Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]1([CH3:23])[CH2:16][C:15]([CH3:18])([CH3:17])[C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([C:19](=O)[CH3:20])[CH:13]=2)[O:8]1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.Cl>C1COCC1.CCCCCC.O>[CH3:6][C:7]1([CH3:23])[CH2:16][C:15]([CH3:17])([CH3:18])[C:14]2[C:9](=[CH:10][C:11]([CH3:22])=[C:12]([C:19]#[CH:20])[CH:13]=2)[O:8]1
Reactant: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: Cl
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: O
Product: C#Cc1cc2c(cc1C)OC(C)(C)CC2(C)C
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 455 mg (4.5 mmol) of disopropylamine in 5 ml of dry THF at -78 degrees C. was added under argon 3 ml of 1.5M n-BuLi in hexane. The mixture was stirred at -78 degrees C. for a further 45 min and then treated with a solution of 1.07 g (4.3 mmol) of 2,2,4,4,7-pentamethyl-6-acetyl-chroman (Compound 47) in 4 ml of dry THF. The reaction mixture was stirred at -78 degrees C. for 1 h and then treated with 776 mg (4.5 mmol) of diethyl chlorophosphate. The mixture was allowed to warm to room temperature and then transferred by a double-ended needle into a solution of lithium diisopropyl amide in 10 ml dry THF at -78 degrees C. which was prepared as described above using 910 mg (9.0 mmol) of diisopropylamine and 6 ml of 1.5M (9.0 mmol) n-BuLi in hexane. The mixture was stirred at room temperature fur 15 h and then poured into 10 ml of iced water. The mixture was acidified to pH=2 with 10% HCl solution. The organic layer was separated and the aqueous layer extracted with pentane. The organic extracts were combined and washed successively with water, saturated NaHCO3 and saturated NaCl solutions and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by Kugelrohr distillation (82 degrees C., 0.3 mm) to give the title compound as a pale yellow oil. PHR (CDCl3): & 1.32 (6H, s), 1.34 (6H, s), 1.81 (2H, s), 2.36 (3H, s), 3.18 (1H, s), 6.64 (1H, s), 7.40 1H (s). MS exact mass, m/e 228.1520 (calcd. for C16H20O, 228.1514).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[CH:23]=[CH:24][C:25]=1[F:26]>CC(O)C>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Solvent: CC(C)O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
An amount of 4-chloro-7-methoxy-6-nitro-quinoline-3-carbonitrile (7.1 g, 26.9 mmol), and 3-chloro-4-fluoro-phenylamine (3.9 g, 26.8 mmol), were stirred in 2-propanol (70 mL), and heated at reflux for 2 hours. The mixture was cooled to room temperature and stirred for an additional 20 hours. The reaction mixture was evaporated to dryness, stirred with ethyl acetate and saturated sodium bicarbonate solution. After separation of the layers, the organic layer was washed with saturated brine solution and dried on magnesium sulfate, to give a dark green powder (9.9 g, 99%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21](Br)[CH:20]=2)([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)[N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[N:32][CH:33]=1>CN(C=O)C.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[N:12]=[C:11]([CH2:17][CH3:18])[CH:10]=2)([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:30]3[CH:31]=[N:32][CH:33]=[C:28]([F:27])[CH:29]=3)[CH:20]=2)[N:3]=1
Reactant: CCc1cc(C2(c3ccc(F)c(Br)c3)N=C(N)N(C)C2=O)cc(CC)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(F)c1
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C2(c3ccc(F)c(-c4cncc(F)c4)c3)N=C(N)N(C)C2=O)cc(CC)n1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
