Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([OH:20])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[N:11]([CH2:22][CH3:23])[C:12]1[N:17]=[C:16]([CH:18]([O:20][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:19])[CH:15]=[C:14]([CH3:21])[N:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCN(c1nc(C)cc(C(C)O)n1)c1ccc(C(C)C)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(c1nc(C)cc(C(C)OS(C)(=O)=O)n1)c1ccc(C(C)C)cc1Br
Temperature: 0 °C
Yield: 81.2 %

Procedure:
A mixture of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-hydroxyethyl)-6-methylpyrimidinamine (1.1 g, 2.7 mmol), triethylamine (1.5 mL, 11 mmol) and dichloromethane (15 mL) was stirred at 0° C. under a nitrogen atmosphere. Methanesulfonylchloride (364 mg, 3.2 mmol) was added dropwise and the reaction mixture was then stirred for 1.5 h. The resulting turbid solution was washed successively with an ice-cold 1N HCl solution, a saturated NaHCO3 solution and a saturated NaCl solution. Drying over MgSO4, filtration and removal of solvent in vacuo gave N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(1-methanesulfonyloxyethyl)-6-methylpyrimidinamine as a clear colorless oil (1.0 g); NMR (CDCl3, 300 MHz): 7.5 (d, 1H, J=1), 7.25-7.1 (m, 2H), 6.55 (s, 1H), 4.3-4.05 (m, 1H), 3.85-3.6 (m, 1H), 3.0-2.5 (m, 4H), 2.5-2.05 (br m, 3H), 1.3 (d, 6H, J=8), 1.2 (t, 3H, J=8); CI-MS: 456, 458 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1)([O-:10])=[O:9]
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1)OCc1ccccc1
Yield: 95.9 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.373 g, 8.660 mmol) and benzyl (3S)-piperidin-3-ylcarbamate (MolBridge, 2.077 g, 8.865 mmol), 1-butanol (10.0 mL) was added followed by DIPEA (1.836 g, 14.20 mmol). The mixture was irradiated with microwaves at 130° C. for 1 h. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound as a yellow solid (2.96 g, 96%). LCMS calc. for C18H21N4O4 (M+H)+: m/z=357.2. found 357.1.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[ClH:36].O1CCOCC1>CCOCC>[ClH:36].[C:1]([NH:4][C@:5]1([C:29]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 3 h

