Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8](SC)=[N:9][CH:10]=1)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>S1C=CC=C1C([O-])=O.[Cu+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(SC)nc1
Reactant: COc1cccc(B(O)O)c1
Agent: [Cu+]
Agent: [Pd]
Agent: O=C([O-])c1cccs1
Product: COC(=O)c1cnc(-c2cccc(OC)c2)nc1
Temperature: 85 °C
Yield: 35.6 %

Procedure:
2-Methylsulfanyl-pyrimidine-5-carboxylicacid methyl ester (323 mg, 1.75 mmol), Copper(I) thiophene-2-carboxylate (501 mg, 2.63 mmol), tetrakis(triphenylphosphine) palladium(0) (202 mg, 0.175 mmol) and 3-methoxyphenylboronic acid (400 mg, 2.63 mmol) are taken in a glass tube, evacuated, refilled with N2, added anhydrous THF (6 mL) and is heated overnight at 85° C. after closing with a cap. The reaction is cooled to rt, diluted with EtOAc and ammonium hydroxide is added. The organic layer is seperated, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by flash silica gel chromatography to afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid methyl ester (152 mg) as a powder. MS: 245 (M+H); 1H NMR (CDCl3): δ 4.00 (s, 3H), 4.82 (d, 2H), 7.55 (m, 2H), 8.46 (m, 1H), 8.53 (s, 1H), 9.33 (s, 2H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].ClC(O[C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=1[CH3:17])=O>>[CH3:17][C:10]1[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=1[Cl:1]
Reactant: [Cl-]
Reactant: Cc1cc(C)c(OC(=O)Cl)c(C)c1
Agent: [Al+3]
Product: Cc1cc(C)c(Cl)c(C)c1
Temperature: 180 °C
Yield: 72 %

Procedure:
0.5 g of anhydrous aluminium chloride was added to 50 g of 2,4,6-trimethylphenyl chloroformate and the mixture was heated at 180° C. for 1.5 hours at normal pressure. The reaction mixture was then cooled and worked up as described in Example 1. 2,4,6-Trimethylchlorobenzene was obtained in a yield of 72%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])(C)(C)C.CN(C)[CH:22]=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncc(Cl)cc1C=O
Temperature: -78 °C
Yield: 56.1 %

Procedure:
To a chilled (−78° C.), stirred solution of the amide (Step 1) (5.0 g, 0.024 mole) in tetrahydrofuran (100 mL) was added t-butyl lithium (1.7M in pentane, 32.4 mL, 0.055 mole) dropwise. Dimethylformamide (2.3 mL, 0.03 mole) was added dropwise at −78° C. over 3 hours and the mixture allowed to warm room temperature. The reaction was quenched with ice water (200 mL) and extracted with ethyl acetate. The resulting organic phase was dried over MgSO4 and was concentrated in vacuo to a volume of 20 mL. A white solid precipitated which was collected by filtration yielding the formylated product (3.24 g, 56%): mp 168.7–170.8° C. 1H NMR (CDCl3/300 MHz) 10.60 (br s, 1H), 9.88 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 1.28 (s, 9H). Anal. Calc'd for C11H13N2O2Cl: C, 54.89; H, 5.44; N, 11.64 Found: C, 54.87; H, 5.42; N, 11.40.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]=[C:9]([NH:15][CH2:16][CH3:17])[C:8]([CH:18]=[O:19])=[CH:7]2)[CH3:2].[BH4-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]=[C:9]([NH:15][CH2:16][CH3:17])[C:8]([CH2:18][OH:19])=[CH:7]2)[CH3:2]
Reactant: CCNc1nc2cc(F)c(OCC)cc2cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1nc2cc(F)c(OCC)cc2cc1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 6-ethoxy-2-(ethylamino)-7-fluoroquinoline-3-carbaldehyde SMA 44102 (63 mg, 0.24 mmol) in THF (10 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (11 mg, 0.29 mmol) and the reaction mixture was stirred for 3 h at RT, then cooled down to 0° C. and quenched with a 6 N aq. HCl solution (5 mL). The mixture was stirred for 10 min at RT before basification to pH=12 with a 10 N aq. NaOH. THF was then removed at 40° C. and the residue was extracted with CH2Cl2 (30 mL). The organic phase was isolated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum to give (6-ethoxy-2-(ethylamino)-7-fluoroquinolin-3-yl)methanol SMA 44104 as a pink solid (61 mg, 96% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([N:13]3[C:17]([CH3:19])([CH3:18])[CH2:16][O:15][C:14]3=[O:20])[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C)C=O>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:18][C:17]1([CH3:19])[CH2:16][O:15][C:14](=[O:20])[N:13]1[C:11]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=2)[N:12]=1
Reactant: CN(C)C=O
Reactant: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2)ns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(C#N)cc2)ns1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 84 %

