Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:7][OH:8])([CH2:5][OH:6])[CH3:4].CO[C:11](OC)([CH3:13])[CH3:12].S(=O)(=O)(O)O>CC(C)=O>[CH3:4][C:3]1([CH2:7][OH:8])[CH2:5][O:6][C:11]([CH3:13])([CH3:12])[O:1][CH2:2]1
Reactant: CC(CO)(CO)CO
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1(CO)COC(C)(C)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
In a three-necked flaks, 1,1,1-tris(hydroxymethyl)ethane (200 g) and 2,2-dimethoxypropane (260 g) were suspended in acetone (150 g), one droplet of concentrated sulfuric acid was added thereto at 0° C., and then the mixture was stirred for 2 hours. The temperature was changed back to a room temperature, and the mixture was stirred for 2 hours. After acetone was distilled off, a fraction obtained at 70° C. under reduced pressure (1.7 mmHg) was collected to obtain (1,4,4-trimethyl-3,5-dioxanyl)methane-1-ol (192 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH:30]=[CH:29][N:28]=[N:27]1>[Cu]>[CH3:9][NH:8][CH2:7][C:6]1[CH:10]=[C:2]([N:27]2[N:28]=[CH:29][CH:30]=[N:26]2)[CH:3]=[CH:4][C:5]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CNCc1cc(Br)ccc1Oc1ccc(SC)cc1
Reactant: c1c[nH]nn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CNCc1cc(-n2nccn2)ccc1Oc1ccc(SC)cc1
Temperature: 160 °C

Procedure:
The bromide of Example 23 (2.0 g, 6 mmol) was mixed with copper powder (378 mg, 6 mmol) 1,2,3-triazole (ca. 5 g, excess), and potassium carbonate (828 mg, 6 mmol) were heated together at 160° C. for 48 h. After cooling to room temperature the reaction mixture was partitioned between sodium hydroxide (3 M) and ethyl acetate. The organic layer was separated and washed with sodium hydroxide (3 M) (3 x), water, and brine, before being dried (MgSO4) and evaporated. The resulting residue was purified by flash chromatography [SiO2; DCM/ MeOH/ 880 NH3 (97.5:2.5:0.25)] to afford, separately, the 1-substitiuted triazole derivative compound of Example 181 and the 2-substituted isomer compound of Example 182. The hydrochloride salt of each was precipitated by treatment with ethereal hydrochloric acid (1 M solution, excess).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1.CC(O)(C)[C:16]#[C:17][C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=1>[Cu]I.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]#[C:17][C:18]2[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24][OH:25])=[CH:20][CH:19]=2)=[C:4]([O:9][C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: FC(F)(F)Oc1cc(Br)ccc1I
Reactant: CC(C)(O)C#Cc1ccc(OCCO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: OCCOc1ccc(C#Cc2ccc(Br)cc2OC(F)(F)F)cc1
Yield: 81.9 %

