Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH3:2][CH:3]([CH3:7])[CH2:4][CH2:5][Zn+].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26](Br)[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:36])[C@@H:22]([NH:32][C:33](=[O:35])[CH3:34])[CH2:23][C:24]2[CH:25]=[C:26]([CH2:5][CH2:4][CH:3]([CH3:7])[CH3:2])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([O:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:16]1[CH3:43])=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)CC[Zn+]
Reactant: CC(=O)N[C@@H](Cc1cc(F)cc(Br)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Br-]
Product: CC(=O)N[C@@H](Cc1cc(F)cc(CCC(C)C)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 78 %

Procedure:
Beginning with 3-methylbutyl zinc bromide and (2R,3S,5R)-5-[(1S,2S)-1-hydroxy-2-acetylamino-3-(3-bromo-5-fluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (0.165 g, 0.287 mmol), the title compound (0.127 g, 78%) may be prepared essentially as described in Preparation 409.
Reaction SMILES: S(Cl)(Cl)=O.[O:5]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21]O>>[CH3:21][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccccc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (2.0 ml, 28.0 mmol) was added dropwise to a solution of 2-phenoxybenzoic acid (5.0 g, 23.3 mmol) in methanol (70 ml). The reaction mixture was stirred at 70° C. for 3 hours. The solvent was removed in vauco. The crude product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[C:15]1[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=[C:19]([Cl:21])[CH:20]=1.O>CN(C=O)C>[Cl:21][C:19]1[CH:20]=[C:15]([NH:9][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=2)[C:16]2[N:17]([CH:22]=[CH:23][N:24]=2)[N:18]=1
Reactant: Clc1cc(Br)c2nccn2n1
Reactant: Nc1cccc(C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
A solution of 6-(trifluoromethyl)pyridin-2-amine (0.668 g, 4.12 mmol) in DMF (5 mL) was added NaH (0.10 g, 4.18 mmol) and stirred for 0.5 h. To the mixture was added 8-bromo-6-chloroimidazo[1,2-b]pyridazine (0.38 g, 1.65 mmol) under N2. The mixture was stirred at room temperature for 16 h then 100 mL of water was added and the precipitate collected by filtration and washed with water to give 6-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.513 g, 99%) as a light brown solid. LC-MS: [M+H]+, 314.1, tR=1.738 min.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=O>CC(O)=O.[Zn]>[OH:1][C:2]1[CH:12]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:10](=[O:11])[NH:9][CH2:7]2
Reactant: O=C1NC(=O)c2cc(O)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1NCc2cc(O)ccc21
Reaction time: 0.67 h
Yield: 20.9 %

Procedure:
To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO2; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m/z 150 ((M+H)+). Step 2. Synthesis of 4-(1-isoindolinon-5-yloxy)-1-nitrobenzene
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].[O-]S([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.[CH3:25][C:26]([CH3:31])([CH3:30])[CH2:27][CH:28]=O>C(Cl)Cl>[C:2]([O:6][C:7](=[O:11])[C@@H:8](/[N:9]=[CH:28]/[CH2:27][C:26]([CH3:31])([CH3:30])[CH3:25])[CH3:10])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CC=O
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](/N=C/CC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
A mixture of L-alanine tert-butyl ester hydrochloride (Bachem) (1.8 g, 10 mmol) and MgSO4 in CH2Cl2 (100 mL) was added triethylamine (1.5 g, 15 mmol). The mixture was stirred at room temperature for 1 h, and 3,3-dimethyl-butyraldehyde (1 g, 10 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered, and the filtrate was washed with water, brine, and concentrated. The residue was dried under reduced pressure to give (S)-2-[3,3-dimethyl-but-(E)-ylideneamino]-propionic acid tert-butyl ester as colorless oil (2.3 g, 100%) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10]C(=O)[NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[Na+].Cl>O>[NH2:8][C:5]1[C:4]([OH:10])=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1O
Temperature: 10 °C
Yield: 52.9 %

Procedure:
6-Bromooxazolo[4,5-b]pyridine-2(3H)-one (K. Rufenacht and H. Kristinsson, Helv. Chim. Acta 59 (5), 1953 [1976]) (4.3 g; 0.02 mole) sodium hydroxide (5 g; 0.125 mole) and water (50 ml) were stirred on the steam bath for 45 minutes. The solution was cooled to approximately 10° C. and carefully acidified with concentrated HCl (considerable foaming). The resulting solid was collected by filtration, washed with water and dried. The yield was 3.0 g (79 percent) of tan solid melting at 187° to 189° C. Recrystallization from aqueous ethanol afforded 2.0 g of tan crystals, melting point 195° to 197° C.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10]O)/[CH3:8])[CH3:3].[OH:12]C/C=C(/C)\CCC=C(C)C>>[CH2:10]=[CH:9][C:7]([CH2:6][CH2:5][CH:4]=[C:2]([CH3:3])[CH3:1])([CH3:8])[OH:12]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: CC(C)=CCC/C(C)=C/CO
Product: C=CC(C)(O)CCC=C(C)C