Procedure:
3-[3-(4-bromophenyl)-1,2,4-thiadiazol-5-yl]-4,4-dimethyl-1,3-oxazolidin-2-one (0.67 g, 1.9 mmol), prepared in step 4 of Example 93, was dissolved in dimethylformamide (19 mL). Zinc cyanide (0.132 g, 1.14 mmol) was added, the mixture was purged with nitrogen for 15 min, and then tetrakis(triphenylphosphine)palladium (0.11 g, 0.095 mmol) was added. The mixture was heated to 120° C. for 2 h, additional tetrakis(triphenylphosphine)palladium (0.11 g, 0.095 mmol) was added and stirring was continued for 45 min. The mixture was cooled, diluted with ethyl acetate, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (10% acetone in hexane) afforded the title compound (0.48 g, 84%) as a white solid. Analytical HPLC: HPLC purity 100% at 210-370 nm, 9.7 min; 100% at 248 nm, 9.7 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C=CC=CC=1.[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl>[CH3:1][N:2]1[CH2:24][CH2:23][C:5]2[N:6]([CH2:14][CH:15]([NH:16][C:31](=[O:33])[CH3:32])[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc2c(c1)c1c(n2CC(N)c2ccncc2)CCN(C)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.4 %

Procedure:
To a solution of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethanamine (500 mg, 1.56 mmol) in DCM (5 mL) was added pyridine (185 mg, 2.3 mmol). After stirring for 5 min at RT, a solution of acetyl chloride (147.2 mg, 1.88 mmol) in DCM (0.5 mL) was added into the reaction mixture, which was stirred at RT for 16 h. The reaction mixture was diluted with DCM and washed with saturated aq NaHCO3 solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was triturated with ether to yield N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-(pyridin-4-yl)ethyl)acetamide (500 mg). 1H NMR (CDCl3, Free base) δ (ppm): 8.42 (d, 2H), 7.25 (s, 1H), 7.15 (d, 1H), 6.92 (d, 2H), 6.9 (d, 1H), 6.2 (d, 1H), 5.3 (q, 1H), 4.4 (dd, 1H), 4.25 (dd, 1H), 3.58 (dd, 2H), 2.6 (m, 2H), 2.55 (s, 3H), 2.43 (s, 3H), 2.3 (m, 2H), 2.03 (s, 3H). Separation by chiral HPLC provided enantiomers II-1a-b.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])([O-])=O>CCO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1cccc(N)c1
Reaction time: 4 h
Yield: 79.6 %

Procedure:
1H (CDCl3, 400 MHz) δ 1.4 (9H, s), 7.6 (1H, dd), 8.3 (1H, d), 8.4 (1H, d), 8.8 (1H, s) ppm. A solution of t-butyl 3-nitrobenzoate (5.8 g, 26 mmol) in EtOH (260 mL) was stirred with 10% palladium-carbon (1.0 g) under an atmosphere of H2 (60 psi) at 23° C. After 4 h, the mixture was filtered and evaporated in vacuo to give t-butyl 3-aminobenzoate (4.0 g, 20.7 mmol) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[NH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([N:7]2[C:3]([N:2]([CH3:12])[CH3:1])=[CH:4][C:5]([C:8]([F:11])([F:9])[F:10])=[N:6]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: CN(C)c1cc(C(F)(F)F)n[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CN(C)c1cc(C(F)(F)F)nn1-c1ccc([N+](=O)[O-])cc1

Procedure:
5-Dimethylamino-3-trifluoromethylpyrazole (2.9 mmol) was reacted with 4-nitrofluorobenzene (2.9 mmol), as described in Method L, to give 1-(4′-nitrophenyl)-5-dimethylamino-3-trifluoromethylpyrazole which was purified by chromatography over silica gel (hexanes/EtOAc, 8:2) (0.423 g, 46%). The nitrophenylpyrazole (1.35 mmol) was reduced by phase transfer hydrogenation, described generally in Method L, to give 1(4′-aminophenyl)-5-dimethylamino-3-trifluoromethylpyrazole as an off-white solid (0.321 g, 84%).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][C:14]=1[C:21]([F:24])([F:23])[F:22]>CCOC(C)=O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=3[N:3]=2)=[CH:15][C:14]=1[C:21]([F:22])([F:23])[F:24]
Reactant: Cn1c(Cl)nc2ccccc21
Reactant: NCc1ccc(F)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Product: Cn1c(NCc2ccc(F)c(C(F)(F)F)c2)nc2ccccc21
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-1-methyl-1H-benzimidazole (915 mg, 5.5 mmol) and 4-fluoro-3-trifluoromethyl-benzylamine (4.24 g, 22.0 mmol) was stirred at 130° C. overnight. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by recrystallization from hexane to yield (4-fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amine MS 324 (M+1)+
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH3:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:21][C:22]1[CH:27]=[C:26]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Cc1cccc(B(O)O)c1
Product: COc1ccc2c(-c3cccc(C)c3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-methyl-phenylboronic acid to give [1-(3-methyl-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 345(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[Cl-].[NH4+].C(O)C>O>[NH2:1][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(Nc2nccs2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1Nc1ccc(Nc2nccs2)cc1

