Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@@H:20]([OH:31])[CH2:21][N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[OH:31][C@@H:20]([CH2:21][N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH2:19][NH:18][C:13](=[O:15])[C@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: COC(=O)[C@@H](C)Oc1cccc2cccnc12
Reactant: NC[C@@H](O)CN1Cc2ccccc2C1
Solvent: CCO
Product: C[C@@H](Oc1cccc2cccnc12)C(=O)NC[C@@H](O)CN1Cc2ccccc2C1
Temperature: 120 °C
Yield: 11 %

Procedure:
To a solution of (R)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (R)-1-amino-3-(isoindolin-2-yl)propan-2-ol (83 mg, 0.433 mmol). The reaction mixture was heated under microwave conditions at 120° C. for 0.5 h, concentrated, and purified by preparative TLC first and then by preparative HPLC purification. (19 mg, yield 11%) MS (ESI+) e/z: 392.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.90 (d, J=2.76 Hz, 1H), 8.34 (d, J=8.28 Hz, 1H), 7.64-7.48 (m, 3H), 7.34-7.24 (m, 1H), 7.23-7.08 (m, 4H), 5.07 (q, J=6.53 Hz, 1H), 3.97-3.71 (m, 5H), 3.49 (dd, J=13.55, 5.27 Hz, 1H), 3.29 (d, J=6.27 Hz, 1H), 2.71 (d, J=6.02 Hz, 2H), 1.72 (d, J=6.53 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:29]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:28][CH2:27]1)(=[O:32])[CH3:31]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: CC(=O)Cl
Reactant: NC1CC1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(C)=O)C1CC1

Procedure:
{2′-[(Acetyl-cyclopropyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-12) was prepared following the procedures of Example 1 and using (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclopropylamine, and acetyl chloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])=[CH:16][CH:15]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:31])=O>CN(C)C=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[CH:11]=[CH:10][C:6]([C:7]([Cl:31])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl

Procedure:
The product from Example 162a (2.0 g, 42.9 mmol) in thionyl chloride (10 mL) containing 1 drop of dimethylformamide and was heated to reflux for 3 hours. Cooled and concentrated under vacuum and dried under high vacuum overnight. The title compound was used without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.O>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Yield: 87.7 %

Procedure:
To a biphasic solution of 4-amino-1-benzylpiperidine (6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2 (200 mL) and water (100 mL) was added benzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0° C. with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO4 and filtered. The solvent was removed in vacuo to obtain 1-benzyl-4-benzamidopiperidine (8.16 g, 87% yield) as a white solid. It was used in the next step without purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=2)=[N:6][CH:7]=1.N([CH:19]([CH3:21])C)C(C)C.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>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.[Cu]I.C1COCC1>[CH3:22][Si:23]([C:26]#[C:27][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:21]#[C:19][Si:23]([CH3:25])([CH3:24])[CH3:22])=[CH:10][N:9]=2)=[N:6][CH:7]=1)([CH3:25])[CH3:24]
Reactant: Brc1ccc(-c2ccc(Br)cn2)nc1
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)NC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1

Procedure:
Firstly, a mixture of 5,5′-dibromo-2,2′-bipyridyl (300 mg, 0.96 mmol), PdCl2(PPh3)2 (60 mg, 0.085 mmol) and CuI (30 mg, 0.16 mmol) was added with dist. THF (18 mL), dist. i-Pr2NH (2.4 mL) and trimethylsilylacetylene (467 μL, 3.3 mmol). The resultant mixture was then stirred under a nitrogen atmosphere at room temperature for 29 hours to obtain a reaction mixture. Subsequently, a salt contained in the reaction mixture was removed through a celite filtration process. The organic layer thus obtained was concentrated to obtain a crude product (I) Then, the obtained crude product (I) was separated and purified by silica gel column chromatography (CH2Cl2=100) to obtain 5,5′-bis(trimethylsilylethynyl)-2,2′-bipyridyl.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(-c2ccsc2)ccc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2ccsc2)cc1C(=O)O
Reaction time: 8 h