Procedure:
A 250 mL 3-neck round bottom flask was charged with (3R,4S)-tert-butyl 3-acetamido-3-(tert-butylcarbamoyl)-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1-carboxylate (4.95 g, 10 mmol) and 4 N HCl/dioxane (50 mL). After stirring for 3 h the solution was diluted with ether (125 mL), stirred a few minutes, filtered, and the solid rinsed with ether, collected, and dried in vacuo to afford an HCl salt of the title compound. This was dissolved in water (30 mL) and treated with sodium hydroxide (0.5 g, 12.5 mmol). The aqueous solution was treated with sufficient potassium carbonate to render the free base product insoluble. The mixture was extracted with methylene chloride (75 mL, then 3×50 mL) and the combined organic solution was washed with saturated aqueous sodium chloride (30 mL), dried (Na2SO4), and concentrated to afford (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (3.40 g, 86%) as a white solid. NMR (CDCl3) δ 8.26 (br s, 1 H), 7.25 (s, 1 H), 3.86 (d, J=9.5 Hz, 1 H), 3.53 (t, J=9.5 Hz, 1 H), 3.20 (d, J=10 Hz, 1 H), 2.98 (m, 1 H), 2.74 (dd, J1=10 Hz, J2=7.5 Hz, 1 H), 2.02 (s, 3 H), 1.50 (m, 1 H), 1.33 (s, 9 H), 1.20-1.40 (m, 3 H), 1.22 (s, 12 H), 0.70-0.80 (m, 2 H). MS (m+1): 396.0.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1([C:13]#N)[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[NH4+].[Cl-].O.C1[CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:23][O:22][CH2:21][CH2:20][CH2:13][C:3]1([N:2]([CH3:15])[CH3:1])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1
Reactant: CN(C)C1(C#N)CCC2(CC1)OCCO2
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COCCCC1(N(C)C)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 8-dimethylamino-1,4-dioxa-spiro[4.5]decane-8-carbonitrile (9.68 g, 46 mmole) in absolute THF (30 ml) was added dropwise while cooling with ice. A viscous precipitate thereby formed, and 100 ml of absolute THF was therefore added to achieve a better mixing. The mixture was stirred for 24 hours at room temperature. 20% NH4Cl solution (100 ml) and water (120 ml) were added while cooling with ice to the reaction mixture, and the organic phase was separated and the aqueous phase was extracted with ether (3×120 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][C:12]#[N:13])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N1CCOCC1)C>CN(C)C=O.O1CCCC1>[C:12]([CH2:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2)#[N:13]
Reactant: CS(=O)(=O)Cl
Reactant: N#CCc1ccc(N)c2[nH]ncc12
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1ccc(CC#N)c2cn[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At 0° C., 1.7 g of 2-(7-amino-1H-indazol-4-yl)acetonitrile in 15 ml of dimethylformamide and 5 ml of tetrahydrofuran is combined with 0.96 ml of methanesulfonyl chloride and 1.56 ml of N-ethylmorpholine and agitated for 16 hours at room temperature. The mixture is concentrated, chromatographed over silica gel with methanol/dichloromethane (1:3), and recrystallized from methanol, thus producing 2.2 g of N-(4-cyanomethyl-1H-indazol-7-yl)methanesulfonamide, mp 223°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:17])[CH2:15][NH2:16])[CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.C(O)(C)(C)C>[NH2:20][C:21]1[CH:29]=[C:28]([F:30])[C:27]([F:31])=[CH:26][C:22]=1[C:23]([NH:16][CH2:15][C:14]([NH:13][CH2:12][CH:9]1[CH2:10][CH2:11][N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=2)[CH2:8]1)=[O:17])=[O:24]
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CC(C)(C)O
Solvent: ClC(Cl)Cl
Product: Nc1cc(F)c(F)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 1-(4-chlorobenzyl)-3-{(glycylamino)methyl}pyrrolidine (0.050 mmol) in CHCl3 (1.35 mL) and tert-butanol (0.05 mL) was treated with 2-amino-4,5-difluorobenzoic acid (0.060 mmol), diisopropylcarbodiimide (0.060 mmol), and HOBt (0.060 mmol). The reaction mixture was stirred at room temperature for 19 h. The mixture was loaded onto Varian™ SCX column, and washed with CH3OH/CDCl3 1:1 (10 mL) and CH3OH (10 mL). Product was eluted off using 2 N NH3 in CH3OH (5 mL) and concentrated to afford 3-[{N-(2-amino-4,5-difluorobenzoyl)glycyl}aminomethyl]-1-(4-chlorobenzyl)pyrrolidine (Compound No. 1506) (22.0 mg, quant): The purity was determined by RPLC/MS (92%); ESI/MS m/e 437 (C21H23ClF2N4O2).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2([NH:19][C:20]([C:22]3[N:26]4[C@@:27]([CH2:40][C:41]5[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][CH:42]=5)([CH3:39])[C:28](=[O:38])[N:29]([C:30]5[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=5)[C:25]4=[N:24][CH:23]=3)=[O:21])[CH2:18][CH2:17]2)=[O:15])[CH:10]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:9]1)=O)(C)(C)C.[C:56]([OH:62])([C:58]([F:61])([F:60])[F:59])=[O:57]>C(Cl)Cl>[F:59][C:58]([F:61])([F:60])[C:56]([OH:62])=[O:57].[C:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][C@@:27]2([CH3:39])[N:26]3[C:22]([C:20]([NH:19][C:16]4([C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[C:49]([OH:51])=[O:50])=[O:15])[CH2:17][CH2:18]4)=[O:21])=[CH:23][N:24]=[C:25]3[N:29]([C:30]3[CH:31]=[C:32]([Cl:37])[CH:33]=[C:34]([Cl:36])[CH:35]=3)[C:28]2=[O:38])=[CH:42][CH:43]=1)#[N:48]
Reactant: CC(C)(C)OC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)N4CCNCC4C(=O)O)CC3)n21
Reaction time: 16 h

