Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1([CH3:22])[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH:12][C:11]1=[O:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)C(C)C)(C)C.[C:32](Cl)([Cl:34])=[O:33].C1(C)C=CC=CC=1.Cl>ClCCl>[C:1]([O:8][CH2:9][C:10]1([CH3:22])[CH2:14][N:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([C:32]([Cl:34])=[O:33])[C:11]1=[O:21])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCCCCC(=O)OCC1(C)CN(c2ccccc2)NC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCCCC(=O)OCC1(C)CN(c2ccccc2)N(C(=O)Cl)C1=O
Reaction time: 2 h

Procedure:
A solution of hexanoic acid, 4-methyl-3-oxo-1-phenyl-pyrazolidin-4-ylmethyl ester (0.74 g, 0.0024 mol) and N,N-diisopropylethylamine (0.36 g, 0.0028 mol) in dichloromethane (8 ml) was added dropwise over 30 min to a stirred solution of a 20% phosgene in toluene solution (1.5 ml, 0.0028 mol) and dichloromethane (8 ml) under an atmosphere of argon. The reaction mixture was cooled using an acetone-solid carbon dioxide bath such that the initial temperature was −30° C. and the reaction remained below −20° C. during the addition. The reaction was stirred for 2 hr at between −30° C. and −20° C. Dilute aqueous hydrochloric acid (8 ml) was added to the cold reaction. The organic layer was washed with saturated aqueous sodium chloride (8 ml), dried over magnesium sulfate, and concentrated in vacuo to give a yellow viscous oil. Analysis was consistent with the desired product. The total yield of product was 0.83 g (96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(NCC)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:23]#[C:22][C:20]([OH:24])([CH3:21])[CH3:19])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2cccc(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one were mixed with 1.10 g (12 mmol) of 2-methyl-3-butyn-2-ol and 20 ml of diethylamine. Then, 70 mg of bis-(triphenyl -phosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide were added thereto and the mixture was stirred at room temperature for 60 hours. The reaction mixture was evaporated and the residue was dissolved in methylene chloride. The solution was washed twice with water, dried over magnesium sulfate and evaporated. After recrystallization of the residue from ethyl acetate there was obtained 7-chloro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 193-194°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:35]1[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:35]4[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([NH2:42])[CH:36]=4)=[CH:17][CH:16]=3)=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: Oc1ccc(-c2nnc(Nc3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cc(Oc2ccc(-c3nnc(Nc4cccc(C(F)(F)F)c4)o3)cc2)nc(N)n1
Temperature: 80 °C
Yield: 37.7 %

Procedure:
4-(5-{[3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (119.7 mg, 0.6 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous K2CO3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na2SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (81.0 mg). Yield 37.7%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[N:15]([CH3:42])[CH:14]=1>>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:23])=[O:24])=[CH:19][CH:20]=3)[N:15]([CH3:42])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2cccc(C#N)c2)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using (3-cyanophenyl)boronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 3-(3-cyanophenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.90 (s, 3 H) 7.56 (dd, J=8.48, 1.60 Hz, 1 H) 7.61-7.69 (m, 2 H) 7.86-7.92 (m, 2 H) 7.94-8.07 (m, 4 H). m/z (ESI) 395.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Product: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2C1
Yield: 65 %

