Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([CH2:25][OH:26])=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([CH:25]=[O:26])=[N:22][N:21]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OCc1nnc(CO)s1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCc1nnc(C=O)s1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of [5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazol-2-yl]methanol (242 mg) in toluene (2 mL) was added manganese dioxide (693 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated to give the title compound (171 mg) as a colorless amorphous solid.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1.ClC1NC2C=CC=CC=2N=1.[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH2:29])([CH3:26])[CH3:25]>CN1C(=O)CCC1.O>[CH:24]([C:27]1[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:4]=2[N:3]=1)([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cl)nc2c1
Reactant: CC(C)c1ccccc1N
Agent: Clc1nc2ccccc2[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccccc1Nc1nc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-5-nitro-1H-benzimidazole (1.5 mmol; prepared from nitration of 2-chloro-1H-benzimidazole; Galy et al, J. Heterocycl. Chem. 1997, 34, 6, 1781-1788) in dry NMP (3 mL) was added 2-isopropylaniline (4 mmol). The resulting solution was subjected to microwave irradiation at 150° C. for 1 h. The contents were cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (2×15 mL). The combined extracts were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue obtained was purified by silica gel chromatography using EtOAc/hexane as eluent to obtain (2-isopropylphenyl)-(5-nitro-1H-benzimidazol-2-yl)-amine as light yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:31][NH:32][CH3:33]>>[CH3:31][N:32]([CH3:33])[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:21][CH:22]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: CNC
Product: CN(C)CCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1

Procedure:
The product from Example 23D and dimethylamine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 378 (M+H)+;
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and Cul (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([N:20]2[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)C.O.[OH-].[Li+].O>O1CCOCC1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C:21]2[N:20]([CH:13]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:12][O:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:38])=[O:3])=[CH:6][CH:7]=3)[C:24]3[CH:25]=[C:26]([F:30])[C:27]([F:29])=[CH:28][C:23]=3[N:22]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To the solution of 0.22 g (0.4 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethoxy}-benzoic acid ethyl ester in 3 mL dioxane, 50 mg (1.2 mmol) lithium hydroxide monohydrate and 3 mL water were added and the solution was stirred for 2 h at 100° C. After cooling to room temperature dioxane was evaporated and 7.6 mL 1N hydrochloric acid was added under stirring. The resulting suspension was filtered, thoroughly washed with water and the filter cake dried under high vacuum to give the product as a white solid (94%). MS (Turbo Spray): m/z=509.2 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=3)=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=3)=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:11]=2[N:10]=1
Reactant: COc1ccccc1-c1nc2cc(C(F)(F)F)cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1nc2cc(C(F)(F)F)cc(C3=CCNCC3)c2[nH]1
Yield: 92 %

Procedure:
Compound 177 (47 mg, 0.099 mmol) was stirred in a solution of DCM (0.8 mL) and TFA (0.200 mL) for 1 hour. After the usual work-up 2-(2-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole was obtained (34 mg, 0.091 mmol, 92% yield). LRMS (ESI): (calc.) 373.4 (found) 374.1 (MH)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([NH:22][OH:23])[CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:24](OC=O)(=[O:26])C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][CH:19]([N:22]([OH:23])[CH:24]=[O:26])[CH2:20][CH3:21])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC=O
Reactant: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)NO
Solvent: C1CCOC1
Product: CCC(CS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)N(O)C=O
Reaction time: 2 h
Yield: 40.5 %

Procedure:
A solution of Example 75C (0.24 g, 0.72 mmol) in THF (30mL) cooled to 0° C. was treated with formic acetic anhydride (64 mg, 0.72 mmol), stirred for 2 hours, partitioned between water and dichloromethane, dried (Mg2SO4), filtered, and concentrated to afford 0.25 g of crude product which was recrystallized in ethyl acetate to provide 106 mg (41%) of the desired product.
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:9].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.CO>[Br:9][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([CH3:8])[CH:2]=1
Reactant: [Br-]
Reactant: Cc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Br)ccc1O
Reaction time: 1 h
Yield: 178.1 %

