Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:41])([F:40])[C:10]1[CH:11]=[C:12]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:13]([N:15]([CH:17]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[CH2:18][C:19](O)=[O:20])[CH3:16])=[O:14].[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[C:45]([CH3:50])[CH:44]=1>C(Cl)Cl>[Cl:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:19](=[O:20])[CH2:18][CH:17]([N:15]([C:13](=[O:14])[C:12]2[CH:11]=[C:10]([C:9]([F:41])([F:8])[F:40])[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=2)[CH3:16])[CH2:22][C:23]2[CH:24]=[CH:25][C:30]3[C:31](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:32]=2)=[C:45]([CH3:50])[CH:44]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1ccc2ccccc2c1
Reactant: Cc1cc(Cl)ccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ccc1NC(=O)CC(Cc1ccc2ccccc2c1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
A solution of 0.055 ml (0.393 mmol) of triethylamine and 38 mg (0.0786 mmol) of 3-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-4-(2-naphthyl)-butanoic acid in 0.5 ml of methylene chloride and a solution of 33.3 mg of 1-propanephosphonic acid anhydride in 0.4 ml of methylene chloride are added in succession to 10.3 mg (0.0943 mmol) of 4-chloro-2-methylaniline and the mixture is left to stand at room temperature overnight (>16 hours). The reaction mixture is then washed with 0.5 ml of a 1N aqueous potassium carbonate solution. The aqueous phase is extracted with a further 0.8 ml of methylene chloride. The combined organic phases are concentrated by evaporation in a vacuum centrifuge. The title compound is obtained in the form of a white foam. TLC: methylene chloride/acetone (7:3) Rf =0.48.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:9][CH:8]=1)[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-t-butyloxycarbonylphenyl)acrylic acid ethyl ester (11.52 g) and 5% palladium-charcoal in ethanol (115 ml) was stirred under hydrogen atmosphere at room temperature. The catalyst was removed by filtration and washed with ethanol. The combined solution was evaporated to give 3-(4-tert-butyloxycarbonylphenyl)propionic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:25]3[CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24]3)[CH:12]=2)=[CH:7][CH:6]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
(3′-Formyl-biphenyl-4-yl)-acetic acid methyl ester (1.22 g), acetic acid (0.23 mL) and iso-indoline (0.48 g) were combined in methanol (10 mL). After 1 hour, sodium triacetoxyborohydride (1.27 g) was added and stirred for 18 hours, at room temperature, under nitrogen. The reaction was quenched with 0.880 ammonia solution and concentrated. The residue was dissolved in methanol and loaded onto a conditioned SCX cartridge (50 g Varian). The cartridge was washed with methanol (3×50 mL), then eluted with methanolic ammonia solution (2×50 mL) and the combined elution fractions evaporated. Purification on silica, eluting with triethylamine/ethyl acetate/iso-hexane [1:19:80], to give the subtitle compound as a dark brown oil (450 mg).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1(=[O:27])[N:17]([CH2:18][C:19]([OH:21])=O)[C:16](=[O:22])[C:15]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:14]12.[C:28](=[N:32]O)([NH2:31])[CH2:29][CH3:30]>O1CCCC1>[CH2:29]([C:28]1[N:32]=[C:19]([CH2:18][N:17]2[C:13](=[O:27])[C:14]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:15]3[C:16]2=[O:22])[O:21][N:31]=1)[CH3:30]
Reactant: CCC(N)=NO
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1noc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 26.0 g of carbonyldimidazole in 250 ml of THF is added to a solution of 65.7 g of phthalimidoacetic acid in 500 ml of tetrahydrofuran (THF) (abs.) at 40° C. After about 1 hour, no generation of gas can be detected any longer. A solution of 28.2 propioamidoxime in 50 ml of THF is now added and stirred for 24 hours at room temperature. After filtering off of the precipitate the filtrate is concentrated in a vacuum and refluxed on a water separator for 6 hours after addition of 500 ml of dry xylene. The still hot solution is separated from the oily residue and concentrated in a vacuum. After crystallization from ethanol, 31.5 g of phthalimide with a melting point of 106-107° C. (76.5% relative to carbonyldiimidazole) is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J10) (294 mg. 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (442 mg, 1.1 mmol) according to the general procedure M. Obtained as an orange solid (509 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]2[O:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:3]=1.[H-].[Na+].[CH2:23](I)[CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:12]2[O:13][C:14]3[C:15]([N:20]=2)=[N:16][CH:17]=[CH:18][CH:19]=3)[CH:3]=1)[CH2:24][CH3:25]
Reactant: Oc1cc(-c2nc3ncccc3o2)cc2c1CCCC2
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1cc(-c2nc3ncccc3o2)cc2c1CCCC2
Reaction time: 0.17 h

