Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:28][CH3:29])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:29][O:28][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[OH:8])[N:16]=[CH:15][CH:14]=[C:13]2[S:19][C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][N:24]=1
Reactant: COc1cc2c(Sc3ncc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: COc1cc2c(Sc3ncc([N+](=O)[O-])s3)ccnc2cc1O
Yield: 88.8 %

Procedure:
2-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]sulfanyl}-5-nitro-1,3-thiazole (2.0 g), trifluoroacetic acid (20 ml) and thioanisole (2 ml) were stirred together at 65° C. for 90 minutes. The mixture was returned to room temperature, the solvent was distilled off under reduced pressure, 40 ml of methanol was added to the residue, and then sodium bicarnobate water was added until the foaming subsided. The precipitated solid was filtered out to obtain 1.4 g of a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]([NH2:9])[CH3:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:9][C@H:7]([C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:8])[CH:16]=[N:17][CH:18]=1
Reactant: Clc1cncc(Cl)n1
Reactant: COc1ccc(C(C)N)cc1
Product: COc1ccc([C@H](C)Nc2cncc(Cl)n2)cc1
Yield: 78.8 %

Procedure:
In a procedure analogous to example 1, reaction of 4-methoxy-α-methyl-benzylamine (700 mg, 4.6 mmol) and 2,6-dichloropyrazine (626 mg, 4.2 mmol) furnished the product (873 mg, 79%).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@@H:10]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH:11]([CH3:13])[CH3:12])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2].Br[C:51]1[NH:55][C:54]([C@@H:56]2[CH2:60][CH2:59][CH2:58][N:57]2[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CN(C=O)C.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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([C:9](=[O:19])[C@H:10]([CH:11]([CH3:13])[CH3:12])[NH:14][C:15]([O:16][CH3:17])=[O:18])[C@H:6]([C:20]2[NH:24][C:23]3[C:25]4[C:30]([CH:31]=[CH:32][C:22]=3[N:21]=2)=[CH:29][C:28]2[C:33]3[C:38]([CH2:39][O:40][C:27]=2[CH:26]=4)=[CH:37][C:36]([C:51]2[NH:55][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[N:53][CH:52]=2)=[CH:35][CH:34]=3)[CH2:5]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(B3OC(C)(C)C(C)(C)O3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCO[C@H]1C[C@@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc([C@@H]4CCCN4C(=O)OC(C)(C)C)[nH]3)ccc2-5)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 85 °C
Reaction time: 6 h
Yield: 33.7 %

Procedure:
To a solution of methyl [(2S)-1-{(2S,4S)-4-ethoxy-2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]pyrrolidin-1-yl}-3-methyl-1-oxobutan-2-yl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85° C. for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)-2-[5-(2-{(2S,4S)-4-ethoxy-1-[N-(methoxycarbonyl)-L-valyl]pyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]pyrrolidine-1-carboxylate (0.16 g, 33%).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:17]>[Pd].C(O)C>[C:11]1([N:4]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:10]3[CH2:2][C:3]2=[O:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1N(c2ccccc2)c2ncccc2C1(Br)Br
Agent: [Pd]
Solvent: CCO
Product: O=C1Cc2cccnc2N1c1ccccc1
Reaction time: 17 h

Procedure:
3,3-dibromo-1-phenyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (600 mg, 1.63 mmol) and 10% by weight palladium on activated charcoal (300 mg) are suspended in absolute ethanol (60 mL). This mixture is allowed to stir under a hydrogen atmosphere at atmospheric pressure for 17 hours. The reaction mixture is filtered through a pad of hyflo, washing the cake well with ethanol. Concentration of the filtrate gives crude 1-phenyl-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one as an orange brown solid. This material was used without any further purification. MS: m/e 211 (M+H), 443 (2M+Na).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17]>C(O)(C)C>[CH3:10][O:11][C:12]([C:13]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:13]([C:12]([O:11][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19]
Reactant: CCOC(N)=CC(=O)OC
Reactant: O=Cc1cccc(Cl)c1
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2cccc(Cl)c2)C1C(=O)OC