Procedure:
To a solution of o-cresol (6.0 g) in dichloromethane (120 ml) and methanol (80 ml) was added little by little the solid of tetrabutylammonium tribromide (27.0 g), and the mixture was stirred for 1 hour and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ether (4 times). The organic layer was washed with saturated brine (twice) and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give solid, which was dried in vacuo to give colorless solid of 4-bromo-2-methylphenol (9.3 g).
Reaction SMILES: ClC(OC)=O.[C:6]([O:10][C:11](=[O:32])[C:12]([CH2:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:23]=1)([CH3:16])[C:13](O)=[O:14])([CH3:9])([CH3:8])[CH3:7].CCN(CC)CC.[BH4-].[Na+].Cl>C1COCC1.CCOC(C)=O>[C:6]([O:10][C:11](=[O:32])[C:12]([CH2:13][OH:14])([CH3:16])[CH2:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:23]=1)([CH3:7])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(C)(C(=O)O)C(=O)OC(C)(C)C)cn1
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(C)(CO)C(=O)OC(C)(C)C)cn1
Reaction time: 0.33 h
Yield: 56.7 %

Procedure:
Methyl chloroformate (75 μL, 0.92 mmol) was added dropwise to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-methyl-malonic acid mono-tert-butyl ester (348 mg, 0.915 mmol) and Et3N (123 μL, 0.92 mmol) in THF (6 mL). The reaction mixture was stirred for 20 min., filtered and added dropwise to a suspension of NaBH4 (39 mg, 1.04 mmol) in THF (6 mL) at 0° C. The reaction was stirred for 16 h at room temperature. 0.2 M HCl was added followed by EtOAc. The organic phase was washed with brine and dried. Concentration under reduced pressure followed by chromathography (toluene/EtOAc, 3:1→1:3) gave 3-(6tert-butoxycarbonylamino-pyridin-3-yl)-2-hydroxymethyl-2-methyl-propionic acid tert-butyl ester (190 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([F:32])[CH:31]=1)[CH2:5][C@H:6]([NH:21]C(=O)OC(C)(C)C)[C@H:7]([OH:20])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=1.[ClH:33]>O1CCOCC1>[ClH:33].[ClH:33].[NH2:21][C@@H:6]([CH2:5][C:4]1[CH:29]=[C:30]([F:32])[CH:31]=[C:2]([F:1])[CH:3]=1)[C@H:7]([OH:20])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=1
Reactant: CC(C)c1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(3-isopropylbenzyl)amino]propylcarbamate (1.5 g, 3.3 mmol) is dissolved in 4 N hydrochloric acid in dioxane (20 mL), and the reaction is stirred at room temperature 3 h. The mixture is concentrated under reduced pressure to afford the title compound. ESI MS m/z 349.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]([C:8]23[N:20]([C:21]([C:23]4[C:24]([CH3:28])=[N:25][O:26][CH:27]=4)=[O:22])[CH2:19][CH2:18][N:9]2[C:10](=[O:17])[C:11]2[N:12]([CH:14]=[CH:15][CH:16]=2)[CH2:13]3)=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C.O>[CH3:28][C:24]1[C:23]([C:21]([N:20]2[C:8]3([C:5]4[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH3:29])[CH:6]=4)[CH2:13][N:12]4[CH:14]=[CH:15][CH:16]=[C:11]4[C:10](=[O:17])[N:9]3[CH2:18][CH2:19]2)=[O:22])=[CH:27][O:26][N:25]=1
Reactant: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(O)nc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: Cc1nocc1C(=O)N1CCN2C(=O)c3cccn3CC12c1ccc(=O)n(C)c1
Reaction time: 2.5 h
Yield: 164 %