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 3.35 g (9.13 mmol) of 4-bromo-2-(trifluoromethoxy)iodobenzene and 19 ml of triethylamine under a nitrogen atmosphere. Then 1.48 g (9.13 mmol) of 2-[4-(3-methyl-3-hydroxybutyne-1-yl)phenoxy]ethanol, 13.7 mg (0.072 mmol) of copper (I) iodide, 63.2 mg (0.24 mmol) of triphenylphosphine, and 13.7 mg (0.020 mmol) of dichlorobis(triphenylphosphine)palladium were added at room temperature, and stirred under reflux for 6 hours. After the insolubles were filtered off and the solvent was distilled off, ethyl acetate was added to the resulting distillate, and the pH was adjusted to an acidity with 1N hydrochloric acid to effect ethyl acetate extraction. The resulting extract was washed with NaCl saturated water, dried over anhydrous sodium sulfate, filtered, and concentrated to thereby obtain 3.85 g of a crude product in the form of a yellowish brown solid. The crude product was then purified by silica gel column chromatography using hexane/ethyl acetate as an eluting solvent to obtain 3.0 g of 2-(4-{2-[4-bromo-2-(trifluoromethoxy)phenyl]ethynyl}phenoxy)ethanol in the form of a light yellow solid in a 82% yield.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2)(=[O:5])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(O)c3C2)CN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3C2)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Trifluoromethanesulfonic anhydride (1.76 g, 6.24 mmol) was added to a stirred, 0° C. mixture of 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.81 g, 4.30 mmol) and Et3N (1.31 g, 12.90 mmol) in DCM (20 mL) and stirred for 18 h. The resulting mixture was poured into saturated aqueous NaHCO3 and extracted into dichloromethane. The organic layer was washed with 10% citric acid solution, dried over Na2SO4 and concentrated to red oil. The oil was purified by column chromatography on silica gel (gradient elution, 10 to 70% EtOAc in hexanes) to give a yellow oil, 1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoro methyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate (1.65 g, 69.4% yield).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (370 mg, 0.001 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (106 mg, 0.004 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (300 mg, 84%) as a light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1.[CH:14]1([C:17]2[CH:21]=[C:20]([NH2:22])[N:19]([CH2:23][CH3:24])[N:18]=2)[CH2:16][CH2:15]1.[BH4-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([CH2:8][NH:22][C:20]2[N:19]([CH2:23][CH3:24])[N:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[CH:21]=2)=[C:6]([O:10][CH3:11])[N:5]=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: COc1nc(Cl)c(C=O)c(OC)n1
Reactant: CCn1nc(C2CC2)cc1N
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nc(C2CC2)cc1NCc1c(Cl)nc(OC)nc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-2,6-dimethoxypyrimidine-5-carbaldehyde (2.4 g, 11.8 mmol), and 3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine (2.15 g, 14.2 mmol) in THF was heated at 50° C. for 3 h. The flask was then removed from the heating bath and cooled in an ice bath and EtOH (13 mL) was added followed by NaBH4 (0.896 g, 23.7 mmol). The resulting mixture was left to gradually warm to rt and stir for 18 h. The excess NaBH4 was quenched slowly with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous layer was further extracted with EtOAc (2×250 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified via FCC (20-75% EtOAc/heptane) to give the title compound N-((4-chloro-2,6-dimethoxypyrimidin-5-yl)methyl)-3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine. MS (ESI+) m/z 338.0 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1CCc2c(O)cccc21
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc2c1CCC2=O)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxyindanone and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (77%, light yellow oil).
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[C:4]([CH3:13])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:28][CH2:29]3)[C:3]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)=[C:4]([CH3:13])[C:5]=2[O:9]1
Reactant: Cc1ccc(-c2c(Br)cc3c(c2C)OC(C)(C)C3)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: Cc1ccc(-c2c(N3CCN(c4ccccc4)CC3)cc3c(c2C)OC(C)(C)C3)cc1
Yield: 3.3 %

Procedure:
By using 5-bromo-2,2,7-trimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (150 mg, 1.49 mmol) synthesized in Reference Example 157 and 1-phenylpiperazine (73.5 mg, 2.23 mmol), the reaction was carried out in the same manner as Example 129 to obtain 20 mg of the title compound as a colorless solid (yield 11%).
Reaction SMILES: C([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1)CCC>[Pd]>[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Agent: [Pd]
Product: O=C(O)c1c[nH]c2ccccc12

Procedure:
reacting the 4-bromomethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrasol-5-yl]biphenyl with 2-transmetalated 1-but-1-yl-1H-indole-3-carboxylic acid in the presence of phosphinated palladium catalyst to give 1-butyl-2-[2'-92-(1-methyl-1-phenylethyl)-2H-tetrasol-5-yl)biphenyl-4-ylmethyl]-1H-indole-3-carboxylic acid; and
Reaction SMILES: [N:1]1([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:28][CH2:27][C@H:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:16]([O:20][C:21](=[O:32])[NH:22][C@H:23]1[CH2:24][CH2:25][C@H:26]([CH2:29][CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][N:8]=3)[CH2:2][CH2:3]2)[CH2:27][CH2:28]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1ccc2c(N3CCNCC3)noc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccccc34)CC2)CC1
Reaction time: 12 h