Procedure:
4-(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-piperazine-1,3-dicarboxylic acid di-tert-butyl ester (256 mg, 0.32 mmol) was dissolved in CH2Cl2 (2 mL) and TFA (2 mL) was added dropwise. After 16 h, the reaction was concentrated in vacuo. The crude orange oil was dissolved in DMSO (1.5 mL), purified via reverse phase HPLC to afford 64 mg of 1-(1-{[(R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclo-propanecarbonyl)-piperazine-2-carboxylic acid trifluoroacetic acid salt as a white solid.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC=C(C)N=1.ClCCCl.[Cl:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][C:44](=[O:57])[NH:45][C@@H:46]([CH:54]2[CH2:56][CH2:55]2)[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=2)[C:35]=1[C:36](O)=[O:37]>>[CH:54]1([C@H:46]([NH:45][C:44]([C:43]2[C:39]3[C:35](=[C:34]([Cl:33])[CH:42]=[CH:41][CH:40]=3)[C:36](=[O:37])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]=2[CH2:11][CH:8]2[CH2:7][CH2:6][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]2)=[O:57])[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([F:53])[CH:48]=2)[CH2:56][CH2:55]1
Reactant: CC(C)(C)N1CCC(CC(=O)Nc2ccccc2)CC1
Reactant: O=C(Cc1cccc(Cl)c1C(=O)O)N[C@H](c1cccc(F)c1)C1CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCCl
Product: CC(C)(C)N1CCC(Cc2c(C(=O)N[C@H](c3cccc(F)c3)C3CC3)c3cccc(Cl)c3c(=O)n2-c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 15.8 %

Procedure:
To a cold (ice bath) mixture of 2-(1-tert-butyl-piperidin-4-yl)-N-phenyl-acetamide (250 mg, 0.91 mmol) and 2,6-dimethylpyridine (0.139 ml, 1.2 mmol) in 1,2-dichloroethane (8 ml) oxalyl chloride (0.07 ml, 0.8 mmol) was added and stirred at 0° C. for 15 min. 2-Chloro-6-({[(S)-cyclopropyl-(3-fluoro-phenyl)-methyl]-carbamoyl}-methyl)-benzoic acid (70 mg, 0.2 mmol) was added and the reaction mixture was stirred in a sealed vessel at 90° C. for 15 hours. It was partitioned between 0.5 M aq. NaOH (40 ml) and ethyl acetate (200 ml), the organic phase washed with water, dried and evaporated. The residue was purified by flash chromatography (SiO2, ethyl acetate-methanol) to give 19 mg of the title compound. LC-MS (m/z) 600.6 (MH+); tR=1.1. 1H NMR (500 MHz, r.t., DMSO-d6): broad signals, a mixture of two atropisomers.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:6]([CH:18]=1)[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:8].[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:5]2[CH:4]=[CH:3][C:2]([C:32]3[CH:31]=[N:30][N:29]([CH3:28])[CH:33]=3)=[CH:18][C:6]=2[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:8])=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccc(F)cc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)OCc3ccc(F)cc3)c2)cn1
Temperature: 90 °C

