Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]CC)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CO.O>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C1CCC(CCc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCC(CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of the product of STEP 2 (1.26 g) in MeOH (20 mL), add water (5 mL) and LiOH (0.61 g) and stir overnight at ambient temperature. Dilute the reaction mixture with water and extract with Et2O. Acidify the aqueous layer with conc.HCl and extract with EtOAc. Separate the organic layer, wash with water and brine, and concentrate to obtain the title compound (1.06 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](O)=[O:6].S(Cl)([Cl:21])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:15][CH2:16][C:17]#[CH:18])[C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5]([Cl:21])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: C#CCOc1cc(C(=O)O)cc(Cl)c1OCC#C
Product: C#CCOc1cc(C(=O)Cl)cc(Cl)c1OCC#C

Procedure:
A mixture of 3-chloro-4,5-dipropargyloxybenzoic acid (10.7 g) and thionyl chloride (30 ml) was stirred under reflux for 1 hour. After cooling, the reaction mixture was evaporated under reduced pressure to give 3-chloro-4,5-dipropargyloxybenzoyl chloride in a quantitative yield.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1>>[CH2:5]([O:4][C:2](=[O:3])[NH:7][C:8]1[N:13]=[N:12][C:11]([N:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH2:18][CH2:19]2)=[CH:10][CH:9]=1)[CH3:6]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCOC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 7, making variations only as required to use ethyl chloroformate in place of n-butyl chloroformate to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a light yellow solid (35% yield). 1H NMR (300 MHz, DMSO-d6) δ 10.30, 7.82-7.85, 7.76, 7.67, 7.52, 7.37, 4.15, 3.15-3.85, 1.10. MS (ES+) m/z 424 (M+1).
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH2:19][CH2:20][CH2:21][OH:22]>C1COCC1>[Si:5]([O:22][CH2:21][CH2:20][CH2:19][C:15]1[S:14][CH:18]=[CH:17][N:16]=1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: OCCCc1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCc1nccs1
Reaction time: 8 h
Yield: 72.3 %

Procedure:
TBDMS-Cl (10.74 g, 71.2 mmol) and imidazole (5.38 g, 76.8 mmol) were added to a solution of 3-thiazol-2-yl-propan-1-ol (10.0 g 69.8 mmol) in THF (350 mL). Stirring was continued at rt overnight. The reaction mixture was partitioned between aq. sat. NH4Cl and Et2O. The aq. layer was extracted again with Et2O, the combined org. extracts were dried over MgSO4, filtered, and solvents were removed in vacuo. Purification of the crude by FC(CH2Cl2/MeOH 95:5) yielded the title compound as an orange oil (13.00 g, 72%). LC-MS: tR=1.05 min, ES+: 258.24.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH2:29]>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([NH:29][CH3:28])[CH2:27][OH:26])[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: CN
Solvent: CCO
Product: CNC(CO)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% methylamine in ethanol, the title compound was obtained as a light orange powder (165 mg) by flash chromatography of mixture of regioisomers which gave ABD783. 1H NMR (400 MHz, CDCl3): δ 2.10 (3H, s), 3.51 (1H, m), 3.60-3.62 (2H, m), 5.10 (3H, br s), 6.70-6.95 (3H, m), 7.10-7.15 (4H, m), 7.20-7.25 (1H, m), 7.34 (2H, d, J=8 Hz) and 7.73 (2H, d, J=8 Hz). MS, m/z: Calcd, 418.11. Found, 418.09 (M).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[S:18](Cl)([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[NH:1]([S:18]([C:21]1[C:33]([CH3:34])=[C:32]2[C:26]([O:27][C:28]([CH2:31]2)([CH3:30])[CH3:29])=[C:24]([CH3:25])[C:22]=1[CH3:23])(=[O:19])=[O:20])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3][OH:4]
Reactant: Cc1c(C)c(S(=O)(=O)Cl)c(C)c2c1OC(C)(C)C2
Reactant: COC(=O)[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 8 h
Yield: 82.7 %