Procedure:
In analogy to Example 22A, the title compound was prepared from ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (100 mg, 0.35 mmol) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline from Example 4A (93 mg, 0.37 mmol) to give 157 mg (72% purity, 65% yield), which was used in the next step without purification.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OC)(OC)OC.C(N(CC)CC)C>O.C1(C)C=CC=CC=1.CN1CCCC1=O>[CH2:2]([O:4][C:5](=[O:8])[CH2:6]/[N:7]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C/N=C/c1ccccc1
Temperature: 5 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
Glycine ethyl ester hydrochloride (69.1 g, 495 mmol) and toluene (215 g) were mixed, and N-methylpyrrolidone (32.5 g) was poured into the mixture at room temperature. Benzaldehyde (50.0 g, 471 mmol) was added dropwise to the obtained mixture, and then trimethyl orthoformate (52.5 g, 495 mmol) was added dropwise. After completion of the dropwise addition, the temperature of the obtained mixture was adjusted to 7° C. and a mixed solution of triethylamine (52.4 g, 518 mmol) and toluene (26.5 g) was added dropwise over 3 hours. After completion of the dropwise addition, the mixture was stirred at a temperature in a range from 7° C. to room temperature for 6 hours. After completion of the reaction, the reaction mixture was cooled to 5° C. and water (140 mL) was added dropwise thereto. Thereafter, stirring was stopped to perform liquid separation and then the obtained organic layer was washed with 20% brine (95 g). The obtained organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain a toluene solution (104.5 g) of (E)-N-phenylmethyleneglycine ethyl ester (86.9 g of pure (E)-N-phenylmethyleneglycine ethyl ester). Yield: 96%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+].B(F)(F)F.[CH3:33]COCC.C(O)(=O)CC>C1COCC1>[CH3:33][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C:12]1[C:13]2[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=2[N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:11]=1
Reactant: CCOCC
Reactant: O=C(O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCC(=O)O
Product: COC(=O)CCCCCc1nn(-c2ccc([N+](=O)[O-])cc2)c2c1CCCC2
Temperature: 70 °C
Yield: 40.4 %

Procedure:
A solution of 6-[4,5,6,7-tetrahydro-1-(4-nitrophenyl)-1H-inda-zol-3-yl]hexanoic acid (1.11 g, 3 mmol) in THF (10 ml) was treated with sodium borohydride (0.175 g) and boron trifluoride etherate (4.7 mmol) in THF (11 ml) during 0.5 hour. The solution was reacted for 18 hours at ambient temperature, treated with propionic acid (2 ml), and heated at 70° C. for 2 hours. The solution was cooled, dilution with water and the precipitate was extracted into ethyl acetate. Drying and evaporation of solvent gave crude title compound (1.69 g) as a viscous residue. Polar impurities were removed by filtration through silica gel (100 g) to yield pure title compound (0.45 g), m.p. 60°-61° C., after methanol crystallization.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=2)=[CH:5][C:4](Br)=[N:3]1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]3[CH2:33][C@H:32]4[C@:34]5([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:45])(=[O:44])[NH:35]5)[C@H:29]([CH2:30][CH2:31]4)[CH2:28][C:27]=3[CH:46]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.[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>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:23]3[CH:24]=[CH:25][C:26]4[CH2:33][C@H:32]5[C@:34]6([CH2:38][N:37]([CH2:39][C:40]([F:43])([F:42])[F:41])[S:36](=[O:44])(=[O:45])[NH:35]6)[C@H:29]([CH2:30][CH2:31]5)[CH2:28][C:27]=4[CH:46]=3)[CH:5]=2)=[N:8][CH:9]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Reactant: Cc1ccc(-c2cc(Br)nn2C)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(-c3ccc4c(c3)C[C@H]3CC[C@@H](C4)[C@]34CN(CC(F)(F)F)S(=O)(=O)N4)nn2C)nc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 22.9 %