Procedure:
A solution of 5.0 mmoles of product from Step D in 5 ml. of dimethylformamide is treated with 5.0 mmoles of sodium hydride/mineral oil emulsion. After stirring 10 minutes 1.0 g. of propyl iodide is added. After stirring 2 hours, the mixture is concentrated in vacuo to remove the dimethylformamide. Water (10 ml.) is added to the residue and the solids are collected and recrystallized from cyclohexane to give 2-(4-propoxy-5,6,7,8-tetrahydronaphth-2-yl)oxazolo[4,5-b]pyridine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)[Cl:21].[C:25]([C:27]1[C:31]([CH:32]=O)=[CH:30][N:29]([C:34]2[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][C:35]=2[Cl:45])[N:28]=1)#[N:26]>ClCCl>[C:25]([C:27]1[C:31]([CH:32]=[C:20]([Cl:24])[Cl:21])=[CH:30][N:29]([C:34]2[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:42])([F:44])[F:43])=[CH:36][C:35]=2[Cl:45])[N:28]=1)#[N:26]
Reactant: ClC(Cl)(Cl)Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C=C(Cl)Cl

Procedure:
A solution of triphenylphosphine (0.983 g) and carbon tetrachloride (0.145 ml) in anhydrous dichloromethane (5 ml) at 0° C. was stirred for 5 minutes. 3-Cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-formylpyrazole (0.25 g) was then added and the mixture was heated under reflux for 5 hours and then evaporated. The residue was purified by column chromatography on silica gel eluting with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 99-101° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][S:9]([O:12][CH2:13][C@:14]([OH:49])([CH3:48])[C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:11])=[O:10]>>[C:1]([O:49][C@@:14]([CH3:48])([C:15](=[O:47])[C@@H:16]([NH:24][C:25](=[O:46])[C@@H:26]([NH:30][C:31](=[O:45])[C@@H:32]([NH:36][C:37]([C:39]1[S:43][C:42]([CH3:44])=[N:41][CH:40]=1)=[O:38])[CH2:33][O:34][CH3:35])[CH2:27][O:28][CH3:29])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][O:12][S:9]([CH3:8])(=[O:10])=[O:11])(=[O:3])[CH3:2]
Reactant: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@](C)(O)COS(C)(=O)=O
Reactant: CC(=O)OC(C)=O
Product: COC[C@H](NC(=O)c1cnc(C)s1)C(=O)N[C@@H](COC)C(=O)N[C@@H](Cc1ccccc1)C(=O)[C@@](C)(COS(C)(=O)=O)OC(C)=O

Procedure:
Prepared according to procedures described above, by reacting acetic anhydride with (2R,4S)-2-hydroxy-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5-carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentyl methanesulfonate. MS for C28H38N4O11S2 m/z: 671 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:15])=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=2[CH:14]=1.C(N(CC)C1C=CC=CC=1)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCCl>[F:15][C:3]1[C:2]([NH:1][C:28]([O:30][CH3:31])=[O:29])=[CH:14][C:6]2[N:7]([CH:11]([CH3:13])[CH3:12])[C:8](=[O:10])[S:9][C:5]=2[CH:4]=1
Reactant: CC(C)n1c(=O)sc2cc(F)c(N)cc21
Reactant: COC(=O)Cl
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)Nc1cc2c(cc1F)sc(=O)n2C(C)C
Yield: 79.6 %

Procedure:
A mixture of 5-amino-6-fluoro-3-isopropyl-2(3H)-benzothiazolone (2.1 g), N,N-diethyianiline (1.5 g) and methyl chloroformate (1.0 g) was dissolved in 1,2-dichloroethane (10 g), and the resultant mixture was heated under reflux for 3 hours. After cooling, the reaction mixture was washed with water, and the organic layer was concentrated. The residue was washed with methanol to give 6-fluoro-5-methoxycarbonylamino -3-isopropyl-2(3H)-benzothiazolone (2.1 g).
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:14]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:13][C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([Cl:21])[CH:5]=1)=[O:3].[OH-].[Na+]>CO>[NH2:1][C:2]([C:4]1[C:14]([NH:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:13][C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:21])[CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1cc(NC(CC)CC)c(C(N)=O)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)Nc1cc(C(=O)O)c(Cl)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 65 %

Procedure:
To a solution of ethyl 4-(aminocarbonyl)-2-chloro-5-(pentan-3-ylamino)benzoate (126.5 mg, 0.40 mmol) in methanol (2 mL) was added 2 N aqueous sodium hydroxide (400 uL, 0.80 mmol). The mixture was stirred 4.5 h at room temperature. After acidification with 1 N hydrochloric acid (800 uL), the volatile solvent were removed. An insoluble solid material was then isolated from the aqueous residue by filtration. The solid was dried to give 4-(aminocarbonyl)-2-chloro-5-(pentan-3-ylamino)benzoic acid (73 mg, 0.26 mmol, 64% yield). 1H NMR (400 MHz, CD3OD): 7.65 (s, 1H), 7.07 (s, 1H), 3.35-3.29 (m, 1H buried), 1.69-1.47 (m, 4H), 0.94 (t, 6H).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH3:19][C:20](=[CH2:27])[CH2:21][O:22][CH:23]1[CH2:26][NH:25][CH2:24]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:27][C:20](=[CH2:19])[CH2:21][O:22][CH:23]1[CH2:26][N:25]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:24]1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: C=C(C)COC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)COC1CN(C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.5 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-[(2-methylprop-2-en-1-yl)oxy]azetidine hydrochloride (78 mg, 0.48 mmol; which may be prepared as described in Step 2), DIPEA (119 μL, 0.72 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was precipitated in methanol/water and then filtered. The resulting solid was dissolved in chloroform and washed with water to give a beige solid. This solid was triturated in diethyl ether to give the title compound (13 mg, 16%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([NH:32][NH2:33])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]1[O:31][C:41](=[O:42])[NH:33][N:32]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2ccccc2[C@H]1c1cc(Cl)ccc1OCc1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-hydrazinocarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (137 mg, 0.29 mmol, 1.0 eq.) and NEt3 (82 μL, 0.59 mmol, 2.0 eq.) in THF (3 mL), 1,1′-carbonyldiimidazole (72 mg, 0.44 mmol, 1.5 eq.) was added. The reaction mixture was stirred at r.t. for 1 hour. The solvent was removed in vacuo. The residue, redissolved in DMF (2.4 mL), was purified by prep. HPLC (column: Waters X-Bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) and evaporated to give the desired product as a white foam.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:39]=[CH:38][C:15]([CH2:16][C@@H:17]([C:35]([OH:37])=[O:36])[NH:18][C:19]([C:21]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=1>C(O)C.C(O)(C(F)(F)F)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:21]2([C:19]([NH:18][C@H:17]([C:35]([OH:37])=[O:36])[CH2:16][C:15]3[CH:38]=[CH:39][C:12]([N:3]4[C:2](=[O:1])[CH:10]5[CH:5]([CH2:6][NH:7][CH2:8][CH2:9]5)[C:4]4=[O:11])=[CH:13][CH:14]=3)=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N4C(=O)c5ccncc5C4=O)cc3)C(=O)O)CCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N4C(=O)C5CCNCC5C4=O)cc3)C(=O)O)CCCC2)cc1
Reaction time: 0.58 h
Yield: 13.8 %

Procedure:
A solution of 4-(2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl)-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (30 mg, 0.057 mmol) in ethanol (4 mL) containing a few drops of TFA was hydrogenated over 10% Pd(C) (6 mg) for 18 hours. The mixture was filtered and evaporated and the residue was purified by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 59.5% acetonitrile was concentrated and mixture was lyophilized to give N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[(3aRS, 7aRS)-(octahydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl)]-L-phenylalanine (4.2 mg), HR FABMS: obs. mass 534.2602. Calcd. mass 534.2604 (M+H). The peak eluting at 62% acetonitrile was concentrated and the mixture lyophilzed to give 4-[(RS)-2,3,5,6,7,7a-hexahydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl]-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (4.9 mg), HR FABMS:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccccn3)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccccn5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(pyridin-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.043 g, 0.11 mmol), and ethanol (2.5 ml) was added 4-methoxybenzaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.44 ml, 0.44 mmol). The reaction mixture was heated at 70° C. for 4 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and then 4% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a yellow solid after trituration with diethyl ether (0.010 g, 19%); 1H-NMR (500 MHz, DMSO-d6) 2.67 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.70 (s, 2H, NCH2), 3.84 (s, 3H, OMe), 7.10 (d, J=8.86 Hz, 2H) and 8.13 (d, J=8.75 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4—OMe), 7.28 (dd, J=5.00, 6.45 Hz, 1H), 7.52 (d, J=7.80 Hz, 1H), 7.79 (td, J=1.75, 7.65 Hz, 1H) and 8.52 (d, J=4.80 Hz, 1H) (pyrid-2-yl protons), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.35 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=[N+]=[N-])[CH:2]=[CH2:3]>CCCCCCC.C(OCC)(=O)C>[Br:15][C:11]1[CH:10]=[C:9]([C:6]23[CH2:3][CH:2]2[CH2:1][O:4][C:5]3=[O:16])[CH:14]=[CH:13][CH:12]=1
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C1OCC2CC12c1cccc(Br)c1

Procedure:
The compound was prepared in an analogous manner as described for intermediate B5A from (3-bromo-phenyl)-diazo-acetic acid allyl ester (intermediate B4B) (8.71 g, 31 mmol). The compound was obtained after silica gel column chromatography with n-heptane/ethyl acetate as light green oil (6.585 g, 84%). MS (ISP): m/z=270.1 [(M+NH4)+] and 272.1 [(M+2+NH4)+].
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[NH2:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([C:24]([NH:14][CH:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=2)[CH3:13])=[O:25])[CH:19]=1
Reactant: Nc1cc(C(=O)O)ncn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: Cl
Product: CC(NC(=O)c1cc(N)ncn1)c1ccc(OCC(F)(F)F)nc1
Yield: 89 %

Procedure:
The title compound is prepared in 89% yield (175 mg, a white solid) from (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (148 mg, 0.58 mmol, Amine-1, single enantiomer) and 6-aminopyrimidine-4-carboxylic acid (80 mg, 0.58 mmol) by the similar manner in Step-1 of Example 8.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35](O)=[O:36])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[S:33][C:32]([CH3:34])=[N:31][C:30]=2[C:35]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:36])=[CH:27][CH:28]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3CCC[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [O:1]([CH2:8][CH2:9]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[O:1]([CH2:8][CH2:9][Cl:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCOc1ccccc1
Reactant: O=S(Cl)Cl
Product: ClCCOc1ccccc1

Procedure:
Reacting 2-phenoxy-ethanol with thionyl chloride in the presence of a catalytic amount of a tetra-alkyl ammonium halide at a temp. of from about 0° C. to 80° C., optionally in the presence of a solvent to form 2-phenoxy-ethyl chloride;
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([NH2:25])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]([NH:25][S:34]([CH3:33])(=[O:36])=[O:35])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(N)COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NS(C)(=O)=O
Yield: 72 %

Procedure:
To a solution of compound from Step 4 (175 mg, 0.5 mmol) and Et3N (210 uL, 1.5 mmol) in 5 mL of CH2Cl2 at 0° C. was added MsCl (41 uL, 0.53 mmol) at 10 uL increment until starting material was no longer present by TLC. The mixture was quenched with saturated aqueous sodium bicarbonate, diluted with EtOAc and washed with 1 M HCl, water and brine, which was then dried (Na2SO4), filtered and concentrated to afford about 155 mg (0.36 mmol, 73%) of N-boc-4-[2-(2-methanesulfonylamino-2-methyl-propoxy)-phenyl]-piperazine as a yellow solid. LRMS (electrospray): 428.1 [M+1].
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].O1CCOCC1.[Br:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>ClCCl>[Br:11][CH:12]([CH3:16])[C:13]([O:15][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:14]
Reactant: CC(Br)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(Br)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
Isobutylene (2.4 g, 42.8 mmoles) was condensed into a pressure bottle at −15° C. Dioxane (6 mL) and 2-bromopropionic acid (3.5 mL, 38.9 mmoles) were added and the mixture was stirred for 5 min, warmed to −10° C., and concentrated sulfuric acid (250 μL) was added. The bottle was scaled, the reaction mixture was stirred overnight at room temperature, and the bottle was then opened and the contents poured into dichloromethane (50 mL). The solution was washed with 2096 potassium carbonate (50 mL), water (50 ml), dried over anhydrous magnesium sulfate and evaporated to give t-butyl bromopropionate (2.17 g, 27%). 1HMR (CDCl3, δ): 4.31 (1H, q, 7.1 Hz), 1.81 (3H, d, 7.1 Hz), 1.52 (9H, s).