Procedure:
H-Ser-OMe, 3.5 g (22.6 mmol), was suspended in (40 mL) of chloroform. Under ice cooling, DIEA (8.7 mL, 49.7 mmol) and Pbf-Cl (5.86 g, 20.3 mmol) were sequentially added and stirred overnight while gradually elevating to room temperature. After the reaction was stopped by adding satd. citric acid aqueous solution, chloroform was distilled off under reduced pressure and the whole was extracted with AcOEt. The organic layer was washed sequentially with satd. citric acid aqueous solution, satd. sodium bicarbonate aqueous solution and satd. sodium chloride aqueous solution, and then dried over anhydrous MgSO4. After concentration under reduced pressure, flash chromatography was performed using AcOEt:n-hexane=1:1 to give Pbf-Ser-OMe (6.94 g, 82.7%).
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS([O-])(=O)=O.O.C(O[CH2:28][CH3:29])(=O)C>CN(C=O)C>[CH:28]1([CH2:29][N:9]2[C:10]3[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:8]2=3)[CH2:4][CH2:3][CH2:2][CH2:10]1
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Reactant: CCOC(C)=O
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCc2c1c1cccc(F)c1n2CC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (1.023 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil; 331 mg) and stirred under nitrogen at room temperature for 30 min. A solution of cyclopentylmethyl(methyl sulphonate (893 mg) in dry DMF (20 ml) was then added over 15 min and stirring was continued for 5 days. Water (20 ml) was added to the reaction mixture which was then concentrated in vacuo to give a solid. This was dissolved in ethyl acetate (300 ml) and methanol (1 ml), and the resulting solution was washed with saturated sodium chloride solution (3×100 ml) and then adsorbed onto silica. Purification by FCC eluting with System A (150:8:1) gave a solid (283 mg) which was recrystallised from ethyl acetate to give the title compound (237 mg) m.p. 175°-176°.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[CH:36][CH:37]=[C:38]3[C:42]=2[NH:41][CH:40]=[CH:39]3)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]4[C:42]=3[NH:41][CH:40]=[CH:39]4)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: CC1(C)OB(c2cccc3cc[nH]c23)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc4cc[nH]c34)nc12
Temperature: 85 °C
Reaction time: 15 h
Yield: 99.5 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (50 mg, 117 μmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (37.0 mg, 152 μmol), potassium carbonate (16.2 mg, 117 μmol) were combined in a reaction tube with a teflon-threaded seal, dioxane (2.5 mL) and water (0.5 mL) were added, then the mixture degassed with nitrogen for 1 min. Tetrakis(triphenylphosphine)palladium(0) (13.5 mg, 11.7 μmol) was added, nitrogen was bubbled through for 1 minute, then the reaction was heated to 85° C. for 6 h, and then at 75° C. for an additional 15 h. The reaction mixture was cooled, concentrated in vacuo, and the residue purified by chromatography (silica, 1-15% ethyl acetate in hexanes) to give N-tert-butyl-2-(1H-indol-7-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg) as an oil which slowly crystallized. MS (M+H)+=464.2.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([C:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[N:10][C:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCC>[N:9]([C:20]1([NH:26][C:27]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)=[N:10][C:11]1([NH:17][C:18]([NH:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NNc1ccccc1
Reactant: O=C=NC1(N=NC2(N=C=O)CCCCC2)CCCCC1
Solvent: CCCCC
Product: O=C(NNc1ccccc1)NC1(N=NC2(NC(=O)NNc3ccccc3)CCCCC2)CCCCC1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4.52 grams (.041 moles) of phenylhydrazine in 25 ml of pentane in a 125 ml erlenmeyer flask cooled in an ice bath was slowly added a solution of 5.77 grams (.0205 moles) of 1,1'-azobis (1-isocyanatocyclohexane) (from Example XCI) in 25 ml of pentane. After the addition was complete, the reaction was stirred an additional 90 minutes at 0° to 5° C. and filtered. The filter cake was washed with cold pentane and air dried. The dry white powder weighed 5.7 grams (57% crude yield) and melted at 148°-151° C. with decomposition. The infrared spectrum of the product contained a strong broad carbonyl band at 1670-1700 cm-1 and NH peaks at 3200-3340 cm-1. The isocyanate band of the starting material at 2225 cm-1 was absent.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[CH3:43]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:37]4[CH:38]=[CH:39][N:34]=[C:35]([CH3:43])[CH:36]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(Br)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc(S(=O)(=O)[C@@H]3C[C@@H](C(=O)NC4(C#N)CC4)[C@H](C(=O)N4CCC(F)(F)C4)C3)c(Cl)c2)ccn1