Procedure:
A mixture of 1-methyl-3-bromo-5-(5-methylpyridin-2-yl)pyrazole from Step 3 (0.081 g, 0.321 mmol), the homochiral boronate from Example 24 Step 1 (0.156 g, 0.321 mmol), cesium carbonate (0.10 g, 0.32 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.04 g, 10 mol %) in N,N-dimethylformamide (3 mL) and water (1 mL) was degassed and flushed with nitrogen, then stirred at 100° C. under nitrogen for 18 hours. The cooled mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL). The extract was dried (Na2SO4), filtered through a plug of silica gel and concentrated. The residual oil was partitioned between water (10 mL) and diethyl ether (10 mL). The organic layer was dried (Na2SO4) and concentrated. The material was purified by normal-phase preparative HPLC, eluting with ethyl acetate-isohexanes, to give the title compound (0.039 g, 23%) as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][C@@H:6]1[OH:20])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](OC(=N)C(Cl)(Cl)Cl)([CH3:30])[CH3:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1CCCCC1.FC(F)(F)S(O)(=O)=O>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:11])=[O:12])[CH2:7][C@@H:6]1[O:20][C:28]([C:25]1[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=1)([CH3:30])[CH3:29])=[O:4]
Reactant: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1O
Reactant: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)[C@H]1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@@H]1OC(C)(C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-benzenesulfonyl)-2-hydroxy-cyclopentanecarboxylic acid methyl ester (100 mg, 0.314 mmol, example 48, step 5) and 2,2,2-trichloro-acetimidic acid 1-(4-chloro-phenyl)-1-methyl-ethyl ester (270 mg, 0.514 mmol) were dissolved in a mixture of DCM (1 ml) and cyclohexane (2 ml). Then a solution of trifluoromethanesulfonic acid (0.836 μl, 0.00941 mmol) in DCM (0.1 ml) was added and the reaction mixture was stirred at room temperature for 6 h. Then saturated NaHCO3 solution was added and the mixture was extracted 3 times with ether. The combined organic layers were dried (Na2SO4) and evaporated. The remaining light yellow oil was purified by silica gel chromatography (heptane/EtOAc 4:1-3:1) to obtain the title compound (47 mg, 32%) as white solid. MS (EI): 488.1 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:7]1([N:10]([CH:37]2[CH2:39][CH2:38]2)[C:11]([C:13]2[N:34]([CH2:35][CH3:36])[C:16]3=[N:17][C:18]([NH:25][C:26]4[S:27][C:28]([C:31](O)=[O:32])=[CH:29][N:30]=4)=[C:19]4[N:23]=[CH:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[O:12])[CH2:9][CH2:8]1>>[CH:37]1([N:10]([CH:7]2[CH2:8][CH2:9]2)[C:11]([C:13]2[N:34]([CH2:35][CH3:36])[C:16]3=[N:17][C:18]([NH:25][C:26]4[S:27][C:28]([C:31]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:32])=[CH:29][N:30]=4)=[C:19]4[N:23]=[CH:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[O:12])[CH2:38][CH2:39]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)O)s3)nc21
Reactant: C1COCCN1
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C(=O)N4CCOCC4)s3)nc21

Procedure:
This compound was prepared according to Example 20 using morpholine and 2-(7-(dicyclopropylcarbamoyl)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-4-ylamino)thiazole-5-carboxylic acid (example 20A) to provide N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-(morpholine-4-carbonyl)thiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide as a white solid.
Reaction SMILES: O[Li].O.[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:12]=[CH:11]2)#[N:5]>O.C1COCC1>[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:11]2)#[N:5]
Reactant: CCOC(=O)Cn1ccc2cccc(C#N)c21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cccc2ccn(CC(=O)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A solution of LiOH.H2O (1.4 g, 34.06 mmol, 3.0 equiv.) in water (10 ml) was added at 0° C. to a solution of ethyl 2-(7-cyano-1H-indol-1-yl)acetate (2.6 g, 11.37 mmol, 1.0 equiv.) in THF, and the mixture was stirred for 2 h at RT. When the reaction was complete (TLC monitoring), the mixture was concentrated under vacuum and the residue was taken up in water (50 ml). Extraction with ethyl acetate (50 ml) was carried out, and then the aqueous phase was adjusted to pH≈3-4 with 10% HCl solution. Extraction with DCM (2×50 ml) was then carried out, and the combined organic phases were washed with sat. NaCl solution, dried over Na2SO4 and concentrated under vacuum. The desired product was isolated in the form of a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](I)[CH3:18]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1NC(=S)NCC(N)=O
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(Cl)ccc1C
Yield: 63.2 %

Procedure:
A mixture of 2-[3-(5-chloro-2-methylphenyl)-thioureido]-acetamide (25.8 g) and ethyl iodide (32.0 g) was heated at reflux in ethanol (500 mL) for 5 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (500 mL) and water (300 mL). The organic phase was washed with water, dried over anhydrous MgSO4, then evaporated to dryness. The residue was triturated with diethyl ether and the solid was collected by filtration and dried to give the title compound (17.0 g) as a yellow solid, m.p. 137°-139° C. Anal. Calcd. for. C12H13Cl N2O S: C, 53.63; H, 4.88; N, 10.42. Found: C, 53.58; H, 4.74; N, 10.32. Mass spectrum (EI, M.+) m/z 268/270. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.45-7.49 (m, 1H), 7.40-7.43 (m, 2H), 4.35 (dd, 2H), 3.07 (m, 2H), 2.1 (s, 3H), and 1.28 ppm (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7](O)=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2].S(Cl)([Cl:16])=O>>[C:1]([C:3]1[CH:11]=[C:10]([F:12])[C:6]([C:7]([Cl:16])=[O:8])=[C:5]([F:13])[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(F)c(C(=O)O)c(F)c1
Reactant: O=S(Cl)Cl
Product: N#Cc1cc(F)c(C(=O)Cl)c(F)c1
Temperature: 25 °C
Yield: 91.18 %