Procedure:
In the fully continuous process variant, catalyst and geraniol or nerol, or a mixture of geraniol and nerol, are simultaneously and continuously metered into a continuous reactor and linalool which is formed is continuously distilled off. In addition, high boilers are discharged by likewise continuously withdrawing a fractional amount of the reactor contents and removing the geraniol, nerol and linalool products of value still present in this fraction from high boilers formed during the reaction by distillation, for example by a simple evaporation or using a column. The involatile catalyst either remains in the high boilers which are fed to a disposal operation, or it may be precipitated from the high boilers by cooling, removed and reused again. The products of value which have been distilled off are recycled back into the reactor.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[NH:11][N:10]=1.Cl[CH2:16][C:17](=[O:22])[CH2:18][O:19][CH2:20][CH3:21]>O1CCOCC1>[CH3:7][O:8][C:9]1[S:13][C:12](=[O:14])[N:11]([CH:18]([O:19][CH2:20][CH3:21])[C:17](=[O:22])[CH3:16])[N:10]=1
Reactant: CCOCC(=O)CCl
Reactant: COc1n[nH]c(=O)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(C(C)=O)n1nc(OC)sc1=O
Reaction time: 20 h
Yield: 85.4 %

Procedure:
69 g of potassium carbonate are added to a solution of 33 g of 5-methoxy-3H-[1,3,4]thiadiazol-2-one in 400 ml of dioxane and the reaction mixture is heated to 60°. Then 31 g of 1-chloro-3-ethoxypropan-2-one are added dropwise within a short period of time and the reaction mixture is stirred at 70° for 20 hours and then, at 20°, is filtered over Celite. The filtrate is concentrated by evaporation. 45 g of the title compound are thus obtained in the form of a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]3)=[C:11]([O:21][CH3:22])[CH:10]=2)[N:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31]>C(OCC)(=O)C>[CH3:22][O:21][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[N:3]=[C:2]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][C:12]=1[N:15]1[CH:19]=[C:18]([CH3:20])[N:17]=[CH:16]1
Reactant: COc1cc(Nc2ncnc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Oc1ccccc1C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(Nc2ncnc(Oc3ccccc3C(F)(F)F)n2)ccc1-n1cnc(C)c1
Yield: 33 %

Procedure:
This compound was prepared from (4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine and 2-hydroxybenzotrifluoride in analogy to example 3. Chromatography on silica gel using ethyl acetate as an eluent gave the title compound as a colorless solid in 33% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>ClCCl>[Cl:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:5]([C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([F:1])[CH:3]=2)=[O:6])=[CH:23][CH:22]=1
Reactant: ClCCOc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OCCCl)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 3-fluoro-4-methoxybenzoyl chloride from the last step and anhydrous AlCl3 (1.30 g, 9.76 mmol) in dry dichloromethane (18 mL) was added (2-chloroethoxy)benzene (1.53 g, 9.76 mmol) in 2 mL dichloromethane at 0° C. After stirring at rt for 25 min, the mixture was poured into 3 N HCl. The mixture was extracted with dichloromethane. The extract was washed with sat. NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated to give the subtitle compound, which would be used for the next step directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:11])[CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH:8]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(OCC)C.O1CCCC1>[CH3:1][O:2][C:3]1[C:4](=[O:11])[CH:5]([C:12](=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][C:7]([CH3:9])([CH3:10])[CH:8]=1
Reactant: COC1=CC(C)(C)CCC1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C1CC(C)(C)C=C(OC)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of 2-methoxy-4,4-dimethyl-cyclohex-2-enone (12.5 g, 81.1 mmol) and diethyl oxalate (12.1 mL, 89.2 mmol) in ethyl ether was treated with a 1M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran under argon atmosphere. The reaction was stirred at room temperature for 2 hours, poured into a 10% NaH2PO4 solution (500 mL) and extracted with diethyl ether (300 mL×2). The organic extracts were washed with brine, dried on Na2SO4 and evaporated to dryness. The crude material was taken up with hexane, stirred and filtered to give the title compound (16.8 g, 81.5% yield) as a yellow crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[OH:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([OH:26])[CH:28]=3)[CH2:15]2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCNC3)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCN(C(=O)c4cccc(O)c4)C3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-2-methyl-5-(piperidin-3-ylmethoxy)-quinoline-3-carboxylate (Example 110b) and 3-hydroxybenzoic acid as a white solid (34%). MS 464 (MH+).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])=[N:13][C:14](Br)=[CH:15][N:16]=1>CN(C=O)C>[NH2:10][C:11]1[C:12]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])=[N:13][C:14]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][N:16]=1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1ccccc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Sc2ccccc2)nc1C(=O)Nc1ccccc1
Temperature: 100 °C
Yield: 36.4 %