Procedure:
A mixture of 3-piperazin-1-yl-1,2-benzisoxazole (1 g, 4.92 mmol), trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (Intermediate A) (1.3 g, 5.41 mmol), in dichloromethane (15 ml) was stirred for 15 minutes at room temperature and sodium triacetoxyborohydride (1.88 g, 8.86 mmol) was added slowly and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was extracted with saturated NaHCO3-solution and two times dichloromethane. The organic layers were dried over sodium sulfate, filtrated and concentrated to dryness. The crude product was purified with column chromatography on silica gel using heptane:ethyl acetate 80:20->10:90. The product fractions were concentrated to give 1.34 g (64% yield) of a white solid. MS (m/e): 429.4 (M+H+).
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:1][CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:22])=[O:21]
Reactant: CCCCC/C=C\CCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\CCCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a cooled solution (0° C.) of (Z)-dec-4-en-1-ol 9 (20 g, 128.0 mmol) and triethylamine (26.7 mL, 191.9 mmol) in anhydrous dichloromethane (200 mL) was slowly added methane sulfonyl chloride (14.9 mL, 191.9 mmol). The solution was stirred for 30 min at room temperature then diluted with dichloromethane (100 mL). The solution was washed with saturated sodium bicarbonate (3×150 mL) and then the combined aqueous washes were extracted with dichloromethane (150 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was filtered through a pad of silica (100% dichloromethane) to afford (Z)-dec-4-enyl methanesulfonate 2 as a yellow oil (28.5 g, 95%). Rf 0.5 (100% CH2Cl2).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][CH:9]([Cl:48])[C:10]([N:12]([CH2:32][CH2:33][C:34](=[O:47])[CH:35]([NH:39]C(=O)OC(C)(C)C)[CH:36]([CH3:38])[CH3:37])[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])[CH:20]=2)[CH:14]=1)=[O:11]>C(Cl)Cl>[NH2:39][CH:35]([CH:36]([CH3:38])[CH3:37])[C:34](=[O:47])[CH2:33][CH2:32][N:12]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=3[Cl:30])[CH:20]=2)[CH:14]=1)[C:10](=[O:11])[CH:9]([Cl:48])[Cl:8]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)CCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 6-(2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamido)-2-methyl-4-oxohexan-3-ylcarbamate (185 mg, 0.29 mmol) in methylene chloride (2 mL) at 0° C. The resulting mixture was allowed to stir at 0° C. for 2 hours, then concentrated under reduced pressure. The residue was dissolved in methylene chloride (2 mL) and concentrated under reduced pressure, twice more. Then lyophilized to produce N-(4-amino-5-methyl-3-oxohexyl)-2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)acetamide (Cpd. No. 3, lot 2, 150 mg) as a light orange solid. 1H NMR (CD3OD): 8.90 (d, 1H), 8.28 (s, 1H), 7.80-7.75 (m, 1H), 7.65-7.55 (m, 3H), 7.38 (s, 1H), 6.62 (s, 1H), 4.38-4.11 (m, 3H), 3.19-3.08 (m, 2H), 2.55-2.41 (m, 1H), 1.15 (d, 3H), 0.90 ppm (d, 3H). MW=544 confirmed by LC-MS, tr=10.55 min (Method Y) MH+=542-546.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:30]2)=CC=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:12]=2[NH:11][C:10](=[S:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=S)Nc2ccc(Cl)cc2C1
Yield: 157.1 %

Procedure:
A mixture of 7-chloro-2-oxo-1,2,3,5-tetrahydro-benzo[1,4]diazepine-4-carboxylic acid tert-butyl ester (41.1 g, 0.139 mol) and 2,4-bis-(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (31.5 g, 0.0763 mol) in tetrahydrofuran (1100 ml) was heated at reflux for 3 h. The solvent was evaporated and the residue was triturated in tert-butyl methyl ether. The precipitate was removed by filtration and the filtrate was concentrated to dryness. The residue was crystallized from hot ethanol to give the title compound (37.5 g, 86.4%) as light yellow solid. MS m/e: 311 (M−H+).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][N:9]([CH2:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:20](=O)[CH2:21][CH2:22][CH2:23][CH:24]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:16]([N:9]([CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17]
Reactant: CCN(CCOc1ccc(N)cc1)c1ccccc1
Reactant: O=CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCN(CCOc1ccc(N2CCCCC2)cc1)c1ccccc1
Reaction time: 8 h
Yield: 73.9 %