Procedure:
A mixture of 4-cyano-2,6-difluorobenzoic acid (0.3 gm, 0.5 mmol) and thionyl chloride (5 mL) were refluxed for about 3 hours. The reaction mixture was cooled to ambient temperature, and concentrated under vacuum at 50° C. to afford 4-cyano-2,6-difluorobenzoyl chloride (0.3 gm, 91.18%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1.[H][H]>C(Cl)Cl.CN(C=O)C.[Pd]>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24]([CH3:29])=[CH:23]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Yield: 87.1 %

Procedure:
A solution of 7-benzyloxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (0.2 g, 0.5 mmol), (prepared as described in Example 48), in a mixture of methylene chloride (5 ml) and DMF (2 ml) containing 10% palladium-on-charcoal (50 mg) was treated with hydrogen at 1.8 atmospheres pressure for 2 hours. The suspension was filtered and the catalyst was washed with methanol followed by methylene chloride. The volatiles were removed from the filtrate by evaporation. The residue was triturated with water. The resulting solid was washed with water and dried under vacuum over phosphorus pentoxide at 60° C. to give 7-hydroxy-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (140 mg, 89%).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and allyl bromide, white powdery 3-[2-(4-allyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccccc3F)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-fluorobenzene boronic acid (201 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 61 mg (59%). MS (m/e) 365.2 (M+1)
Reaction SMILES: [N:1]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH2:10][CH2:9][C@@H:8]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]3)[CH:4]=[CH:3][CH:2]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1.C(Cl)(Cl)Cl>CS(C)=O>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:15][C@@H:8]2[CH2:9][CH2:10][C:11]3[C:6](=[C:5]4[C:14](=[CH:13][CH:12]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[O:7]2)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCc3ccc4ncccc4c3O2)cc1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(C3=CCN(C[C@@H]4CCc5ccc6ncccc6c5O4)CC3)c2c1
Yield: 60.8 %

Procedure:
A solution of (6S)-toluene-4-sulfonic acid 7,8-dihydro-6H-5-oxa-1-aza-phenanthren-6-ylmethyl ester (0.12 g, 0.33 mmole) and 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.14 g, 0.65 mmole) in anhydrous DMSO (25 mL) was stirred at 80° C. for 2 hours. The reaction mixture was then poured into chloroform (100 mL) and washed with water (3×40 mL). The organic layer was dried over sodium sulfate and filtered, and the solvent was removed under vacuum. Column chromatography on silica gel (5% methanol/ethyl acetate) afforded 0.083 g (62%) of the title compound. The oxalate salt was prepared in ethyl acetate and ethanol and had mp 210° C. and [α]25D=+71.43° (c=4.68, DMSO).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:19])[F:18])=[CH:12][NH:11][C:10]=1[CH3:22])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[C:13]([CH:16]([OH:21])[C:17]([F:20])([F:18])[F:19])=[CH:12][NH:11][C:10]=1[CH3:22]
Reactant: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1[nH]cc(C(O)C(F)(F)F)c(=O)c1O
Reaction time: 0.33 h
Yield: 83 %

Procedure:
A mixture of 3-benzyloxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.00 g, 3.19 mmol) and methanol (30 mL) was sonicated to give a clear solution. Pd/C (10 wt %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 0.158 g) was added. The debenzylation reaction was conducted under a hydrogen atmosphere pressurized to 50 psi. The reaction was completed in 20 min. The reaction mixture was diluted with methanol (30 mL), sonicated for 10 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was collected and concentrated in vacuo to give 3-hydroxy-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one as a solid product (0.59 g, 83% yield, HPLC Method 1 (Example 24), RT=7.9 min, HPLC purity (peak percent area): 99.5% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 11.72, (br s, 1H), 7.51 (s, 1H), 5.32 (q, J=7.4 Hz, 1H), 2.20 (s, 3H). MS-ESI (m/z) 224.2 [M+1]+, 206.2 (100%), 186.2, 178.2, 158.2.