Procedure:
A mixture of 2-nitro-N-(4-(2-thiazolylamino)phenyl)aniline (1.2 g, 3.8 mmol), sodium sulfide nona hydrate (4.61, 19.2 mmol), ammonium chloride (1.03 g, 19.2 mmol) and ethanol (40 ml) was stirred at reflux for 40 h. Water (50 ml) was added, the mixture was stirred an d filtered. Yield 0.49 g, 46%. M.p. 184-186° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C.O>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:9]=[CH:10][C:5]=2[N:4]=[CH:3]1
Reactant: CCOC(=O)CBr
Reactant: Cn1cnc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)COc1ccc2ncn(C)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.3 %

Procedure:
The mixture of 1-methyl-1H-benzo[d]imidazol-6-ol (600 mg, 4.03 mmol), BrCH2COOEt (372 mg, 4.03 mmol) and K2CO3 (1.1 g, 8.06 mmol) in DMF (8 mL) was stirred at room temperature for 16 h. DCM (100 mL) and water (100 mL) was then added to the reaction and the organic layer washed with water (50 mL), brine (50 mL) and dried over Na2SO4 before filtering and concentration to give the crude desired product (560 mg, Yield 60%). LCMS (m/z): 235.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:13])=[O:26])[CH:10]=2)[N:5]=[C:4]([C:14]([F:15])([F:17])[F:16])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Yield: 48.5 %

Procedure:
A solution of 4-chloro-6-methylthio-2-trifluoromethylquinazoline (0.4 g, 1.4 mmol) and m-chloroperbenzoic acid (0.3 g, 1.4 mmol) in chloroform (14 mL) was stirred at 0° C. for 0.5 h. The reaction mixture was washed with saturated sodium bisulfite solution, 1M sodium bicarbonate solution, and brine. The solution was dried (Na2SO4), filtered, and concentrated to give the title compound (0.2 g, 49%); m.p. 105-107° C.
Reaction SMILES: C(N1CCN(C(=O)C(C2C3C(=C(OC)N=CC=3OC)NC=2)=O)CC1)(=[O:8])C1C=CC=CC=1.C(N1CCN([C:46](=[O:58])[C:47]([C:49]2[C:57]3[C:52](=[N:53][CH:54]=[CH:55][CH:56]=3)[NH:51][CH:50]=2)=[O:48])[C@H](C)C1)(=O)C1C=CC=CC=1.COC1C=NC(OC)=C2C=1C(C(=O)C([O-])=O)=CN2.[K+:78]>>[NH:51]1[C:52]2[C:57](=[CH:56][CH:55]=[CH:54][N:53]=2)[C:49]([C:47](=[O:48])[C:46]([O-:58])=[O:8])=[CH:50]1.[K+:78]
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)CC3)c[nH]c12
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)c1c[nH]c2ncccc12
Agent: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12
Agent: [K+]
Product: O=C([O-])C(=O)c1c[nH]c2ncccc12