Procedure:
Methyl 2-Methoxy-5-(thiophene-3-yl)benzoate (124 mg) was dissolved in a solvent mixture of tetrahydrofuran/methanol/water (2/1/1, 3 ml). Lithium hydroxide (53 mg) was added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the residue was added to 3 N hydrochloric acid. The white solid thus precipitated was taken by the filtration as the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8](C)[C:9](=O)OC(C)(C)C)=[C:4]([I:17])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([I:17])[CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)(methyl)carbamate (62.5 g, 0.172 mol) in 500 mL of anhydrous DCM was added 180 mL of TFA. Then the solution was stirred at room temperature for 4 hrs. Concentrated to remove the solvent, and purified by flash chromatography to afford 45.1 g 6-chloro-4-iodo-N-methylpyridin-3-amine as a yellow solid (Yield: 97.3%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)CC)C>C(#N)C>[ClH:18].[NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([F:25])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([N:29]([CH3:30])[CH3:28])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:7]=1
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN(C)c1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 120.8 %

Procedure:
1-(5-Amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg), dimethylamine hydrochloride (94 mg) and triethylamine (140 mg) were added to acetonitrile (10 ml), and the mixture was heated and stirred overnight at 60° C. After the reaction mixture was allowed to cool, the solvent was distilled off under reduced pressure. Ethanol and concentrated hydrochloric acid were added to the residue, and the mixture was concentrated again under reduced pressure. Ethanol was added to the residue, and solids were collected by filtration. The solids were washed successively with ethanol and diethyl ether to obtain the title compound (70 mg) as a yellow powder.
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH:13]([N:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH2:12][N:11]([C:21]([C:23]2[C:24]([Cl:39])=[C:25]([NH:31]C(=O)OC(C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[CH:28]=2)=[O:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C:25]1[CH:26]=[C:27]([CH:28]=[C:23]([C:21]([N:11]2[CH2:12][CH:13]([N:14]3[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10]2)=[O:22])[C:24]=1[Cl:39])[C:29]#[N:30]
Reactant: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(NC(=O)OC(C)(C)C)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(C2CN(C(=O)c3cc(C#N)cc(N)c3Cl)CC2O[Si](C)(C)C(C)(C)C)CC1
Yield: 86.5 %