Procedure:
The title compound was prepared in analogy to example 196 using (1R,2R,4R)-4-(2-chloro-4-bromo-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (Example 187 step 4) and 2-picoline-4-boronic acid. Light yellow solid (59%). MS (EI): 577.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][N:23]3[CH:27]=[C:26]([Cl:28])[N:25]=[N:24]3)[O:19][C:18]2=[O:29])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.Br[C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:38]=[N:39][N:40]([CH3:42])[N:41]=2)=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][C@H:20]([CH2:22][N:23]3[CH:27]=[C:26]([Cl:28])[N:25]=[N:24]3)[O:19][C:18]2=[O:29])[CH:5]=[CH:6][C:7]=1[C:31]1[CH:36]=[N:35][C:34]([C:37]2[N:38]=[N:39][N:40]([CH3:42])[N:41]=2)=[CH:33][CH:32]=1
Reactant: Cn1nnc(-c2ccc(Br)cn2)n1
Reactant: CC1(C)OB(c2ccc(N3C[C@H](Cn4cc(Cl)nn4)OC3=O)cc2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccc(-c3ccc(N4C[C@H](Cn5cc(Cl)nn5)OC4=O)cc3F)cn2)n1
Temperature: 70 °C

Procedure:
A mixture of (5R)-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5-(4-chloro-1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (300 mg, 0.71 mmol), 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (170 mg, 0.71 mmol), and sodium carbonate (226 mg, 2.13 mmol) in N,N-dimethylformamide:water (5 mL, 10:1) was degassed, flushed with nitrogen, and treated with tetrakis(triphenylphosphine)palladium (0) (82 mg, 10 mol %). The reaction mixture was heated at 70° C. for 3 hours, cooled to room temperature, and evaporated to dryness under reduced pressure. The involatile residue was purified by chromatography on silica gel [elution with dichloromethane:N,N-dimethylformamide (25:1 to 20:1)]. The product fraction was concentrated to a small volume (˜3 mL) and treated with dichloromethane (5 mL) and hexanes (15 mL) to precipitate the product as a colorless amorphous solid (229 mg, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH2:11][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 1-(4-chlorophenyl)-1,3-butanedione (0.6 g) and diethyl oxalate (0.83 ml) in 1,2-dimethoxyethane (2 ml) was added to a stirred suspension of sodium hydride (0.44 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (5 ml) under nitrogen. The stirred mixture was heated under reflux for 1 hour, cooled and acidified with 2M hydrochloric acid (10 ml). The brown solid which formed was recrystallised from ethanol-water to give the title product (mp 93°-94° C.).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[Br:13]Br.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:13][C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]2[O:10][CH2:9][O:8][C:7]=2[CH:11]=1
Reactant: BrBr
Reactant: CC(C)c1ccc2c(c1)OCO2
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc2c(cc1Br)OCO2
Temperature: 10 °C
Reaction time: 8.5 h
Yield: 100.6 %

Procedure:
2.94 g of 5-isopropyl-1,3-benzodioxole was dissolved in 30 ml of carbon tetrachloride to obtain a solution. A solution of 3.15 g of bromine in 5 ml of carbon tetrachloride was dropwise added to the solution at a temperature of -5° to 5° C. The obtained mixture was stirred at 10° C. for 8.5 hours. Nitrogen gas was passed through the resulting mixture, followed by the addition of a saturated aqueous solution of sodium hydrogencarbonate and an aqueous solution of sodium thiosulfate. The obtained mixture was extracted with chloroform and the organic layer was washed with a saturated aqueous solution of common salt, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain 4.38 g of the title compound as a crude oil.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CCO.C1COCC1.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH2:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Reaction time: 12 h
Yield: 96.5 %

Procedure:
To a mixed solution of 4-amino-3-nitrobenzonitrile (8 g) in EtOH/THF (40 ml/40 ml) was added Pd—C (50% wet) (0.8 g), followed by stirring under an H2 atmosphere for 12 hours. The reaction solution was filtered through celite, and concentrated. The residue was powdered/washed with a mixed solvent of IPE and IPA, and collected by filtration to obtain 3,4-diaminobenzonitrile (6.3 g) as orange powders.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].C(Cl)(=O)C([Cl:15])=O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:15])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Product: O=C(Cl)c1ccc(Br)c(Cl)c1