Procedure:
Upon heating a solution of 7.1 g of 3-chlorobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 50 ml of isopropanol for 6 hours, 2-amino-4-(3-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 158°C (isopropanol) is obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][Si:15]([CH3:21])([CH3:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=[O:13])(=[O:7])=[O:6].CC(C)=[O:26]>>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[C@@H:11]([O:14][Si:15]([CH3:21])([CH3:20])[C:16]([CH3:18])([CH3:17])[CH3:19])[C:12]([OH:26])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@H](C=O)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)=O
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Yield: 79 %

Procedure:
Following the general procedure of the oxidation of aldehydes to carboxylic acids of Description 13, (3R)-2,2-dimethyl-4-oxo-3-(1,1,2,2-tetramethyl-1-silapropoxy)butyl (3-chloropropyl)sulfonate (15b) (1.1 g, 2.8 mmol) dissolved in 20 mL of acetone was reacted with 1.4 mL of Jones-reagent (2.0 M in water). After work-up, 0.9 g (79% yield) of the title compound (15) was obtained as a colorless oil. 1H NMR (400 MHz, CDCl3): δ=0.13 (s, 3H), 0.16 (s, 3H), 0.98 (s, 9H), 1.05 (s, 3H), 1.11 (s, 3H), 2.32-2.39 (m, 2H), 3.33-3.36 (m, 2H), 3.69-3.72 (m, 2H), 4.04 (d, J=9.6 Hz, 1H), 4.09 (s, 1H), 4.12 (d, J=9.6 Hz, 1H) ppm. MS (ESI) m/z 403.00 (M+H)+; 401.05 (M−H)−. The analytical data was consistent with the proposed structure.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]([OH:31])[CH:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:31])[CH:25]([CH3:30])[C:26](=[O:29])[CH2:27][CH3:28])[CH2:20][CH2:19]1)=[O:17])([CH3:13])([CH3:12])[CH3:14]
Reactant: CCC(=O)C(C)C(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)C(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A solution of oxalyl chloride (0.34 mL, 3.9 mmol) in methylene chloride (12 mL) at −78° C. was treated with DMSO (0.43 mL, 6.0 mmol) and the resulting mixture was stirred cold for 10 min. A solution of 1-(t-butoxycarbonyl)-4-(1-(RS)-hydroxy-2-(RS)-methyl-3-oxopent-1-yl)piperidine (514 mg, 1.7 mmol) (from Step C) was added and the resulting solution was stirred cold for 1 h. N,N-Diisopropylethylamine (2.4 mL, 13.7 mmol) was added and the resulting mixture was warmed to 0° C. The reaction was quenched with 1.0 N HCl (25 mL) and extracted with ether (100 mL). The extract was dried over magnesium sulfate and concentrated. MPLC (Biotage) on a 40 S silica cartridge using 2:1 v/v hexanes/ethyl acetate as the eluent afforded 435 mg (85%) of the title compound.
Reaction SMILES: [NH2:1][C@:2]1([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[C@H:6]([CH2:7]O)[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[C:21]([NH:29][C:30]1[S:31][CH2:7][C@@H:6]2[CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3][C@:2]2([C:16]2[S:20][N:19]=[CH:18][CH:17]=2)[N:1]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CO)[C@](N)(c2ccns2)C1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccns2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl (3R,4R)-3-amino-4-(hydroxymethyl)-3-isothiazol-5-yl-pyrrolidine-1-carboxylate (148.10 g, 494.67 mmol) and tetrahydrofuran (1.48 L) are added together and the solution is cooled to 0° C. Benzoyl isothiocyanate (82.34 g, 504.56 mmol) is added over 5 minutes and the reaction mixture is stirred for 30 minutes at 0° C. and then warmed to room temperature over 1 hour. 1,1′-Carbonyldiimidazole (92.24 g, 568.87 mmol) is added and the reaction mixture is stirred at room temperature for 2 h. The mixture is heated to 65° C. and stirred for a further 12 hours. The reaction mixture is concentrated under reduced pressure and the oily residue is partitioned between water (1.5 L) and ethyl acetate (1.5 L). The pH is adjusted with citric acid 50% w/w aq. solution to 4.0 and the organic layer is separated. The aqueous layer is extracted with MTBE (2×500 mL), the organics are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product is slurried in MTBE (740.50 mL) at 60° C. then at room temperature for 45 minutes. The solid is collected, washed with MTBE (4×150 mL), and dried under vacuum overnight to give the title compound as an off white solid (162.68 g, 74.0%). ES/MS (m/e): 445 (M+H), ee=99.5%.