Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[S:5][C:4]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:3]1.[OH:27][C@@H:28]([CH2:41][NH2:42])[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1>>[OH:27][C@@H:28]([CH2:41][NH:42][CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]([CH:7]=[C:6]3[S:5][C:4]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:3][C:2]3=[O:1])=[CH:9][CH:10]=2)[CH2:15][CH2:16]1)[CH2:29][O:30][C:31]1[C:39]2[NH:38][C:37](=[O:40])[NH:36][C:35]=2[CH:34]=[CH:33][CH:32]=1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCCCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1N=C(N2CCCCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(4-oxo-2-piperidin-1-yl -4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one (which was obtained in Intermediate 25) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (Jesudason, C. D., et al., EP 0 764 640) according to the procedure of Example 1 as a pale yellowish solid; mp>140° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 2 H), 1.55-1.75 (m, 6 H), 1.80-2.00 (m, 2 H), 2.60-2.95 (m, 5 H), 3.50-4.10 (m, 9 H), 4.89 (brs, 1 H), 6.57 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.2 Hz, 1 H), 6.87 (t, J=8.1 Hz, 1 H), 7.01 (d, J=8.9 Hz, 2 H), 7.45 (d, J=8.9 Hz, 2 H), 7.51 (s, 1 H), 10.60 (s, 1 H), 10.70 (brs, 1 H); MS (ES) m/z: 289.1 ((M+2H)2+, 100%), 577.1 (MH+, 100%), 577.1 (MH+, 50%); HRMS Calcd. for C30H37N6O4S (MH+): 577.2597. Found: 577.2625.
Reaction SMILES: [CH:1]12[C@@H:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]1[S:4][CH:3]=[CH:2]2.B(O[O-])=[O:13].O.[Na+].O>O1CCCC1>[OH:13][C@H:2]1[CH:1]2[CH:5]([C@@H:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:4][CH2:3]1
Reactant: O=BO[O-]
Reactant: CCOC(=O)[C@@H]1C2C=CSC21
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@H]1C2SC[C@@H](O)C21
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl (6S)-4-thiabicyclo[3.1.0]hex-2-ene-6-carboxylate (22.2 g, 131 mmol) in 136 mL of tetrahydrofuran under nitrogen at 0° C. is added borane-THF complex (98 mL, 98 mmol) over 15-20 minutes. After stiffing at 0° C. for 30 minutes, the reaction is allowed to warm to 15° C. and stir until complete by HPLC (1.5-2 hours). The reaction is cooled to 0° C. and transferred over 10-15 minutes to 111 mL of a pre-cooled (0° C.) 1 N pH 7 buffer solution while maintaining the temperature at 0° C. To the mixture is added sodium perborate monohydrate (15.6 g, 157 mmol) as a solid in five portions such that the temperature is maintained below 20° C. The solution is allowed to warm to room temperature and stir for 1 hour followed by the addition of 222 mL of water. After stirring for 2 hours, the peroxides are quenched by adding sodium thiosulfate pentahydrate (9.7 g) dissolved in 24 mL of water followed by stirring for 10 minutes. The mixture is extracted with ethyl acetate (2×222 mL). The combined organic extracts are washed with saturated aqueous sodium bicarbonate (1×222 mL) followed by brine (1×222 mL) and concentration in vacuo to dryness. The crude product is dissolved in 1,2-dichloroethane (1 mL per 1 g of crude oil) and loaded onto a silica gel column (4 g of silica gel per 1 g of crude oil slurried and packed in 15% ethyl acetate-heptane). The column is eluted with 15% ethyl acetate-heptane until product is visible by TLC, at which time the solvent is switched to 50% ethyl acetate-heptane. All fractions containing the title product are combined and concentrated in vacuo to an oil. Overall yield is in the 55-65% range.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]=[C:6]2[CH2:13][NH2:14]>CO.CC(O)=O.[Pd]>[CH3:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH2:14]