Procedure:
Compound IVa, N-(benzoyl)-N′-[(4,7-dimethoxy-6-azaindol-3-yl)-oxoacetyl]piperazine, was prepared by the same method used to prepare compound 5a but the starting material was Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate. The compound was purified by silica gel chromatography using EtOAc as the eluting solvent to give a white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.0 (s, 1H), 8.15 (s, 1H), 7.40 (m, 6H), 4.00 (s, 3H), 3.83 (s, 3H), 3.63-3.34 (m, 8H); 13C NMR (125 MHz, DMSO-d6) δ 185.5, 169.3, 166.5, 146.2, 145.7, 136.6, 135.3, 129.6, 128.4, 126.9, 122.2, 122.1, 119.2, 114.4, 56.8, 52.9, 45.5, 39.9. MS m/z: (M+H)+ calcd for C22H23N4O5: 423.17; found 423.19. HPLC retention time: 1.33 minutes (column B). Anal. Calcd. For C22H21N4O5: C, 62.7; H, 5.02; N, 13.29. Found. C, 61.92; H, 5.41; 13.01. Melting Point: 229.5-232° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(=O)C.[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.ClCCl>[F:11][C:12]1[CH:13]=[C:14]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:33]([CH2:36][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:32][C:22]=2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][N:29]=[N:28][CH:27]=2)=[O:24])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: C1COCCN1
Reactant: O=Cc1ccc(OCc2ccc(F)c(F)c2)c(C(=O)Nc2ccnnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(Nc1ccnnc1)c1cc(CN2CCOCC2)ccc1OCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Morpholine (0.05 ml, 0.54 mmol) and acetic acid (0.03 ml, 0.54 mmol) were added to a solution of 2-{[(3,4-difluorophenyl)methyl]oxy}-5-formyl-N-4-pyridazinylbenzamide (may be prepared by Example 79; 200 mg, 0.54 mmol) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Sodium triacetoxyborohydride (172 mg, 0.81 mmol) was then added and the mixture was stirred at 50° C. overnight. Saturated sodium hydrogencarbonate (10 ml) was added and the mixture stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml). The organics were combined and evaporated under reduced pressure. The residue was purified by MDAP to yield the title compound. 147 mg.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccc(F)cc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(F)cc1)CS(=O)(=O)/C=C/c1ccc(F)cc1
Yield: 74 %

Procedure:
A solution of 4-fluorobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 74% yield. m.p. 183-185° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[C:16](=[O:27])[NH:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[O:20][N:19]=1)=O)(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:1].[C:23]([C:21]1[O:20][N:19]=[C:18]([NH:17][C:16]([C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:9]2)=[O:27])[CH:22]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCCCC[C@H]1C(=O)Nc1cc(C(C)(C)C)on1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCCN2)no1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
HCl in dioxane (10.0 mL) is added slowly at 0° C. to a solution of (S)-2-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-perhydro-azepine-1-carboxylic acid tert-butyl ester (0.70 g, 1.90 mmol) in DCM (15.0 mL). After stirring the reaction mixture at 0° C. for 3 hours, the solvent is removed under reduced pressure to afford the title product that is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][C:5](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3]1>CO.[Pd]>[CH3:1][C:2]1([CH3:14])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C=C1C=CC(C)(C)CC1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CC1CCC(C)(C)CC1
Reaction time: 48 h
Yield: 88.8 %

Procedure:
A solution of ethyl 2-(4,4-dimethyl-2-cyclohexene-1-ylidene)acetate (Preparation 13, 4.0 g, 21 mmol) in methanol (40 ml) was treated with 5% palladium on carbon, and the suspension was placed under an atmosphere of hydrogen (60 p.s.i.) at room temperature for 48 h. The mixture was filtered through a short pad of silica (40 g) and the filtrate was concentrated in vacuo to afford the title compound as a colourless oil (3.7 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[CH3:1][C:2]1[C:3]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1Nc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cccnc1Nc1ccc(N)cc1

Procedure:
The 3-methyl-N-(4-nitrophenyl)pyrid-2-amine (7) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([OH:27])=[CH:10][CH:11]=3)[N:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:34][C:35]([F:50])([C:46]([F:49])([F:48])[F:47])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[S:38](F)(=[O:40])=[O:39]>CN(C=O)C>[F:43][C:37]([F:42])([S:38]([O:27][C:9]1[CH:8]=[C:7]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([O:25][CH3:26])([CH3:24])[CH3:23])[CH:18]=3)[O:13][C:12]2=[CH:11][CH:10]=1)(=[O:40])=[O:39])[C:36]([F:44])([F:45])[C:35]([F:50])([F:34])[C:46]([F:49])([F:48])[F:47]
Reactant: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(O)ccc1O2
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@@]1(COC(N)=N1)c1cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc1O2
Reaction time: 0.17 h

Procedure:
A 25-mL flask was charged with (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (577.53 mg, 1.581 mmol), cesium carbonate (566 mg, 1.739 mmol), and DMF (7903 μL). The resulting mixture was stirred for 10 min, then the vial was submerged in an ice-bath for 10 min. nonafluorobutanesulfonyl fluoride (306 μL, 1.739 mmol) was added dropwise over 2 minutes. The mixture was stirred for 2 hours, then quenched with saturated aqueous ammonium chloride (10 mL), and partitioned between water (15 mL) and EtOAc (15 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on an 80-g Redi-Sep column, eluting with 0-50% of a 90:10 mixture of DCM/MeOH in DCM to give (R)-2′-amino-3-(3-methoxy-3-methylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate as a white solid.