A mixture of 2-amino-5-(3-bromo-4-fluorophenyl]-5-(2,6-diethyl-pyridin-4-yl)-3-methyl-3,5-dihydro-imidazol-4-one (0.12 g, 0.286 mmol), 5-fluoropyridin-3-yl(tributly)tin (0.166 g, 0.43 mmol) and bis(triphenylphosphino)palladium(II) chloride (0.016 g, 0.023 mmol) in DMF (5 mL) was degassed and heated at 150° C. for 0.5 h. The mixture was cooled to room temperature and diluted with ethyl acetate (50 mL) and 2% aqueous lithium chloride (20 mL). The organic layer was separated, washed with 2% aqueous lithium chloride, dried over sodium sulfate, filtered, and concentrated. Purification of the resultant residue by flash chromatography (silica, 97:3:0.25 methylene chloride/methanol/concentrated ammonium hydroxide) afforded the title product (0.085 g, 68%) as a white solid, mp 155-157° C.; 1H NMR (300 MHz, CD3OD) 8.55 (d, J=1.5 Hz, 1H), 8.49 (d, J=2.7 Hz, 1H), 7.82 (d, J=9.6 Hz, 1H), 7.60-7.57 (m, 2H), 7.27 (dd, J=10.2, 8.7 Hz, 1H), 7.15 (s, 2H), 3.13 (s, 3H), 2.74 (q, J=7.5 Hz, 4H), 1.23 (t, J=7.5 Hz, 6H); IR (ATR) 3064, 2969, 2935, 1733, 1670, 1597, 1459, 1412, 1328, 1228, 989, 881, 783, 702 cm−1; ESI MS m/z 436 [C24H23F2N5O+H]+. Anal. Calcd for C24H23F2N5O: C, 66.19; H, 5.32; N, 16.08.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:12])=[CH:9][S:8][C:7]=1[NH:13]C(OC(C)(C)C)=O)=[O:5])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[NH4+].[Cl-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]#[CH:12])=[CH:9][S:8][C:7]=1[NH2:13])=[O:5])[CH3:2]
Reactant: C#Cc1csc(NC(=O)OC(C)(C)C)c1C(=O)OCC
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C#Cc1csc(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
2-t-Butoxycarbonylamino-4-ethynyl-thiophene-3-carboxylic acid ethyl ester (5.86 g, 19.85 mmol) was dissolved in anhydrous CH2Cl2 (125 mL). This was treated with 2,6-lutidine (4.62 mL, 39.70 mmol) followed by dropwise addition of t-butyldimethylsilyl trifluoromethanesulfonate (6.84 mL, 29.77 mmol). This was stirred at room temperature for 2 hr. Next it was poured into sat. NH4Cl (100 mL) and then extracted with EtOAc (3×100 mL). The combined extracts were washed with H2O (1×100 mL), and brine (1×100 mL). The organic layer was dried (Na2SO4), filtered and the solvent removed in vacuo. The residue was dissolved in anhydrous THF (85 mL) and treated with tetrabutylammonium fluoride (19.85 mL, 19.85 mmol, 1 M in THF). The reaction was then stirred at room temperature for 1 hr. The reaction was poured into sat. NH4Cl (100 mL) and then extracted with EtOAc (3×100 mL). The combined extracts were washed with H2O (1×100 mL), and brine (1×100 mL). The extracts were dried (Na2SO4), filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (SiO2, 1 EtOAc/9 hexanes) to afford the title compound (3.0 g, 77%). MS m/e (CI) 196.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 1.38 (t, 2H), 3.07 (s, 1H), 4.32 (q, 2H), 6.04 (s, 2H), 6.54 (s, 1H), 7.26 (s, 1H); MS m/e (CI) 196.0 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[C:15]2[C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=O)C.C(=O)(O)[O-].[Na+]>Cl>[NH2:4][C:5]1[C:15]2[C:14](=[O:16])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[CH2:11][O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c1C(=O)c1ccccc1CO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1cccc2c1C(=O)c1ccccc1CO2
Yield: 81 %

Procedure:
In concentrated hydrochloric acid (10 ml), 1-acetamido-6,11-dihydrodibenz[b,e]oxepin-11-one obtained in Reference Example 3(0.25 g, 0.94 mmol) was heated under reflux for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate (25 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure to give 1-amino-6,11-dihydrodibenz[b,e]oxepin-11-one as a yellow solid (0.17 g, 81%).