Procedure:
Following the procedures described in Example 36: 4-bromo-3-chlorobenzoic acid and oxalyl chloride were reacted to provide 4-bromo-3-chloro-benzoyl chloride, which was then reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-Bromo-3-chloro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted as described in Example 36, Step 3 to provide 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester, which was then hydrolyzed to 5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid as described in Example 36, Step 4. 5-(4-Bromo-3-chloro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were reacted to provide [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester as described in Example 36, Step 5.
Reaction SMILES: [NH2:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1.[CH3:15][O-:16].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:11]([O:16][CH3:15])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[C:7]([F:13])[CH:8]=2)[N:3]=1
Reactant: Nc1nc2cc(F)c(F)cc2nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2cc(F)c(F)cc2nc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.4 %

Procedure:
To 2-amino-3-chloro-6,7-di fluoroquinoxaline (610 mg, 2.83 mmol) dissolved in tetrahydrofuran (40 ml), 25 wt % sodium methoxide (6.12 g, 28.3 mmol) in methanol was added at room temperature and stirred further at room temperature for 1.5 hour. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with ethyl acetate and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 570 mg of the titled compound (yield, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25]>ClCCl>[Cl:29][CH2:28][CH2:27][O:26][C:24]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:25]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(N)c1COc1cccn2c(C=O)c(C)nc12
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1COc1cccn2c(C=O)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzyloxy)-3-formyl-2-methylimidazo[1,2-a]pyridine (2.36 g) and 2-chloroethyl chloroformate (1.3 g) in dichloromethane (150 ml) give the title compound as a brown oil which is used directly for further reaction in 3b.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([NH:12][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1cc(-c2ccccc2)no1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cc(-c2ccccc2)no1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
To a solution of 3-phenylisoxazole-5-amine (420 mg, 2.62 mmol) and pyridine (0.636 ml, 7.87 mmol) in tetrahydrofuran (5 ml) was added 2,2,2-trichloroethyl chloroformate (0.542 ml, 3.93 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (750 mg, 85.3%) as a solid.
Reaction SMILES: I([O-])(=O)(=O)=O.Cl[O-].[Na+].[O:9]=[C:10]1[CH2:17][C:14]([CH3:16])([CH3:15])[CH2:13]C(C)=[CH:11]1.[C:19](=[O:22])([O-])[O-:20].[Na+].[Na+]>C(Cl)Cl>[O:9]=[C:10]([CH3:11])[CH2:17][C:14]([CH3:16])([CH3:15])[CH2:13][C:19]([OH:20])=[O:22]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClCCl
Product: CC(=O)CC(C)(C)CC(=O)O

Procedure:
The above oxidation procedure was repeated, except that in place of periodate there was utilized sodium hypochlorite. There was added slowly about 2700 parts of an aqueous 5% sodium hypochlorite solution to a solution of 56 parts of isophorone in about 200 parts of methylene chloride. An exothermic reaction resulted causing the methylene chloride to reflux. The organic phase was analyzed shortly after the addition was complete and it was found that all of the isophorone had reacted. The aqueous layer was made basic with sodium carbonate and the reaction mixture was filtered. The aqueous phase was washed with methylene chloride and then acidified by slowly adding it to a 2 phase mixture of concentrated hydrochloric acid and methylene chloride. The organic phase was separated and the aqueous phase was extracted with several portions of fresh methylene chloride. Upon combining the various organic layers which were dried and evaporated, there was obtained 37.7 parts of 5-keto-3,3-dimethylhexanoic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)[CH3:16].O>C1COCC1>[CH2:15]([O:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][C:4]1([CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14])[CH3:16]
Reactant: CCOC(=O)CCCCBr
Reactant: CC1CCc2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC1(C)CCc2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 0.86 g NaH in 40 mL of dry THF are added 5.0 g 2-methyl-1-tetralon in 20 mL of THF. After stirring for 30 min, 7.5 g ethyl-5-bromo-pentanoate in 20 mL of THF are added and the mixture is refluxed for 6 h. The cooled mixture is poured into water and extracted with ethylacetate. The extract is evaporated yielding crude ethyl-5-(2-Methyl-1-oxo-1,2,3,4-tetrahydro-naphthalen-2-yl)-pentanoate (6a) which is purified by column chromatography, yielding 3.6 g of pure 6a. 6a is converted to 6b in an analogous manner to that described for the conversion of 1c to 1d in example 1. 6b was obtained as an oil, MS (APCI): 274.1 (M−1).