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:3]1.[C:23]1([C:29]2[NH:30][C:31]3[C:36]([C:37](=O)[CH:38]=2)=[CH:35][C:34]([CH:40]=[CH2:41])=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:23]1([C:29]2[CH:38]=[C:37]([O:1][C@H:2]3[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[CH2:3]3)[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([CH:40]=[CH2:41])[CH:35]=3)[N:30]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1C(=O)OCC[Si](C)(C)C
Reactant: C=Cc1ccc2[nH]c(-c3ccccc3)cc(=O)c2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OCC[Si](C)(C)C)N(C(=O)OC(C)(C)C)C3)c2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
To a solution of 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate 3 (1.0 g, 3.02 mmol) in THF (30 mL) was added 2-phenyl-6-vinylquinolin-4(1H)-one 2 (0.78 g, 3.17 mmol) and PPh3 (1.19 g, 4.52 mmol). The flask was then cooled to 0° C. and diethylazodicarboxylate (0.713 mL, 4.52 mmol) was added slowly. The mixture was then warmed to RT and stirred overnight (16 h). At this time, the starting material to product ratio was 2:1. The reaction was re-cooled to 0° C., and additional PPh3 (1.19 g, 4.52 mmol) and diethylazodicarboxylate (0.713 mL, 4.52 mmol) were added. After stirring for an additional 19 h, only a small amount of starting material remained. Silica gel was then added to the reaction and the mixture was filtered through silica gel with EtOAc as the eluent. The crude mixture was then purified on silica (5-40% EtOAc/hexanes) to yield 0.85 g (50% yield) of 1-tert-butyl 2-[2-(trimethylsilyl)ethyl] (2S,4R)-4-[(2-phenyl-6-vinylquinolin-4-yl)oxy]pyrrolidine-1,2-dicarboxylate 5. 1H NMR (500 MHz, CDCl3) ppm: mixture of amide rotamers: 8.43 (m, 1H), 8.13-8.09 (m, 2H), 7.92 and 7.91 (2 br s, 2H), 7.56 (m, 3H), 7.12 and 7.11 (2 br s, 1H), 6.92 (br dd, J=17.5 Hz, 10.5 Hz, 1H), 6.02 (d, J=17.5 Hz, 1H), 5.58 (d, J=10.5 Hz, 1H), 5.53 and 5.49 (2 br s, 1H), 4.64 and 4.54 (2 app t, J=7.5 Hz, 1H), 4.27 (app t, J=7 Hz, 2H), 4.07 (m, 1.5H), 3.89 (br d, J=13 Hz, 0.5H), 2.81 (m, 1H), 2.55 (m, 1H), 1.47 and 1.45 (2 s, 9H), 1.04 (m, 2H), 0.07 and 0.06 (2 s, 9H). LRMS (CI, [M+H]) Calc'd=561.4. found=561.4. HRMS (APCI, [M+H]+) Calc'd for C32H41N2O5Si: 561.2779. found: 561.2749.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5]C[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:61][CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:58][CH:59]5[CH2:60][CH2:61][N:62]([CH2:65][C:66]([N:68]([CH3:70])[CH3:69])=[O:67])[CH2:63][CH2:64]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:5][CH2:6]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(=O)CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CCN(CC(=O)N(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for the synthesis of the compound 16 using HATU except that 2-(4-aminopiperidin-1-yl)-N,N-dimethylacetamide was used. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-2.17 (m, 14 H) 2.94 (d, J=10.61 Hz, 6 H) 3.01-3.20 (m, 2 H) 3.33 (s, 3 H) 4.06 (t, J=13.89 Hz, 5 H) 4.24 (d, J=4.55 Hz, 2 H) 4.78 (t, J=7.45 Hz, 1 H) 7.43-7.62 (m, 2 H) 8.06 (br. s., 1 H) 8.27 (s, 2 H) 8.36 (d, J=7.07 Hz, 1 H) 9.52 (br. s., 1 H) [M+H] calc'd for C30H40F2N8O4, 614; found 614.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:6]=2[CH:24]=1.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.O.[Cu]I>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([N:7]2[CH2:8][C@@H:9]([CH3:16])[C:10]3=[N:14][N:13]=[C:12]([CH3:15])[N:11]3[C:5]3[CH:4]=[CH:3][C:2]([N:25]4[CH:29]=[N:28][CH:27]=[N:26]4)=[CH:24][C:6]2=3)=[CH:18][CH:19]=1
Reactant: c1nc[nH]n1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc2n1-c1ccc(-n3cncn3)cc1N(c1ccc(Cl)cc1)C[C@H]2C
Temperature: 150 °C
Reaction time: 16 h
Yield: 25.5 %