Procedure:
A mixture of (4-fluorophenyl)methyl 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoate (420 mg, 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (208 mg, 1.00 mmol), tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol) and K2CO3 (414 mg, 3 mmol) in 1,4-dioxane (10 ml) and water (2 ml) was stirred under nitrogen and heated at 90° C. for 16 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed with water (50 ml) and brine (50 ml), dried over Na2SO4, and concentrated to give the crude product. The crude product was purified by a silica gel column (eluting with dichloromethane/methanol=50:1) yield the title compound as a white solid. 360 mg.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C@H:8]1[CH2:12][N:11]([S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C@H:10]([CH2:26][OH:27])[CH2:9]1)([CH3:6])([CH3:5])[CH3:4].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CS(C)=O>[CH2:28]([O:27][CH2:26][C@@H:10]1[CH2:9][C@@H:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])[CH2:12][N:11]1[S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](CO)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)O[C@@H]1C[C@@H](COCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
R2-ether formation: To a slurry of sodium hydride (60% in mineral oil, 2.75 g) in DMSO (100 ml) were added (2S,4R)-[4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidin-2-yl]-methanol (11.2 g) in portions within 0.5 h and benzyl bromide (7.2 ml) dropwise within 0.5 h at 20° C. The reaction mixture was stirred at room temperature for 1.5 h, poured onto ice/water and extracted with EtOAc. The organic phases were washed with water and brine, dried over magnesium sulphate and concentrated. The residue was crystallized from acetone/Et2O/hexane to obtain (2S,4R)-2-benzyloxymethyl-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine (10.05 g) as a colorless solid, mp 101-103° C., MS: 454 (MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[S:28]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:7][CH:6]=1)([CH3:27])(=[O:30])=[O:29]
Reactant: CC(C)(C)OC(=O)CCc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With a 4.82 g (18.3 mmols) portion of t-butyl 3-[4-(3-hydroxypropyl)phenyl]propionate were admixed 5.09 ml (36.6 mmols) of triethylamine, 2.84 ml (36.6 mmols) of methanesulfonyl chloride and 50 ml of methylene chloride. The mixture was stirred at room temperature for 12 hours, concentrated and then diluted with benzene. The benzene layer was washed with saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated, giving 6.29 g (yield 100%) of t-butyl 3-[4-(3-mesyloxypropyl)phenyl]propionate in the form of an oil. This product was used for the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=O)[C:3]=12)=[O:6].O.[NH2:14][NH2:15]>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:7])[NH:14][NH:15][C:5]2=[O:6]
Reactant: O=C1OC(=O)c2c(Cl)cccc21
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Temperature: 125 °C

Procedure:
3-Chloro-phthalic anhydride (5a, purchased from TCI) (10 g, 54.95 mmol) was dissolved in glacial acetic acid (100 mL), and hydrazine hydrate (20 mL) was added dropwise at 0° C., and then refluxed for two hours at 125° C. When the reaction was completed, the solution was cooled down to room temperature, filtrated, and washed with water until the filtrate pH 6.0, and then dried to give 5-chloro-2,3-dihydrophthalazin-1,4-dione (5b), 10.08 g white solid (yield 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]1[O:16][CH2:15][CH2:14][O:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]1[CH2:14][CH2:15][O:16][CH:12]1[CH2:11][NH:4][C:3]1[CH:5]=[C:6]([Cl:9])[CH:7]=[CH:8][C:2]=1[CH3:1]
Reactant: Cc1ccc(Cl)cc1N
Reactant: ClCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NCC1OCCO1
Reaction time: 26 h