Procedure:
To a solution of 10a-(6-hydroxypyridin-3-yl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (142) (20 mg, 0.053 mmol) and cesium carbonate (10 mg, 0.031 mmol) in DMF (2 mL) was added methyl iodide (20 μL, 0.32 mmol). LCMS after 2.5 hours showed approx. 50% conversion so extra methyl iodide (30 μL, 0.48 mmol) was added. LCMS after a further 1.75 hours showed no additional progress, so extra cesium carbonate (15 mg, 0.046 mmol) was added. LCMS after 1.5 hours showed the reaction was almost complete, and after 2 hours the mixture was diluted with water (approx. 10 mL) and freeze-dried to yield a white solid. The solid was partitioned between water (5 mL) and dichloromethane (5 mL). The organic layer was separated and the aqueous layer extracted with dichloromethane (2×5 mL). The organic layers were combined, dried (MgSO4), and concentrated in vacuo to yield a white solid. The material was purified by flash chromatography using the Biotage SP4 (4 g cartridge, dichloromethane 3 CV, 0 to 10% methanol-dichloromethane 20 CV, hold 5 CV) and freeze-dried from acetonitrile-water to give 1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-10a-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (143) as a white solid (20 mg, 96%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([CH2:26][OH:27])[C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([N:21]1[CH2:25][CH:24]([CH:26]=[O:27])[C@H:23]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:22]1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CO
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC1C=O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Dimethyl sulfoxide (5.10 mL, 59.3 mmol) was added to a solution of oxalylchloride (5.00 mL, 57.3 mmol) in dichloromethane (100 mL), and the mixture was stirred at −78° C. for 20 minutes. Subsequently, a solution of (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-hydroxymethylpyrrolidine (8.00 g, 22.8 mmol) in dichloromethane (85 mL) was added dropwise slowly thereto, followed by stirring at the same temperature for 30 minutes, and further at −43° C. for 1 hour. Subsequently, triethylamine (30 mL) was added thereto, and the temperature of the resultant mixture was elevated to an ice cooling temperature, followed by stirring for 45 minutes. Thereafter, a 10% aqueous citric acid solution (100 mL) was added to the resultant mixture, followed by stirring for 10 minutes. The obtained aqueous layer was extracted with dichloromethane (200 mL×2). The combined organic layer was washed by saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, to thereby yield a crude aldehyde as a pale yellow oilily substance. Subsequently, triethylamine (0.50 mL, 3.59 mmol) was added to a solution of the crude aldehyde compound (2.5 g, 7.18 mmol) in dichloromethane (10 mL). The resultant mixture was stirred at room temperature for 24 hours, and triethylamine (0.50 mL, 3.59 mmol) was further added thereto, followed by stirring for another 24 hours. Thereafter, silica gel (100 g) was added to the reaction mixture, followed by stirring for 24 hours. The reaction mixture was concentrated under reduced pressure, and left to stand for 24 hours. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=7:3), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:3)) as a colorless oily substance (750 mg, 28%).
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](OC)=[O:17]>C1COCC1.C(O)(=O)C.O>[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[C:16](=[O:17])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1ccccc1C
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)c1ccccc1C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
n-Butyl lithium (1.58N, 52.5 ml, 83 mmol) was added dropwise to a stirred solution of dimethyl methylphosphonate (10.3 g, 83 mmol) in 100 ml of anhydrous THF at -78° C. under argon atmosphere. After 30 minutes, methyl o-methylbenzoate (5.0 g, 33 mmol) in 10 ml of anhydrous THF was added dropwise. After being stirred for 30 minutes, this reaction mixture was allowed to warm to 0° C., diluted with 5 ml of acetic acid and 10 ml of water, and concentrated. 20 ml of water was added and the mixture was extracted with ethyl acetate (50 ml×2). The combined ethyl acetate layers were washed with water (20 ml×1) and brine (20 ml×1), dried over anhydrous sodium sulfate, and concentrated. The residue was distilled under reduced pressure to give an oil of dimethyl 2-o-methylphenyl-2-oxoethylphosphonate (68 g, 28.1 mmol, yield 85.1%, b.p. 134°-136° C./0.21 mmHg), which was assigned the structure by the following data:
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.[CH:20]1([C@@:23]2([CH2:30][S:31](Cl)(=[O:33])=[O:32])[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24]2)[CH2:22][CH2:21]1>>[CH:20]1([C@:23]2([CH2:30][S:31]([N:15]3[CH2:14][CH2:13][C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:7]5[CH:8]=[N:9][C:4]([CH:1]6[CH2:3][CH2:2]6)=[N:5][CH:6]=5)[CH:11]=4)[CH2:16]3)(=[O:32])=[O:33])[NH:24][C:25](=[O:29])[NH:26][C:27]2=[O:28])[CH2:21][CH2:22]1
Reactant: c1cc2c(cc1-c1cnc(C3CC3)nc1)CCNC2
Reactant: O=C1NC(=O)[C@](CS(=O)(=O)Cl)(C2CC2)N1
Product: O=C1NC(=O)[C@](CS(=O)(=O)N2CCc3cc(-c4cnc(C5CC5)nc4)ccc3C2)(C2CC2)N1