Procedure:
Benzenethiol (73.29 mg, 68.30 μL, 0.6652 mmol) was added slowly to a suspension of sodium hydride (60% dispersion in mineral oil) (19.16 mg, 21.29 μL, 0.7983 mmol) in anhydrous DMF (1.300 mL) at 0° C. The reaction mixture was stirred until the evolution of H2 ceased. 3-Amino-6-bromo-N-phenyl-pyrazine-2-carboxamide (130 mg, 0.4435 mmol) was added followed by Cu2O (15.87 mg, 0.1109 mmol) and reaction mixture heated to 100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and quenched with crushed ice. The aqueous layer was extracted with EtOAc (×3) and the combined organic extracts washed with ammonium hydroxide (×1), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (52 mg, 31% Yield). 1H NMR (400.0 MHz, DMSO) δ 7.19-7.23 (m, 1H), 7.43-7.54 (m, 7H), 7.77-7.80 (m, 4H), 8.37 (s, 1H) and 10.15 (s, 1H) ppm; MS (ES+) 322.99.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.I[CH3:33]>C1COCC1>[CH2:11]([C@@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:24](=[O:31])[C@H:25]([CH3:33])[CH2:26][C:27]([F:28])([F:29])[F:30])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCC(F)(F)F)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H](CC(F)(F)F)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (57 mL, 1.0 M in THF, 57 mmol) in THF (250 mL) at −40° C. was added (4R)-4-benzyl-3-(4,4,4-trifluorobutanoyl)-1,3-oxazolidin-2-one (15.60 g, 51.78 mmol) in THF (250 mL) dropwise over 15 min. After 1 h, iodomethane (4.2 mL, 67 mmol) was added. After 3 h, the reaction mixture was warmed to −20° C. for about 20 min. The mixture was quenched with saturated aqueous ammonium chloride (NH4Cl) (300 mL) and then extracted with EtOAc (2×300 mL), dried using Na2SO4, and concentrated. Flash chromatography (eluent: 1:9 EtOAc-hexane) provided (4R)-4-benzyl-3-[(2R)-4,4,4-trifluoro-2-methylbutanoyl]-1,3-oxazolidin-2-one (12.04 g, 74%) as a colorless oil. [α]D25=−98.68° (c=1% SOLUTION, DMSO).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:23]([O:26]C)=[N:24][N:25]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)([CH3:3])[CH3:2]>CC(O)=O.Br>[CH:1]([NH:4][C:5]1[C:6]2[N:7]([C:23](=[O:26])[NH:24][N:25]=2)[C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1)=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COc1nnc2c(NC(C)C)nc3cc(CN4CCN(C)CC4)ccc3n12
Agent: Br
Solvent: CC(=O)O
Product: CC(C)Nc1nc2cc(CN3CCN(C)CC3)ccc2n2c(=O)[nH]nc12
Temperature: 90 °C

Procedure:
A solution of isopropyl-[1-methoxy-7-(4-methyl-piperazin-1-ylmethyl)-[1,2,4]triazolo[4,3-a]quinoxalin-4-yl]amine (12 mg) in AcOH (1 mL) and 48% HBr (0.5 mL) was stirred at 23° C. for 90 min., then was heated to 90° C. for 100 min. After cooling to 23° C., the solution was concentrated. The resulting residue was concentrated from toluene. Trituration of the residue with MeOH/EtOAc afforded the title compound as a light yellow solid. MS (M+H)+=356.4.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[N:9]=2)[CH2:3]1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH2:26][C:27](O)=[O:28])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[NH:12]1[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=[C:8]1[CH:4]1[CH2:5][CH2:6][CH2:7][N:2]([C:27](=[O:28])[CH2:26][C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[CH2:3]1
Reactant: c1ccc2[nH]c(C3CCCNC3)nc2c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCCC(c2nc3ccccc3[nH]2)C1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
To a flask containing 2-(piperidin-3-yl)-1H-benzo[d]imidazole hydrochloride (200.0 mg, 0.841 mmol) and (R)-3-(tert-butoxycarbonylamino)-4-(4-chlorophenyl) butanoic acid (282.5 mg, 0.900 mmol) was added dichloromethane (5 mL) and triethylamine (0.23 mL, 1.683 mmol); the reaction mixture was stirred at room temperature until all the components dissolved. To the solution was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (193.5 mg, 1.010 mmol) followed by N-hydroxybenzotriazole (142.1 mg, 1.052 mmol). The solution was stirred at ambient temperature for 12 hrs and diluted with excess DCM (5 mL). The solution was washed with water (2×8 mL) and brine (lx 5 mL), and then the organic layer was collected, dried with Na2SO4, and concentrated to yield tert-butyl (2R)-4-(3-(1H-benzo[d]imidazol-2-yl)piperidin-1-yl)-1-(4-chlorophenyl)-4-oxobutan-2-ylcarbamate (3A) as an amorphous solid (415.9 mg, 99.5% yield). ESI-MS: m/z 497.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([OH:20])=[O:19])[CH2:17][CH2:16]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:13]([C:15]1([C:18]([O:20][CH3:26])=[O:19])[CH2:16][CH2:17]1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)C2(C(=O)O)CC2)cc1CNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1(C(=O)c2ccc(OC)c(CNC(=O)OC(C)(C)C)c2)CC1
Reaction time: 0.5 h