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[N:10]=[C:9]([F:11])[CH:8]=[C:7](F)[N:6]=1>CO>[F:4][C:5]1[N:10]=[C:9]([F:11])[CH:8]=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: Fc1cc(F)nc(F)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(F)nc(F)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
335.8 g (1.865 mol) of 30% strength sodium methylate (in methanol) were added at -20° C. to a mixture of 250 g (1.865 mol) of 2,4,6-trifluoropyrimidine in 1.4 1 of methanol within 45 minutes, and the mixture was stirred at this temperature for a further 30 minutes. The reaction mixture was then allowed to warm to 25° C. and concentrated to about 1/5 of its volume.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][CH2:6][CH2:7][O:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38][CH3:39])[CH2:12][CH2:11][CH2:10]1>C(O)C>[CH3:1][NH:2][C:3]([NH:5][CH2:6][CH2:7][O:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38][CH3:39])[CH2:12][CH2:11][CH2:10]1)=[S:4]
Reactant: CN=C=S
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(OCCN)c2cc(Cl)ccc21
Solvent: CCO
Product: CNC(=S)NCCOC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2OC)c2ccc(Cl)cc21

Procedure:
0.13 ml of methyl isothiocyanate was added to 20 ml of a suspension of 0.5 g of 5-(2-aminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine in ethanol. The mixture was refluxed for 3 hours. The reaction mixture was subjected to vacuum distillation to remove ethanol. The residue was mixed with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and then subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography (elutant: dichloromethane/methanol =50/1) to obtain 0.46 g of 5-(2-methylaminothiocarbonylaminoethoxy)-7-chloro-1-[2-methoxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([Br:11])[C:5]=1[NH2:12].[OH-].[Na+].C(OCC)C.O>CO>[NH2:12][C:5]1[C:6]([Br:11])=[N:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:13])=[O:2]
Reactant: COC(=O)c1cc(Cl)nc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: Nc1c(C(=O)O)cc(Cl)nc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-2-bromo-6-chloroisonicotinic acid methyl ester (260 mg) (example 3, step 5) was dissolved in methanol (2 mL), 2N aqueous sodium hydroxide solution (2 mL) was added and the reaction mixture was stirred for 2 hours at reflux. After cooling to room temperature, diethyl ether and water were added and the layers were separated. The aqueous layer was washed with diethyl ether and acidified by addition of 2N hydrochloric acid. The formed precipitate was extracted with MTB-ether (3×), the combined organic layer was washed with brine, dried over MgSO4 and concentrated in vacuum to afford 246 mg of
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](OCCCC)=[O:14].Cl>O1CCCC1.O>[F:9][C:10]1([F:20])[CH2:12][CH:11]1[C:13](=[O:14])[CH2:2][C:1]#[N:3]
Reactant: CC#N
Reactant: CCCCOC(=O)C1CC1(F)F
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)C1CC1(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of acetonitrile (0.97 mL, 18.5 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. and treated with n-butyllithium in hexanes (11.7 mL, 19.0 mmol) over 5 minutes. The reaction mixture was stirred for 30 minutes, and then n-butyl 2,2-difluorocyclopropane carboxylate (3.0 g, 16.8 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into water (25 mL) and acidified by addition of 10% aqueous hydrochloric acid. The organic layers were extracted into diethyl ether (3×30 mL), dried (MgSO4) and concentrated to afford crude 3-(2,2-difluorocyclopropyl)-3-oxo-propionitrile (2 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:21])[C:7](=[O:20])[C:8]([F:19])([F:18])[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([CH:29]=1)[NH2:28]>Cl.CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([F:19])([F:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[CH:4]=[N:3][C:2]([NH:28][C:27]4[CH:29]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:30])=[N:12][C:11]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1ccc(F)cc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one (100 mg, 0.32 mmol), 5-fluoro-2-methylaniline (60 mg, 0.48 mmol), i-PrOH (2 mL) and conc. HCl (5 drops) were heated to 100° C. overnight to give the title compound. The final compound was purified by reverse phase HPLC and basified to give the free base (50 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.40-1.96 (m, 9 H) 2.22 (s, 3 H) 3.99 (t, J=14 Hz, 2 H) 4.62 (t, J=8 Hz, 1 H) 6.81 (td, J=8, 3 Hz, 1 H) 7.19 (t, J=8 Hz, 1 H) 7.58 (dd, J=12, 3 Hz, 1 H) 8.20 (s, 1 H) 8.57 (s, 1 H). [M+H] calc'd for C20H22F3N5O, 406; found 406.