Procedure:
The title compound was prepared from 6-[2-(cyclopropyl)pyrimidin-5-yl]-1,2,3,4-tetrahydroisoquinoline and (4S)-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl)methanesulfonyl chloride using the general method described in Example 1.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@@H:4]([CH2:22]CS([O-])(=O)=O)[O:3]1.[K].[C:29]1(=[O:39])[NH:33][C:32](=[O:34])[C:31]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:30]12.C(Cl)Cl.CO.O>CN(C=O)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([CH2:22][N:33]2[C:29](=[O:39])[C:30]3[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:34])[O:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1COCCN1c1ccc2c(c1)OC[C@H]1[C@@H](CCS(=O)(=O)[O-])OC(=O)N21
Agent: [K]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 84.2 %

Procedure:
Compound ((3R,3aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methylmethanesulfonate (3.91 g, 9.81 mmol) prepared as above in (c) was dissolved in 50 ml of DMF. Phthalimide potassium (2.72 g, 14.72 mmol) was added and the mixture was allowed to react at 80° C. for 2 h. TLC (DCM/MeOH=10/1) was employed to monitor the reaction. After the reaction completed, water (80 ml) was added for dilution. There was white solid precipitated, which was filtered and dried. The filtrate was extracted with EA (50 ml×3). The organic phase was combined, and washed sequentially with water (30 ml) and saturated NaCl (30 ml) solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to afford totally 3.71 g of white solid, yield: 84.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:23])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5]
Reactant: COC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C(C)n1ccc2cc(O)ccc21
Temperature: 60 °C

Procedure:
To a solution of 2-(5-benzyloxy-indol-1-yl)-propionic acid methyl ester (Example 3, 20.0 g, 64.7 mmol) in absolute ethanol (150 mL) was added Pd(OH)2 (2.0 g, 10 wt %) suspended in ethanol (50 mL). Ammonium formate (8.1 g, 129.3 mmol) was added and the resulting mixture was heated to 60° C. for 4 h. The reaction mixture was cooled to rt and the palladium was filtered through a plug of silica gel. The filtrate was concentrated to give a light yellow oil which was used in the following step without further purification (13 g, 92%). LC/MS m/z 220 (M+H)+, RT 8.01 min; 1H NMR (400 MHz, acetone-d6) δ 7.78 (br s, 1H), 7.28 (d, 1H), 7.20 (d, 1H), 6.97 (d, 1H), 6.77 (dd, 1H), 6.36 (d, 1H), 5.23 (q, 1H), 3.62 (s, 3H), 1.78 (d, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]2([C:21]([O:23]CC)=[O:22])[CH2:20][CH2:19]2)[CH:13]=1>ClCCl>[C:21]([C:18]1([C:14]2[CH:13]=[N+:12]([O-:6])[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:19]1)([OH:23])=[O:22]
Reactant: CCOC(=O)C1(c2cccnc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(O)C1(c2ccc[n+]([O-])c2)CC1
Reaction time: 16 h
Yield: 58.1 %

Procedure:
70% meta-Chloroperoxybenzoic acid (1.2 g, 4.9 mmol) was added to a solution of ethyl 1-(pyridin-3-yl)cyclopropanecarboxylate (400 mg, 2.4 mmol) in dichloromethane (5 mL) at room temperature and stirred for 16 h. The resulting precipitate was filtered and triturated with dichloromethane to afford the title compound (250 mg).
Reaction SMILES: [CH3:1][OH:2].[Br:3][C:4]1[CH:11]=[C:10](F)[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[CH:11]=[C:10]([O:2][CH3:1])[C:7]([C:8]#[N:9])=[C:6]([F:13])[CH:5]=1
Reactant: CO
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Br)cc(F)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To methanol (0.28 mL, 6.9 mmol) and 4-bromo-2,6-difluorobenzonitrile (1500 mg, 6.88 mmol) in THF (34 mL) was added NaHMDS (6.88 mL, 1.0 M in THF, 6.88 mmol) at 0° C. The reaction mixture was stirred at rt overnight, and diluted with brine, extracted with EtOAc. The organic layer was dried, and evaporated. The crude product was purified by column chromatography (0-30% EtOAc/Hex) to give 4-bromo-2-fluoro-6-methoxybenzonitrile.