Procedure:
(+/−)-tert-butyl (3-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)-2-chloro-5-cyanophenyl)carbamate (120 mg, 0.208 mmol) was treated with TFA (25% in 1,2-dichloroethane, 2 mL, 6.49 mmol) at room temperature for 1 h. The reaction mixture was diluted with dichloromethane and washed with cold saturated sodium bicarbonate/1N aqueous sodium hydroxide (pH 10). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 1-7.5% methanol/dichloromethane). (+/−)-3-amino-5-(3-((tert-butyldimethylsilyl)oxy)-4-(4-methylpiperazin-1-yl)pyrrolidine-1-carbonyl)-4-chlorobenzonitrile (86 mg) was obtained as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:30])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:38]1([CH2:41][NH:42][CH2:43][CH2:44][CH3:45])[CH2:40][CH2:39]1>C(O)C>[CH:38]1([CH2:41][N:42]([CH2:43][CH2:44][CH3:45])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:30])=[O:9])[CH:3]=2)[CH2:40][CH2:39]1
Reactant: CCCNCC1CC1
Reactant: Cc1cc(S(=O)(=O)NCCC(=O)OC(C)(C)C)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of tert-butyl 3-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate (Intermediate 34, 140 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and then filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)propanoate which was used directly without any further purification. The residue was redissolved in DCM (4.5 ml) and treated with TFA (0.5 ml). After stirring at RT for 2 hours the solvent was removed in vacuo to give the title compound as an off-white solid.
Reaction SMILES: N1C=CC=CC=1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OB(O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyridine (0.37 mL, 4.6 mmol) was added to a suspension of N-hydroxyphthalimide (664 mg, 4.1 mmol), 4-chlorophenylboronic acid (635 mg, 4.1 mmol), and powdered 4 Å molecular sieves (1.02 g) in CH2Cl2 (20 mL). Cupric acetate monohydrate (812 mg, 4.1 mmol) was added, and the mixture was stirred open to the atmosphere at room temperature for 18 hours. Silica gel (10 g) was added, and the slurry was concentrated to dryness under vacuum. The residue was applied to the top of a flash chromatography column, and eluted with hexanes:ethyl acetate (80:20) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.11-7.17 (m, 2 H), 7.27-7.34 (m, 2 H), 7.79-7.87 (m, 2 H), 7.88-7.95 ppm (m, 2 H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2cccnc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2cccnc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogen carbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1-pyridin-3-yl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.45 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[C:16](Cl)(=O)[C:17](Cl)=O.[CH3:22]N(C=O)C.CN1CCOCC1>C(Cl)Cl.C1COCC1>[CH2:22]([O:14][C:13]([C:11]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1)=[O:15])[CH:16]=[CH2:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: C=CCOC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nitroterephthalic acid (6.33 g) in methylene chloride (75 ml) and THF (15 ml) was converted to the mono acid chloride using oxalyl chloride (2.63 ml), DMF (2.55 ml) and N-methylmorpholine (7.95 ml) at −10° C. After 1 hour the solvents were removed and, without further purification, the product was dissolved in allyl alcohol (20 ml) and THF (10 ml) and stirred overnight at ambient temperature. The solvents were removed and the residue partitioned between EtOAc and aqueous NaHCO3. Acidification of the NaHCO3 solution and extraction with EtOAc gave the product, 4-allyloxycarbonyl-2-nitrobenzoic acid (6.8 g). Nmr (CDCl3): δ 4.89 (d, 2H); 5.31-5.49 (m, 2H); 5.95-6.15 (m, 1H); 7.94 (d, 1H); 8.36 (dd, 1H); 8.54 (d, 1H). Without purification, this acid was converted by the method above to the acid chloride which was dissolved in THF (100 ml) at 0° C. Ammonia gas was bubbled into the solution until the reaction was completed. The solution was partitioned between EtOAc and water, and the product from the organic fraction purified on silica, eluting with methylene chloride followed by EtOAc. The product (4 g), containing a small impurity, was reduced with SnCl2 by a similar method to that in example 12 giving 4-allyloxycarbonyl-2-aminobenzamide. Nmr (DMSO-d6): δ 4.79 (d, 2H); 5.22-5.46 (m, 2H); 5.91-6.13 (m, 1H); 7.02 (dd. 1H); 7.37 (d, 1H); 7.61 (d, 1H). (2S,4S)-4-Acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-carboxy-pyrrolidine (1.58 g) was converted to the acid chloride by suspension in methylene chloride (25 ml) and addition of oxalyl chloride (1.52 ml). A few drops of DMF were added. After 2 hours the solvents were evaporated and the acid chloride, dissolved in methylene chloride (10 ml), was added under argon to a solution of 4-allyloxycarbonyl-2-amino-benzamide (0.52 g) in THF (10 ml) and methylene chloride (5 ml) containing N-methylmorpholine (0.38 ml) at 0° C. The reaction was left overnight and partitioned between methylene chloride and dilute aqueous HCl. The methylene chloride fraction was washed with water, brine and dried. Purification was by silica chromatography, eluting with increasing concentrations of EtOAc in methylene chloride, giving (2S,4S)-4-acetylthio-1-(4-nitrobenzyloxycarbonyl)-2-(3-allyloxy-carbonyl-6-carbamoylphenylcarbamoyl)pyrrolidine (0.84 g). Nmr (CDCl3): δ 2.25 (quintet, 1H);.2.29 (s, 3H); 2.83 (m, 1H); 3.53 (dd, 1H); 4.02 (quintet, 1H); 4.2 (dd, 1H); 4.49 (dd, 1H); 4.85 (d, 2H); 5.23-5.46 (m, 2H); 5.97-6.13 (m, 1H); 7.31-7.5 (broad, 2H); 7.57 (d, 1H); 7.75 (dd, 1H); 7.81-7.95 (broad, 2H); 9.27 (d, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH2:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:30](O)(=[O:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:17])([CH3:18])[CH3:16])[CH2:10][C@H:9]1[CH2:28][NH:29][C:30](=[O:32])[CH3:31])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@@H](CN)N(C(=O)OC(C)(C)C)C2)CC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of (2S,4S)-t-BOC-2-(aminomethyl)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]pyrrolidine (500 mg, 1.21 mmol) prepared in Step A of Example B7 in DMF was added dropwise acetic acid (80 mg, 1.3 mmol), HBTU (490 mg, 1.28 mmol) and DIPEA (0.56 ml, 3.22 mmol) in order. After the reaction mixture was stirred at rt for 5 h, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with a saturated NaHCO3 aqueous solution, water and 1N HCl. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/2) to give the title compound (508 mg, 93%).
Reaction SMILES: Br[CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].Cl.[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH2:19])[CH3:15].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:14]([O:16][C:17](=[O:20])[CH2:18][NH:19][CH:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4])[CH3:15]
Reactant: CCOC(=O)CN
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.808 mmol) of 2-bromo-1-(4-chlorophenyl)propan-1-one from Example 112A are dissolved in 1 ml acetonitrile and treated with 226 mg (1.616 mmol) of glycine ethyl ester hydrochloride and 209 mg (1.616 mmol) of N,N-diisopropylethylamine. After stirring overnight at room temperature, the reaction mixture is evaporated and the residue is partitioned between water and dichloromethane. The organic phase is separated, dried over sodium sulphate and concentrated. The crude product is purified by flash chromatography on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 200:1). 91 mg (42% of theory) of the target compound are thus obtained.
Reaction SMILES: CI.[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:8][CH:7]=1)([O-])=O.[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:20][N:11]([CH2:10][C:9]1[CH:18]=[CH:19][C:6]([NH2:3])=[CH:7][CH:8]=1)[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: O=[N+]([O-])c1ccc(CNC[C@H]2CCCO2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1ccc(N)cc1)C[C@H]1CCCO1
Reaction time: 4 h

