C/COc1ccc(C(=O)c2ccc(Br)cc2)cc1)CC(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 314.6 %

Procedure:
A suspension of 0.4 g of (E)-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetonitrile (Ex. 2j) and 0.04 g of potassium carbonate in 3 ml of dimethyl sulphoxide is cooled to 0° C. and treated with 1 ml of 30% hydrogen peroxide solution. The reaction mixture is warmed to room temperature and stirred overnight. For the working up, the mixture is treated with 10 ml of water and the separated crystals are filtered off and washed with water. There is obtained 0.38 g of (E)-2-[[4-[4-(4-bromo-benzoyl)-phenoxy]-but-2-enyl]-methyl-amino]-acetamide, MS: m/e 372 (M+ -H2NCO, 1Br).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[I:12]I>C(O)C.O.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:46])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][C:35]=2[CH3:44])[C:15]1=[O:45])=[O:12])C(=O)OC(C)(C)C.[ClH:47]>O1CCOCC1.CCOCC>[ClH:47].[CH3:21][C@@H:20]1[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][C:35]=2[CH3:44])[C:15](=[O:45])[C@H:14]1[NH:13][C:11](=[O:12])[C@@H:10]([NH:2][CH3:1])[CH3:46]
Reactant: Cc1cnc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)cnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Reaction time: 2 h
Yield: 90 %

Procedure:
A rt suspension of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (140 mg, 215 μmol) in 4 M HCl in dioxane (1.07 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (113.4 mg, 90%) as a white solid. MS m/z 552 (MH)+.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[C:22](OS(C3C(C)=CC(C)=CC=3C)(=O)=O)=[N:23][C:24]([NH2:28])=[N:25][C:26]=2[CH3:27])=[C:16]([O:42][CH3:43])[CH:15]=1)(=O)=O.[CH2:44]([NH2:49])[CH2:45][CH2:46][CH2:47][CH3:48]>O1CCOCC1>[NH2:28][C:24]1[N:25]=[C:26]([CH3:27])[C:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([OH:13])=[CH:15][C:16]=2[O:42][CH3:43])=[C:22]([NH:49][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[N:23]=1
Reactant: COc1cc(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: CCCCCN
Solvent: C1COCCO1
Product: CCCCCNc1nc(N)nc(C)c1Cc1ccc(O)cc1OC

Procedure:
A mixture of the product from step (iv) (9.51 g) and pentylamine (12 ml) in dioxane (100 ml) was heated under reflux for 48 h. The solvent was evaporated and the residue partitioned between EtOAc/water. The organics were separated, washed with aq NaHCO3 soln, water, dried and evaporated under reduced pressure. The residue was dissolved in MeOH (200 ml) then aq NaOH (2M, 40 ml) added and the mixture heated under reflux for 6 h. The mixture was acidified to pH 7 with aq 2M HCl, the solvent evaporated under reduced pressure and the residue partitioned between DCM/water. The organics were separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate and filtered to afford the subtitle compound, 2.43 g.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1COCC1.CN1CCOCC1.[CH2:29]([O:31][C:32]([C@@:34]1([NH2:39])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:33])[CH3:30]>>[C:4]([O:3][C:1]([N:8]1[CH2:16][C@H:14]([OH:15])[CH2:13][C@H:9]1[C:10](=[O:12])[NH:39][C@:34]1([C:32]([O:31][CH2:29][CH3:30])=[O:33])[CH2:36][C@H:35]1[CH:37]=[CH2:38])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: -23 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4.87 g (21.0 mmol) of Boc-(2S,4R)-hydroxyproline in 25 mL of THF 2.03 mL (20.0 mmol) of NMM was added. A suspension was formed. The mixture was cooled to −23° C. and 2.85 g (20.0 mmol) of isobutylchloroformiate was added. After stirring for 10 min additional 4.25 g (42.0 mmol) of NMM was added. To this mixture the solution of (1R,2S)-1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared in example 1 was added at a temperature of −15° C. within 5 min. The reaction mixture was stirred for 2.5 h at 0° C. Salts were filtered off and the filtrate was treated with 20 mL of aqueous HCl (0.5 N). The solvents were removed at 50° C. under reduced pressure using a rotary evaporator and the residue was extracted twice with 50 mL of EtOAc. The extract was washed with 40 mL of water and 40 mL of aqueous Na2CO3 solution (10 wt %), and dried over sodium sulfate. Finally the solvent was removed completely to give 8.19 g of (2S,4R)-2-((1R,2S)-1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a yellow oil. The product was used in the next step without further purification.