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([C:26](OCC)=[O:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:7][C:6]=1[C:15]1[C:16]2[CH:25]=[C:24]([CH2:26][OH:27])[NH:23][C:17]=2[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=1
Reactant: CCOC(=O)c1cc2c(-c3cc(S(C)(=O)=O)ccc3Oc3ccc(F)cc3F)cn(C)c(=O)c2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)c2cc(CO)[nH]c2c1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.3 %

Procedure:
To a suspension of Example 252f (0.20 g, 0.40 mmol) in tetrahydrofuran (5 mL) stirring at 0° C. was added lithium aluminum hydride (1M in tetrahydrofuran, 0.398 mL, 0.398 mmol) and the mixture was stirred at 0° C. for two hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (30 mL) and water (20 mL). The mixture was filtered to remove the undissolved materials. The aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was triturated with dichloromethane and the resulting solid was filtered and dried to provide the title compound (0.10 g, 55% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.86 (dd, J=2.4, 6.4 Hz, 1H), 7.56-7.38 (m, 3H), 7.20-7.15 (m, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.18 (s, 1H), 5.11 (t, J=5.6 Hz, 1H), 4.50 (d, J=5.6 Hz, 2H), 3.57 (s, 3H), 3.16 (s, 3H). MS (ESI+) m/z 461.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O.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>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][S:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][C:29]=4[F:28])[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CS1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cnccc1F
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: NC1=N[C@@]2(CS1)c1cc(-c3cnccc3F)ccc1Oc1ncc(Br)cc12
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A pressure reaction vessel was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (1.2 g, 2.53 mmol, prepared as described in Method BB26), potassium carbonate (1.75 g, 12.66 mmol), 4-fluoropyridin-3-ylboronic acid (0.71 g, 5.06 mmol), tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol), dioxane (16.87 mL) and water (8.44 mL). The reaction was stirred and heated at 100° C. for 45 min. After cooling for rt, LCMS showed about 50% conversion. More Pd(PPh3)4 (30 mg) and 4-fluoropyridin-3-ylboronic acid (300 mg) were added and reaction was heated at 100° C. for another 30 min. After cooling for rt, the organic layer was separated with a separatory funnel, dried over sodium sulfate, filtered, and concentrated to afford yellow oil which was purified with reverse phase HPLC. Fractions containing product were concentrated and saturated aq. NaHCO3 (25 mL) was added. A white solid precipitated out of solution which was filtered off and dried to afford a white solid, (S)-3-bromo-7-(4-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine (0.51 g, 1.15 mmol, 46% yield). MS m/z=443.0 [M+H]+. Calc'd for C19H12BrFN4OS: 441.99.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][NH:16][CH2:17][C:18]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:3].C(N(CC)CC)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:11])[CH3:12])[C:5]=1[NH:13][C:14](=[O:29])[CH2:15][N:16]([S:43]([C:40]1[CH:41]=[CH:42][C:37]([CH3:47])=[CH:38][CH:39]=1)(=[O:45])=[O:44])[CH2:17][C:18]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH3:1]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC1(c2ccccc2)CCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)Nc2c(C(C)C)cccc2C(C)C)CC2(c3ccccc3)CCCC2)cc1
Reaction time: 120 h

Procedure:
To a mixture of the product of Example 6 (0.45 g) and excess triethylamine at room temperature was added 0.22 g p-toluene sulfonyl chloride. This mixture was diluted with ethyl acetate, concentrated, and triethylamine and ethyl acetate added a second time. The reaction mixture was then concentrated to a brown oil. After sitting 5 days at room temperature, the oil was taken up in ethyl acetate, washed with NaHCO3 and NaCl solutions, dried over MgSO4, filtered, and concentrated to an oil. The oil was purified by chromatography on silica gel using hexane/EtoAc, 8/21 as eluant. The appropriate fractions were concentrated to an oil which crystallized upon trituration with hexane. 0.44 g (69%). NMR (CDCl3) δ 1.17 (6H, d), δ 1.64-1.82 (4H, m), δ 2.03 (4H, m), δ 2.42 (3H, s), δ 2.97 (2H, m), δ 3.42 (2H, s), δ 3.55 (2H, s), δ 7.13-7.65 (12H, m). IR (KBr) 3370, 2965, 2870, 1673, 1497, 1328, 1158, 1092, 755, 550 cm-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[NH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:3]([CH:2]=[O:1])[C:4]=2[CH:5]=[CH:6]1
Reactant: OCc1cccc2[nH]ccc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Tetrapropylammonium perruthenate (0.3 g, 0.85 mmol) was added in portions to a mixture of alcohol product from Step A (2.5 g, 17 mmol), N-methylmorpholine N-oxide (3.0 g, 25 mmol) and 4 Å molecular sieves (3.0 g) in anhydrous methylene chloride (30 mL) at room temperature. The mixture was stirred at room temperature under nitrogen for 1 h and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by chromatography (SiO2, CH2Cl2) to provide indole-4-aldehyde as a white powder (2.0 g, 80%): 1H NMR (300 MHz, CDCl3) δ10.2 (s, 1H), 8.52 (br s, 1H), 7.64-7.69 (m, 2H), 7.31-7.44 (m, 3H); CI MS m/z=146 [C9H7NO+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:47]=[CH:46][C:8]([N:9]([C:13](=[O:45])[C@H:14]([OH:44])[C@@H:15]([OH:43])[C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:41]#[N:42])=[C:23]([CH2:25][N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=2)=[O:17])[CH2:10][CH2:11]Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C>CC(O)(C)C.CS(C)=O>[C:1]([NH:4][C:5]1[CH:47]=[CH:46][C:8]([N:9]2[CH2:10][CH2:11][O:44][C@H:14]([C@@H:15]([OH:43])[C:16]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:41]#[N:42])=[C:23]([CH2:25][N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=3)=[O:17])[C:13]2=[O:45])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(N(CCCl)C(=O)[C@H](O)[C@@H](O)C(=O)Nc2ccc(C#N)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(N2CCO[C@H]([C@@H](O)C(=O)Nc3ccc(C#N)c(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3)C2=O)cc1
Yield: 35.9 %

Procedure:
According to the Step 7-5 in synthetic method for EXAMPLE 7, compound 39-4 (4.3 g) and DMF were used instead of 7-4 and t-BuOH-DMSO to obtain compound 39-5 (1.46 g) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]=[CH:7][C:6]2=[O:14].Br[CH:18]1[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]1Br.BrC1C2=CC=CC=C2C1I.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:12]=[CH:11][C:10]2[C:9](=[O:13])[C:8]3[C:7](=[CH:19][C:20]4[C:21]([CH:18]=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:6](=[O:14])[C:5]=2[CH:4]=1
Reactant: O=C1C=CC(=O)c2cc(C(F)(F)F)ccc21
Reactant: BrC1c2ccccc2C1Br
Agent: BrC1c2ccccc2C1I
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(C(F)(F)F)cc2C(=O)c2cc3ccccc3cc21
Reaction time: 16 h

Procedure:
A mixture of 5.65 g (25 mmol) of 6-(trifluoromethyl)-1,4-naphthoquinone, 9.82 g (ca. 37 mmol) of 1,2-dibromobenzocyclobutene (contaminated with a small amount of 2-bromo-1-iodobenzocyclobutene) and 100 ml of xylene is kept for 16 hours under reflux using a water separator. The mixture is cooled and the precipitate is isolated by filtration and washed with xylene. The yield is 5.82 g (71%); m.p. 253°-254° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:11]O)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].S(Cl)([Cl:15])=O>>[CH3:1][C:2]1[C:3]([CH2:11][Cl:15])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: COc1c(C)cnc(CO)c1C
Product: COc1c(C)cnc(CCl)c1C

Procedure:
If desired, the 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine prepared in this way is then reacted with thionyl chloride to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine.