Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[O:9][N:8]=2)=[CH:3][CH:2]=1.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH2:11][C:10]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:9][N:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(c1ccncc1)=NO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C2=NOC3(CCNCC3)C2)ccn1

Procedure:
tert-Butyl 3-(pyridin-4-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carboxylate (0.48 g, 1.5 mmol) was dissolved in methylene chloride (10 ml), the solution was cooled and trifluoroacetic acid (1.2 ml, 15 mmol) was slowly added. After refluxing for 2 h, the solvent was removed in vacuo and the residue was co-evaporated with 30 ml each of toluene and methanol. Yield: 0.74 g (100%)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][NH:21][S:22]([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[Cl:1][C:2]1[C:3]([N:21]([CH2:20][C:16]2[CH:15]=[C:14]3[C:19](=[CH:18][CH:17]=2)[N:11]([CH3:10])[CH:12]=[CH:13]3)[S:22]([C:25]2[CH:26]=[CH:27][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:33][CH:34]=2)(=[O:23])=[O:24])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Fc1ncc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(ccn3C)c2)c2ncc(Cl)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 3,5-dichloro-2-fluoropyridine and methyl 4-(N-((1-methyl-1H-indol-5-yl)methyl)sulfamoyl)benzoate (step-1 of Example 6).
Reaction SMILES: COCCN(S(F)(F)F)CCOC.[C:14]([O:18][C:19]([NH:21][C@H:22]([CH3:33])[C:23]([NH:25][CH:26]([CH2:31][OH:32])[C:27]([O:29][CH3:30])=[O:28])=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].BrC(Cl)(Cl)Cl>C(Cl)Cl>[C:14]([O:18][C:19]([NH:21][C@@H:22]([C:23]1[O:32][CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[N:25]=1)[CH3:33])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Agent: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc([C@@H](C)NC(=O)OC(C)(C)C)n1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Deoxo-fluor™ (Bis-(2-methoxy)amino sulfur trifluoride, 1.4 mL, 7.6 mmol) was added drop-wise to a solution of methyl 2-((R)-2-(tert-butoxycarbonylamino)propanamido)-3-hydroxypropanoate (2.0 g, 6.9 mmol) in CH2Cl2 (50 mL) at −20° C. The solution was stirred for 30 min and BrCCl3 (2.45 mL, 24.8 mmol) was added drop-wise. The reaction was stirred at 2-3° C., for 8 h., quenched with sat. aq. NaHCO3 solution and extracted with ethyl acetate. The organic layer was concentrated and chromatographed on silica gel (30% ethyl acetate/70% hexanes) to yield 65% of (R)-methyl 2-(1-(tert-butoxycarbonylamino)ethyl)oxazole-4-carboxylate.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:16][C@@H:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C@@:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[C@H:13]2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=2[F:39])=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].[Li+].[Cl-]>CCO.C1COCC1>[Cl:38][C:34]1[C:33]([F:39])=[C:32]([CH:13]2[C:14]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[F:31])([C:22]#[N:23])[CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][N:12]2[C:10](=[O:11])[C:7]2[CH:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)c1ccc(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)CC1CN(C(=O)c2ccc(CO)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To a solution of rac-4-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-benzoic acid methyl ester (130.0 mg, 0.222 mmol) in EtOH (1.0 mL) and THF (1.0 mL) was added NaBH4 (36.0 mg, 0.96 mmol) and LiCl (40.7 mg, 0.96 mmol). The reaction mixture was stirred at rt overnight. Work up and the residue was purified by RP-HPLC to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(4-hydroxymethyl-benzoyl)-pyrrolidine-3-carbonitrile (5.7 mg, 4.6%). HRMS (ES+) m/z Calcd for C30H28Cl2F2N2O2+H [(M+H): 557.1568; Found: 557.1569.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][N:4]([CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[CH3:5].[CH3:17][NH:18][CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1>C1C=CC=CC=1>[OH:1][CH:2]([CH2:16][N:18]([CH:19]1[CH2:24][C:23]([CH3:26])([CH3:25])[NH:22][C:21]([CH3:28])([CH3:27])[CH2:20]1)[CH3:17])[CH2:3][N:4]([CH3:5])[CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1
Reactant: CN(CC1CO1)C1CC(C)(C)NC(C)(C)C1
Reactant: CNC1CC(C)(C)NC(C)(C)C1
Solvent: c1ccccc1
Product: CN(CC(O)CN(C)C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 3 h

Procedure:
A mixture of 2.2 g of 4-[N-(2,3-epoxypropyl)-N-methylamino]-2,2,6,6-tetramethylpiperidine and 1.7 g of 4-methylamino-2,2,6,6-tetramethylpiperidine in 20 ml of benzene was refluxed, with stirring, for 3 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure and then the resulting residue was distilled in vacuo, giving the desired compound in the form of a colourless, viscous oil boiling at 194°-196° C. at 0.2 mmHg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH2:4][CH2:3]1.[S].[OH-].[Na+].[Cl-].[Ca+2].[Cl-].CCOCCOCCO>C1C=CC=CC=1.Cl>[CH:12]([N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2)[C:6]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:7][C:8]1=[O:15])([CH3:14])[CH3:13]
Reactant: CC1CCc2c(-c3ccccc3)nc(=O)n(C(C)C)c2C1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCCOCCO
Solvent: c1ccccc1
Product: Cc1ccc2c(-c3ccccc3)nc(=O)n(C(C)C)c2c1
Temperature: 65 °C

Procedure:
A mixture of 28.2 g. of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro-2(1H) quinazolinone, 9.6 g. of sulfur, 10 gms of sodium hydroxide, 20 gms of calcium chloride and 200 mls of carbitol (2-[2-ethoxyethoxy]ethanol) is heated under a nitrogen blanket at 150° C. for 2 hours. The resulting mixture is then cooled to 65° C., 500 mls. of benzene added and the mixture cooled with stirring to 15° C. and the liquid phase decanted. The organic phase is washed with water and evaporated to obtain an oil which is dissolved in a mixture of 100 mls of benzene and 100 mls of 50% aqueous hydrochloric acid. The resulting mixture is stirred for one hour at room temperature, the phases separated and the acid phase treated with 50 mls of benzene. The acid phase is neutralized with 50% sodium hydroxide solution, extracted with 150 mls of benzene and the benzene extracts washed with water until neutral. After drying over sodium sulfate, the benzene solution is evaporated to obtain the crude product which is recrystallized from ethylacetate to obtain 1-isopropyl-4-phenyl-7-methyl-2[1H]quinazolinone, m.p. 141°-142° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH:11]=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([NH2:16])[C:14]#[CH:15].CO.[BH4-].[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[C:1]([O:5][C:6]([N:8]([CH3:9])[CH2:10][CH2:11][NH:16][CH2:13][C:14]#[CH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C#CCNCCN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
2.7 mL (9.1 mmol) of titanium isopropoxide and 1.2 g (7 mmol) of (tert-butoxycarbonyl-methyl-amino)-acetaldehyde (prepared according to the method described by Kato, Shiro et al., J. Chem. Soc. Perkin Trans. 1, 1997, 21, 3219-26) are added to a solution of 1.16 g (21 mmol) of propargylamine in 50 mL of anhydrous tetrahydrofuran. The solution is stirred for 5 hours at room temperature then 5 mL of anhydrous methanol and 317 mg (8.4 mmol) of sodium borohydride is added. Stirring is continued for a further 2 hours then 2 mL of water is added. The reaction mixture is filtered then the solvents are evaporated. The residue is purified by chromatography on silica (eluent dichloromethane/methanol 98/2) to give 550 mg (37%) of N-tert-butoxycarbonyl-N-methyl-N′-prop-2-ynyl-ethane-1,2-diamine in the form of a colourless oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.B(F)(F)[F:11].[F:14][B-:15]([F:18])([F:17])[F:16].[H+].FF>O>[F:14][B-:15]([F:18])([F:17])[F:16].[F:14][B-:15]([F:18])([F:17])[F:16].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:11])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: [O-][N+]12CCN(CC1)CC2
Reactant: FB(F)F
Agent: FF
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: O
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 159.7 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (25.6 g, 0.2 mole), boron trifluoride gas (13.6 g, 0.2 mole), and tetrafluoroboric acid (10 M solution, 20 mL, 0.2 mole) in water (400 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 0.2 mole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 51.4 grams of 1-hydroxyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) (80% yield).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH3:10].[Cl:14][C:15]1[N:24]=[C:23]2[C:18]([CH:19]=[CH:20][C:21]([N:25]3[CH:33]([OH:34])[C:32]4[C:27](=[CH:28][CH:29]=[C:30]([C:35]([F:38])([F:37])[F:36])[CH:31]=4)[C:26]3=[O:39])=[N:22]2)=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:7]([NH:11][C:12]([O:34][CH:33]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:35]([F:37])([F:38])[F:36])[CH:31]=2)[C:26](=[O:39])[N:25]1[C:21]1[CH:20]=[CH:19][C:18]2[C:23](=[N:24][C:15]([Cl:14])=[CH:16][CH:17]=2)[N:22]=1)=[O:13])[CH2:8][CH2:9][CH3:10]
Reactant: O=C1c2ccc(C(F)(F)F)cc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCNC(=O)OC1c2cc(C(F)(F)F)ccc2C(=O)N1c1ccc2ccc(Cl)nc2n1

Procedure:
Pyridine (10 cc.) and n-butyl isocyanate (11.2 cc.) are added to a suspension of 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-5-trifluoromethyl-isoindolin-1-one (3.8 g.) in acetonitrile (380 cc.). The mixture is heated to the reflux temperature and triethylamine (0.5 cc.) is then added. Refluxing is continued for 1 hour and 30 minutes until dissolution. The reaction mixture is then concentrated under reduced pressure (40 mm.Hg), and the residue is recrystallised from acetonitrile (48 cc.) to give 3-n-butylaminocarbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-5-trifluoromethyl-isoindolin-1-one (3.5 g.) melting at 120° C. and then at 176° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:3][CH2:2]1.C(O)([C:29]([F:32])([F:31])[F:30])=O.N1CCC(N2C3C=CC(C4NN=NN=4)=CC=3OC3C2=CC=CC=3)CC1.[S:59]1[CH:63]=[CH:62][CH:61]=[C:60]1[CH:64]=O.N1C=CN=C1C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>>[S:59]1[CH:63]=[CH:62][CH:61]=[C:60]1[CH2:64][N:1]1[CH2:2][CH2:3][CH:4]([N:7]2[C:20]3[CH:19]=[CH:18][C:17]([C:21]4[NH:25][C:24](=[O:26])[O:23][N:22]=4)=[CH:16][C:15]=3[O:14][C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:5][CH2:6]1.[C:24]([OH:23])([C:29]([F:32])([F:31])[F:30])=[O:26]
Reactant: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCNCC2)no1
Reactant: O=Cc1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Agent: O=Cc1ncc[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccc3c(c2)Oc2ccccc2N3C2CCN(Cc3cccs3)CC2)no1

Procedure:
Using an adaptation of the method described in Procedure 7, substituting the TFA salt of 3-(10-piperidin-4-yl-10H-phenoxazin-3-yl)-4H-[1,2,4]oxadiazol-5-one, 2b for the TFA salt of 10-piperidin-4-yl-3-(1H-tetrazol-5-yl)-10H-phenoxazine, 6a, 2-thiophene carboxaldehyde for 1H-imidazole-2-carboxaldehyde and sodium triacetoxyborohydride for tetramethylammonium triacetoxyborohydride, the title compound 3-[10-(1-thiophen-2-ylmethyl-piperidin-4-yl)-10H-phenoxazin-3-yl]-4H-[1,2,4]oxadiazol-5-one, 5b was obtained as a TFA salt after purification via reverse phase HPLC (eluent: CH3CN in H2O containing 0.1% TFA). MS m/z (MH+) 446.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18](O)(=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C:18]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CC(C)CC(=O)O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CC(C)CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 10.0 mg (0.10 mMol) isovaleric acid, 17.0 mg (100+%) of the title compound were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O.C1C=CC=CC=1>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(N)cn1
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(N=Cc2ccc(Cl)c(Cl)c2)cn1

Procedure:
The starting material is prepared as follows: The mixture of 7 g of 5-aminopyridine-2-carboxylic acid methyl ester, 8.9 g of 3,4-dichlorobenzaldehyde, and 40 ml benzene are refluxed for 29 hours on a water-separating trap. The initial suspension becomes a clear solution, which is evaporated. The solid residue is triturated with diethyl ether and recrystallized from acetonitrile, to yield the 5-(3,4-dichlorobenzylideneamino)-pyridine-2-carboxylic acid methyl ester melting at 202°-207°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C@@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13].CCN(C(C)C)C(C)C.O>CN(C=O)C.CCOC(C)=O>[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C@@H:17]([NH:24][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:13]
Reactant: CCOC(=O)C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Nc1nc(Cl)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 2,6-dichloro-3-nitro-pyridine (0.75 g, 3.58 mmol) in DMF (30 ml) were added (R)-3-amino-3-phenylpropanoic acid ethyl ester (0.83 g, 4.29 mmol) and DIPEA (1.25 ml, 7.15 mmol). The reaction mixture was stirred at 70° C. overnight after which time it was poured into water (200 ml) and EtOAc. The layers were separated and the aqueous phase was extracted once more with EtOAc. The combined organics were washed with water twice and dried (MgSO4). Filtered and concentrated to give the crude product as an orange oil which was then purified by silica gel flash column chromatography (12 g silica gel, 5% EtOAc/Hexane) to afford 0.80 g (64%) of the title compound as a orange oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:21]=[CH:22][C:23]([NH2:28])=[CH:24][CH:25]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: Nc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 60.9 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and p-phenylenediamine (540 mg, 5 mmol) to give 115 mg of the title compound (61%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.11 (s, 1H), 10.32 (s, 1H), 9.93 (br, 2H), 7.67 (d, 1H, J=8.9 Hz), 7.29 (d, 2H, J=8.6 Hz), 7.50 (dd, 2H, J=8.6 Hz), 7.23 (bs, 1H), 7.20 (bs, 1H), 5.18~5.27 (m, 1H), 3.08 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.56~2.70 (m, 2H), 2.08 (dm, 1H, J=13.5 Hz), 1.82~1.96 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>ClCCl>[Cl:21][C:16]([CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of compound 2.0 g of 1-(benzyloxycarbonyl)pyrrolidine-2-carboxylic acid (1.0 g, 4.01 mmol) in anhydrous dichloromethane (10 mL) was added dropwise thionyl chloride (0.573 g, 4.81 mmol) at 0° C. After the addition, the solution was stirred at room temperature overnight. Solvent was removed in vacuum to give benzyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate.
Reaction SMILES: C[CH2:2][C:3]([O:5]CC)=S.ClCl.[CH2:10]([O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:11].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:10]([O:12][C:13]1[CH:19]=[C:18]2[C:16](=[CH:15][CH:14]=1)[NH:17][C:3](=[O:5])[CH2:2]2)[CH3:11]
Reactant: CCOc1ccc(N)cc1
Reactant: CCOC(=S)CC
Agent: ClCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
23.6 g of ethyl methylthioacetate in 60 ml of DCM are added to a solution, cooled to about -70° C., of 12.5 g of chlorine in 400 ml of DCM. After stirring for 5 minutes at the same temperature, a solution of 4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture is stirred for one hour at about -70° C., 39.3 ml of triethylamine are added and the resulting mixture is allowed to warm up to room temperature. 200 ml of water are added and the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure. The residue is taken up with 500 ml of isopropanol and 20 ml of concentrated hydrochloric acid. The mixture is stirred for about 16 hours at room temperature and filtered and the precipitate is separated off. The filtrate is concentrated under reduced pressure to give the expected product.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:22])=[CH:11][C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][C:9]1[C:10]([CH3:22])=[CH:11][C:12]2[O:16][C:15]([CH3:18])([CH3:17])[CH:14]([OH:19])[C:13]=2[C:20]=1[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(c(C)c1NCc1ccccc1)C(=O)C(C)(C)O2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc2c(c(C)c1NCc1ccccc1)C(O)C(C)(C)O2
Reaction time: 2 h

Procedure:
To a solution of 5-(benzylamino)-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one obtained in Reference Example 51 (8.5 g, 28.8 mmol) in methanol (20 mL) was added sodium borohydride (2.18 g, 57.6 mmol) at room temperature, and the mixture was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, 5-(benzylamino)-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-3-ol. To a mixture of said compound with trifluoroacetic acid (30 mL) was added triethylsilane (10 mL, 64 mmol) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and to the residue was added a saturated sodium hydrogen carbonate solution to alkalify the aqueous layer, which was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was crystallized with ethyl acetate-hexane to obtain 4.1 g (yield 51%) of the title compound. Melting point: 80-81° C. (ethyl acetate-hexane).
Reaction SMILES: [Br-].[C:2]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:8][CH:7]=1)([O:4][CH3:5])=[O:3].CC(C)([O-])C.[K+].[CH:38]1([CH:44]([N:47]2[C:51]3[CH:52]=[C:53]([F:57])[C:54]([F:56])=[CH:55][C:50]=3[N:49]=[C:48]2[C:58]2[C:59]([O:66][CH3:67])=[N:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)[CH:45]=O)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>O1CCCC1>[CH3:5][O:4][C:2](=[O:3])[C:6]1[CH:7]=[CH:8][C:9](/[CH:10]=[CH:45]/[CH:44]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[N:47]2[C:51]3[CH:52]=[C:53]([F:57])[C:54]([F:56])=[CH:55][C:50]=3[N:49]=[C:48]2[C:58]2[C:59]([O:66][CH3:67])=[N:60][C:61]([O:64][CH3:65])=[CH:62][CH:63]=2)=[CH:30][CH:31]=1
Reactant: COc1ccc(-c2nc3cc(F)c(F)cc3n2C(C=O)C2CCCCC2)c(OC)n1
Reactant: COC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(C2CCCCC2)n2c(-c3ccc(OC)nc3OC)nc3cc(F)c(F)cc32)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 296 mg (0.60 mmol) 4-carbomethoxybenzyl triphenylphosphonium bromide in 5 ml tetrahydrofuran was added 68 mg (0.602 mmol) potassium tert-butoxide at 0° C. and the reaction mixture was stirred for 15 min. Then, 250 mg (0.60 mmol) cyclohexyl-[2-(2,6-dimethoxy-pyridin-3-yl)-5,6-difluoro-benzoimidazol-1-yl]-acetaldehyde was added at 0° C. The cooling bath was removed and the reaction mixture was stirred for 4 hours at room temperature. The reaction was poured on 30 ml 10% aqueous citric acid and 30 ml ethyl acetate and the layers were separated. The aqueous layer was extracted a second time with 30 ml ethyl acetate. The combined organic layers were washed with 30 ml brine, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by silica chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless solid (67%). MS (TurboSpray): m/z=547.2 [M+H].