Procedure:
2-Methyl-5-chloroaniline (75 grams), 2-chloromethyl- 1,3-dioxolane (25 grams), potassium carbonate (22 grams) and dimethylformamide (50 ml) were charged with a glass reaction vessel equipped with a mechanical stirrer, thermometer, and reflux condenser. The reaction mixture was heated, with stirring, for a period of about 26 hours. After this time the reaction mixture was filtered and then distilled to yield the desired product N-(1,3-dioxolan-2-ylmethyl)-2-methyl-5-chloroaniline having a boiling point of 116° to 118°C at 0.1 mm of Hg pressure.
Reaction SMILES: [BH4-].[Na+].O.[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:22])[F:21]>C(O)(C)C>[F:4][C:5]1([F:23])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]([OH:16])[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[C:6]1([F:21])[F:22]
Reactant: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OC1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 190 mg. (0.005 mole) of sodium borohydride in 1 ml. of water is added dropwise to a stirred solution of 830 mg. (0.00296 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cyclohepten-5-one in 10 ml. of isopropyl alcohol. After stirring the mixture for 3 hours at room temperature and 30 minutes at reflux, the isopropyl alcohol is evaporated under reduced pressure. The residue is partitioned between benzene and water and the benzene extract is separated, washed, and dried. Evaporation under reduced pressure leaves the product as the residual pale yellow oil. A sample for analysis is evaporatively distilled at 80° C. and 0.1 mm.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].N(OC(C)(C)C)=O.N[C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16]>C(O)(=O)C>[C:1]([O:4][C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC[C@H](N)C(=O)O
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@H](OC(C)=O)C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Sodium acetate (11.9 g, 146 mmol) and tert-butyl nitrite (15.0 g, 146 mmol) were added to an acetic acid (300 mL) solution of (2S)-2-aminobutyric acid (10.0 g, 97.0 mmol) under ice cooling, and the mixture was stirred at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, then water was added to the reaction mixture, and the resulting mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with water and brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and further, the resulting residue was azeotropically boiled twice with 1,4-dioxane (50 mL) to give the title compound (8.4 g, yield: 60%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:18](Cl)[CH:19]=[CH2:20].[I-].[K+]>O1CCCC1>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH:19]=[CH2:18]
Reactant: C=CCCl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1ccc(C(=O)c2ccccc2)cc1

Procedure:
4-Hydroxybenzophenone (100 parts) was dissolved in tetrahydrofuran (100 parts). Potassium hydroxide (30.9 parts) was added, heated and stirred until completely dissolved. Allyl chloride (46.4 parts) and potassium iodide (42 parts) were added to this solution. The mixture was refluxed for 8 hours. After cooling, it was washed with water and the solvent removed by distillation. A crude product of the desired 4-allyloxybenzophenone was obtained. It was recrystallized in n-hexane to obtain 110 parts of 4-allyloxybenzophenone (melting point 71° C.) at 72% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C@@H:12]([NH:18][C:19](=[O:35])[C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:13][CH2:14][C:15](O)=[O:16])[CH2:6][CH2:5]2.O1CCOCC1.N.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C>[C:15]([CH2:14][CH2:13][C@H:12]([NH:18][C:19]([C@@H:20]([NH:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:35])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)(=[O:16])[NH2:44]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)CN2CCc3cc(F)ccc32)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)CN2CCc3cc(F)ccc32)c1
Reaction time: 8 h
Yield: 84.9 %

Procedure:
The title compound of Example 43 (30 mg, 61 μmol) was treated with dioxane (2 mL) and concentrated ammonia (0.2 mL). HATU (35 mg, 92 μmol) was added and the reaction was stirred overnight. Another portion of HATU (80 mg, 210 μmol) was added and the reaction was stirred for an additional 3 hours. The reaction was then diluted with ethyl acetate and extracted once with 1 M NaOH solution. The organics were dried over MgSO4 and the solvent was removed. The residue was purified by silica gel column chromatography using DCM and methanol as solvents to afford the title compound (25 mg, 84%); 1H NMR (CDCl3, 400 MHz) δ 0.90 (s, 3H), 0.91 (s, 3H), 0.88-0.99 (m, 1H), 1.58-1.80 (m, 4H), 1.97-2.12 (m, 2H), 2.23-2.30 (m, 2H), 2.37 (s, 3H), 2.82 (s, 2H), 2.85-3.04 (m, 3H), 3.15 (dd, 1H, J1=6.5, J2=13.6), 3.34 (dd, 1H, J1=8.4, J2=16.9), 3.48 (dd, 1H, J1=8.1, J2=16.0), 4.12-4.21 (m, 1H), 4.40-4.72 (m, 1H), 5.86 (s, 1H), 6.32-6.47 (m, 2H), 6.72 (dd, 1H, J1=J2=8.4), 6.79 (d, 1H, J=7.4), 6.94 (d, 1H, J=7.6), 7.06 (d, 1H, J=8.4), 7.23-7.36 (m, 2H), 7.52-7.61 (m, 2H); HPLC-MS calcd. for C27H35FN4O3 (M+H+) 483.3, found 483.5.