Procedure:
Methyl iodide (0.728 mL, 11.7 mmol) was added to (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 40b (1.84 g, 7.80 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in DMF (30 mL). After 4 hrs, the reaction is was diluted with water and extracted with ethyl ether. The combined extracts are were washed with water, dried over MgSO4, and evaporated to prepare 1.43 g of methyl-(4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 150a. Using the procedure of Example 40, Compound 150a was used in place of (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 40b and carried forward to provide 4-({methyl-[(2R)-tetrahydro-furan-2-ylmethyl]-amino}-methyl)-phenylamine Compound 150b. Using the procedure of Example 1, 5-(5-chloro-2-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-1-thia-3,5, 6,8-tetraaza-acenaphthylene-2-carboxylic acid Compound 147c was used in place of Compound 1 and Compound 150b was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to give Compound 75. MS 579, 581 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].ClC([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O.O.[C:18](OC(C)C)(=[O:20])C>>[C:18](=[N:1][CH2:2][CH2:3][CH:4]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:5])=[O:20]
Reactant: CC(=O)OC(C)C
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: O
Product: O=C=NCCC(O)OCc1ccccc1
Temperature: 0 °C
Yield: 82 %

Procedure:
To a 12 L 3-neck round bottom flask was added isopropyl acetate (6.5 L). The solvent was cooled to 0° C. in an ice-water bath and 3-amino-1-propanol (1.14 Kg, 15.1 mol, 2.15 eq) was added in one portion. To this rapidly stirring solution, benzyl chloroformate (1.20 Kg, 7.03 mol, 1.0 eq) was added dropwise over 2 h while maintaining the internal temperature of the flask between 10° C. and 15° C. After the addition was complete, the reaction mixture was allowed to stir between 10° C. and 15° C. for an additional 0.3 h after which time water (3.5 L) was added in one portion. The solution was then partitioned and washed with an additional 2×3.5 L of water. The organic layer was dried over potassium carbonate and concentrated to give a solid that was dissolved in excess isopropyl acetate and precipitated from solution by adding the compound to heptane. The solid was filtered under nitrogen to yield 1.20 Kg (82%) of the desired product as a colorless solid.