Procedure:
Under a solution of 1.069 g of 1-(3-{[(t-butoxycarbonyl)amino]methyl}-4-methoxybenzoyl)-1-cyclopropanecarboxylic acid in 10 ml of methanol was added 8 ml of trimethylsilyldiazomethane (2N solution in hexane). After stirring for 30 minutes, the solution was treated with acetic acid until its color faded, and then concentrated. The residue was purified by silica gel column chromatography, to give 0.974 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:21]=1.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH:18]([CH3:20])[CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:21]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CC(C)C1(c2cccs2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-isopropyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.83 (dd, J=7.1, 2.2 Hz, 1H), 7.67 (dd, J=8.4, 2.0 Hz, 1H), 7.60 (m, 2H), 7.53 (m, 1H), 7.52 (m, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.05 (dd, J=3.6, 1.3 Hz, 1H), 7.02 (dd, J=5.0, 3.7 Hz, 1H), 4.21 (d, J=14.4 Hz, 1H), 3.90 (d, J=14.4 Hz, 1H), 2.81 (m, 1H), 0.91 (m, 6H); Anal. Calc. for C22H10ClFNO2S: C, 63.53; H, 4.60; N, 3.37. Found: C, 63.34; H, 4.92; N, 2.97.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23](=O)[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][C:10]=1[C:23]([CH3:24])=[CH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=C(C)c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Methyltriphenylphosphonium bromide (1.1 eq) was suspended in an. THF and cooled to 0° C. under nitrogen. 1.6M nButyllithium in hexanes (1.1 eq) was added drop wise, and stirred for 30 minutes. 1-(2,4-Bis-benzyloxy-phenyl)-ethanone (1 eq) was dissolved in an. THF and added drop wise to the suspension. When addition was completed, the ice bath was removed and the reaction mixture was stirred at room temperature under nitrogen overnight. Methanol was added to the reaction mixture and the resulting solution was evaporated in vacuo. Hexane was added to the resulting oil and heated to reflux for 30 minutes, then filtered through Celite. The liquor was evaporated in vacuo to give an oil which was purified by column chromatography, eluting with 30% EtOAc in hexane, to give 2,4-Bis-benzyloxy-1-isopropenyl-benzene.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[Al](C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](OC)=[O:39])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]>>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N:18]1[C:23]2[N:24]=[C:25]([NH:36][CH2:37][C:38](=[O:39])[N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[CH3:35])[C:22]=2[CH:21]=[CH:20][C:19]1=[O:42]
Reactant: COC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C1CCNC1
Agent: C[Al](C)C
Product: Cc1cc(F)ccc1-c1nc(NCC(=O)N2CCCC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 47.9 %

Procedure:
Following the general procedure outlined in Example 193, pyrrolidine (0.18 mL, 2.2 mmol), trimethylaluminum (1.1 mL, 2.2 mmol) and the product of Example 190 (100 mg, 0.22 mmol) were reacted to give the desired product 52 mg (48%). LC-MS: 494.4 (MH+, m/z), 2.10 (Rt, min).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.I[C:12]1[CH:13]=C(C=C[C:20]=1CCC)C(O)=O>>[C:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)#[C:12][CH3:13]
Reactant: O=C(O)c1ccc(I)nc1
Reactant: CCCc1ccc(C(=O)O)cc1I
Product: CC#Cc1ccc(C(=O)O)cn1
Yield: 45 %

Procedure:
When 6-iodonicotinic acid was substituted for the 3-iodo-4-propylbenzoic acid in Example 47, Step B, the similar process afforded the title compound in 45% yield, as yellow solid. 1H-NMR (CDCl3) 2.12 (s, 3H); 7.25 (broad s, 1H+H2O); 7.46 (dd, 1H, J=0.6, 7.6 Hz); 8.2 (dd, 1H, J=2.16, 6 Hz); 9.23 (dd, 1H, J=0.8, 1.4 Hz).