Procedure:
A mixture of (R)-8-bromo-6-(4-chlorophenyl)-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (40.2 mg, 0.1 mmol), 1H-1,2,4-triazole (13.8 mg, 0.2 mmol), copper(I) iodide (3.8 mg, 0.02 mmol), and cesium carbonate (59 mg, 0.18 mmol) in N-methyl-2-pyrrolidone (3 mL) was stirred at 150° C. for 16 hours. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3*20 mL). The combined organic layer was washed with water (3*20 mL) and brine (3*20 mL) in turns, dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (silica-gel, dichloromethane/methanol=15:1) to give (R)-6-(4-chlorophenyl)-1,4-dimethyl-8-(1H-1,2,4-triazol-1-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as a white solid (10 mg, 25.7%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[C:9]([F:12])[C:8]([O:13][CH3:14])=[C:7]([F:15])[C:3]=1[C:4]([OH:6])=[O:5].COC(C1C2N=C(N)[NH:25][C:24]=2C=CC=1)=O.BrC#N>CO>[NH2:25][C:24]1[NH:11][C:10]2[C:9]([F:12])=[C:8]([O:13][CH3:14])[C:7]([F:15])=[C:3]([C:4]([OH:6])=[O:5])[C:2]=2[N:1]=1
Reactant: COC(=O)c1cccc2[nH]c(N)nc12
Reactant: COc1c(F)c(N)c(N)c(C(=O)O)c1F
Agent: N#CBr
Solvent: CO
Product: COc1c(F)c(C(=O)O)c2nc(N)[nH]c2c1F

Procedure:
1.2 g (5.5 mmol) of 2,3-diamino-4,6-difluoro-5-methoxy-benzoic acid was subjected to a similar cyclization condition as illustrated in intermediate A by using 1.7 g (16.5 mmol) of BrCN in methanol to produce 2-amino-5,7-difluoro-6-methoxy-1H-benzoimidazole-4-carboxylic acid. LCMS: 244 (M+1)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][NH2:12].C1COCC1>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH3:11])=[O:6]
Reactant: CN
Reactant: O=C(Cl)c1cccc(I)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(I)c1
Reaction time: 8 h
Yield: 26 %