Procedure:
Compound 20 (120 mg, 0.47 mmol) and glutaraldehyde (46 mg, 0.23 mmol) was dissolved in 10 mL 1,2-dichloroethane and sodium triacetoxyborohydride (400 mg, 1.89 mmol) was added portionwise over 6 hrs and reaction was stirred overnight. The reaction was quenched with sat. sodium carbonate, extracted with EtOAc (2×25 mL), washed with water and then brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography provide the compound 22 (55 mg, 0.17 mmol, 36% yield). 1H NMR (CDCl3, 400 MHz) δ 7.23-7.28 (m, 2H), 6.68-6.94 (m, 7H), 4.10 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.4 Hz, 2H), 3.50 (q, J=7.2 Hz, 2H), 3.05 (t, J=5.6 Hz, 4H), 1.72-1.78 (m, 4H), 1.54-1.60 (m, 2H), 1.22 (t, J=6.8 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C21H29N2O [M+H]+: 325.2280, found: 325.2227.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (39.1 g, 119 mmol) in CH2Cl2 (400 mL) and AcOH (40 mL) was added acetaldehyde (24.7 g, 476 mmol) and sodium triacetoxyborohydride (79.6 g, 357 mmol). The reaction mixture was stirred at RT for 24 hours. Then saturated NaHCO3 aq. was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2Heptane/EtOAc=3/1) to give the titled compound as a viscous oil (44.1 g, quantitative yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm; 7.62 (s, 1H), 7.52 (s, 1H), 3.80 (m, 5H), 3.31 (m, 2H), 2.97-3.05 (m, 2H), 2.87-2.96 (m, 1H), 2.38 (s, 3H), 1.52-1.61 (m, 2H), 1.37-1.50 (m, 2H), 0.87 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([N:7]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])C1C=CC=CC=1)=[O:6])C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])=[O:26])([CH3:21])[CH3:22]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C(C)C)cccc1C(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(=O)Nc1ccccc1O
Yield: 85 %

Procedure:
N-(2,6-Diisopropylphenyl)-oxanilic acid ethyl ester (2.78 g, 10 mmol, 1 eq) and 2-aminophenol (1.31 g, 12 mmol, 1.2 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (2.78 ml, 20 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (2.9 g, 8.5 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 8.84 (s, 1H), 8.12 (s, 1H), 7.50 (dd, J=8.25, 1.8 Hz 1H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.16 (dt, J=7.7, 1.5 Hz, 1H), 6.95 (comp m, 2H), 3.03 (septet, J=6.6 Hz, 2H), 1.22 (d, J=6.9, 12H); 3C NMR (75 MHz, CDCl3) δ 158.9, 158.2, 148.2, 146.1, 129.4, 127.9, 124.2, 124.0, 122.3, 121.2, 119.1, 29.2, 23.9. Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23; O, 14.10. Found: C, 34.90; H, 4.64; N, 5.79.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:10][CH:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:23][CH2:22][CH2:21][C:20]4[N:16]([N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[CH:19]=4)[C:15]=3[CH:32]=2)[CH2:8]1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C>C1COCC1>[CH:29]([N:25]1[C:24]([C:18]2[CH:19]=[C:20]3[N:16]([C:15]4[CH:32]=[C:11]([CH:9]5[CH2:10][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8]5)[CH:12]=[CH:13][C:14]=4[O:23][CH2:22][CH2:21]3)[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: COC(=O)C(C)(C)N1CC(c2ccc3c(c2)-n2nc(-c4ncnn4C(C)C)cc2CCO3)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C3CN(C(C)(C)CO)C3)ccc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 9-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (200 mg, 0.55 mmol), 2-bromo-2-methyl propionate (71 L, 0.55 mmol), triethylamine (75 L, 0.55 mmol) in DMF was heated at 55° C. for 30 h before concentrating in vacuo. The residue was partitioned between 10% MeOH in DCM and water, the aqueous extracted with 10% MeOH in DCM and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) to give 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 23%). To a solution of 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulen-9-yl]-azetidin-1-yl}-2-methyl-propionic acid methyl ester 63 (56 mg, 0.12 mmol) in THF (1.5 mL) at −78° C. was added DIBAL (1.5 M solution in toluene, 0.24 mL, 0.36 mmol) and the mixture allowed to warm to RT over 18 h. The mixture was cooled to 0° C., further DIBAL (0.12 mL, 0.18 mmol) added dropwise and stirring continued for 45 min. The reaction was quenched by the addition of MeOH (0.5 mL) followed by Rochelle's salt saturated aqueous solution (0.5 mL), then diluted with ethyl acetate and filtered through Celite®, washing with ethyl acetate. The filtrate was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH (+2M NH3) in DCM) to give 170 as a white solid, as illustrated in FIG. 13 (27 mg, 53%). 1H NMR (400 MHz, CDCl3): δ 7.95 (s, 1H); 7.85 (d, J=2.18 Hz, 1H); 7.23 (d, J=2.23 Hz, 1H); 7.17 (d, J=8.29 Hz, 1H); 6.87 (s, 1H); 5.74-5.66 (m, 1H); 4.55 (t, J=6.02 Hz, 2H); 3.71 (s, 3H); 3.43 (s, 2H); 3.28 (s, 2H); 3.16 (t, J=6.03 Hz, 2H); 1.59 (d, J=6.62 Hz, 6H); 1.04 (s, 6H). 1 Exchangeable proton not observed. LCMS: RT=6.43 min, M+H+=423