Procedure:
To a cooled (0° C.) solution of 3-iodobenzoyl chloride (2.66 g; 10.0 mmol) in DCM (10 mL) was slowly added a 2 M solution of methylamine in THF (10 mL, 2.0 eq.). Upon completion of the addition, the ice bath was removed and the mixture was stirred overnight. All volatiles were removed in vacuo and the residue was treated with aq. NaHCO3 (25 mL) and subsequently extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel to give the desired 3-iodo-N-methylbenzamide (0.67 g, 26% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]I)=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1.[CH3:36][NH:37][CH2:38][CH:39]([OH:48])[CH:40]([OH:47])[CH:41]([OH:46])[CH:42]([OH:45])[CH2:43][OH:44]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:37]([CH3:36])[CH2:38][CH:39]([OH:48])[CH:40]([OH:47])[CH:41]([OH:46])[CH:42]([OH:45])[CH2:43][OH:44])=[CH:14][CH:13]=3)[CH:10]([CH2:24][CH2:25][CH:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[OH:27])[C:9]2=[O:35])=[CH:4][CH:3]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCI)cc2)N1c1ccc(F)cc1
Reactant: CNCC(O)C(O)C(O)C(O)CO
Solvent: CN(C)C=O
Product: CN(CCCCOc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)CC(O)C(O)C(O)C(O)CO
Temperature: 50 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
100 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(4-iodobutoxy)phenyl]azetidin-2-one are dissolved in 5 ml of absolute dimethylformamide. 132 mg of 6-methylaminohexane-1,2,3,4,5-pentaol are then added, and the reaction solution is stirred at 50° C. for 2 h. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified by preparative HPLC. The product (89 mg) is obtained as an oil. C35H44F2N2O8 (658) MS (ESI): M+
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[S:17][CH:18]=2)([CH:9]([CH3:11])[CH3:10])[O:5][C:6](=[O:8])[CH:7]=1.[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:23]([C:27]1[CH:32]=[C:31]([CH2:33][OH:34])[C:30]([CH3:35])=[CH:29][C:28]=1[S:36][C:7]1[C:6](=[O:8])[O:5][C:4]([CH2:12][CH2:13][C:14]2[N:15]=[C:16]([NH:19][C:20](=[O:22])[CH3:21])[S:17][CH:18]=2)([CH:9]([CH3:11])[CH3:10])[CH2:3][C:2]=1[OH:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(=O)Nc1nc(CCC2(C(C)C)CC(O)=CC(=O)O2)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(CCC2(C(C)C)CC(O)=C(Sc3cc(C)c(CO)cc3C(C)(C)C)C(=O)O2)cs1

Procedure:
The title compound was prepared according to General Method 16a using N-{4-[2-(4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-thiazol-2-yl}-acetamide (Example E-13; 0.49 g, 1.5 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.66 g, 1.8 mmol), potassium carbonate (0.83 g, 6.0 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 128-130° C.
Reaction SMILES: C([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=3[NH:14][C:13]2=[O:22])[CH2:8][CH2:7]1)(OCC)=O.[OH-].[Na+].[Cl-].[NH4+]>O>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]2[N:12]([CH:9]3[CH2:8][CH2:7][NH:6][CH2:11][CH2:10]3)[C:13](=[O:22])[NH:14][C:15]=2[CH:20]=1
Reactant: CCOC(=O)N1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1

Procedure:
A mixture of 22.3 g of 1-carbethoxy-4-(5-chlorobenzimidazol-2-on-1-yl)-piperidine, 13 g of 50% strength sodium hydroxide solution and 90 ml of water was boiled under reflux for 24 hours. After the mixture had been cooled, the solution was stirred with 8.5 g of ammonium chloride for 30 minutes and extracted with chloroform, and the undissolved material was filtered off and discarded. The chloroform solution was dried and evaporated. The product crystallized, and has a melting point of 220° C.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][Si](CC)(CC)CC)([CH3:6])[C:3]([NH2:5])=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C([O-])(O)=O.[Na+]>C1COCC1>[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4])#[CH:14]
Reactant: CC[Si](C#Cc1ccccc1C(C)(C)C(N)=O)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccccc1C(C)(C)C(N)=O

Procedure:
A solution of 2-methyl-2-(2-((triethylsilyl)ethynyl)phenyl)propanamide A35 (0.116 g, 0.385 mmol) in THF (5 mL) was stirred with TBAF (1.0 M in THF, 0.40 mL, 0.40 mmol) at 0° C. for 2 minutes. Sat. aq. NaHCO3 (20 mL) was added and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organics were washed with brine, dried (MgSO4) and the solvent was removed in vacuo. The resultant yellow oil was purified by column chromatography (Biotage Isolera, 24 g SiO2 cartridge, 20-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A36 as a yellow solid (0.060 g, 83%). LCMS-D: rt 3.02 min; m/z 188 [M+H]+.