Reactant: Cc1ccc2c(c1)C(CN)=CCO2
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc2c(c1)C(CN)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.4 %

Procedure:
To a solution of 1-(6-methyl-2H-chromen-4-yl)methanamine hydrochloride (700 mg, 3.3 mmol) in MeOH (20 mL) and AcOH (2 mL) under N2 was added 10% Pd/C (70 mg) at rt. The suspension was stirred at rt overnight under 50 psi of H2. The reaction was filtered and concentrated. The residue was dissolved in EtOAc and washed with sat. Na2CO3, and the organics were concentrated to give 400 mg (68%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 1.98-2.09 (2H, m), 2.28 (3H, s), 2.80-2.83 (1H, m), 2.88-2.96 (1H, m), 3.09 (1H, dd, J=4.5, 12.6 Hz), 4.17 (2H, t, J=6.3 Hz), 6.73 (1H, d, J=8.4 Hz), 6.91-6.97 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])(C)(C)C.CCCCCC.CN(C)[CH:28]=[O:29]>O1CCCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[C:2]([CH:28]=[O:29])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc2c(c1)oc1ccccc12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1)oc1ccccc12
Temperature: -78 °C

Procedure:
Combine 3-bromodibenzofuran (0.5 g, 2.0 mmol) and tetrahydrofuran (30 ml). Cool to about −78° C. Add a solution of t-butyllithium, 1.6 M solution in hexane (2.2 ml, 3.0 mmol), then warm to about 0° C. for 10 min. Cool to about −78° C. and add dimethylformamide (0.5 ml, 5.9 mmol). Warm to room temperature, quench with water, and extract with dichloromethane. Combine the organic layers and wash sequentially with distilled water and brine and then dry (Na2SO4), filter, and concentrate to give a residue. Chromatograph the residue eluting with 8:2 hexane:EtOAc to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:6][C:5]2[C:7]([O:20][C:21]3[CH:22]=[C:23]([F:30])[C:24]([C:27]([OH:29])=O)=[N:25][CH:26]=3)=[CH:8][C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)=[CH:10][C:4]=2[O:3]1.[CH2:32]([NH2:34])[CH3:33]>>[CH2:32]([NH:34][C:27]([C:24]1[C:23]([F:30])=[CH:22][C:21]([O:20][C:7]2[C:5]3[CH2:6][C:2]([CH3:1])([CH3:31])[O:3][C:4]=3[CH:10]=[C:9]([C:11](=[O:19])[NH:12][C:13]3[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=3)[CH:8]=2)=[CH:26][N:25]=1)=[O:29])[CH3:33]
Reactant: Cn1ccc(NC(=O)c2cc(Oc3cnc(C(=O)O)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: CCN
Product: CCNC(=O)c1ncc(Oc2cc(C(=O)Nc3ccn(C)n3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 176, from 5-[2,2-dimethyl-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-4-yloxy]-3-fluoro-pyridine-2-carboxylic acid (176a) and ethyl amine (1.0 mL, 2.0 M solution in THF) to give a white solid (203 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1 H) 8.12 (d, J=2.02 Hz, 1 H) 7.65 (t, J=5.43 Hz, 1 H) 7.23-7.32 (m, 1 H) 6.96-7.12 (m, 3 H) 6.78 (d, J=2.02 Hz, 1 H) 3.77 (s, 3 H) 3.40-3.58 (m, 2 H) 2.89 (s, 2 H) 1.50 (s, 6 H) 1.26 (t, J=7.20 Hz, 3 H); LCMS for C23H24FN5O4 m/z 454.20 (M+H+); Anal. Calcd. for C23H24FN5O4.0.10 AcOH: C, 60.65; H, 5.35; N, 15.24. Found: C, 60.62; H, 5.36; N, 15.28.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:22].C[OH:24].[OH-].[Na+]>O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:2]([F:1])=[C:7]([F:8])[CH:6]=[C:5]([F:9])[C:4]=2[F:10])=[C:14]([CH2:13][C:12]([OH:24])=[O:22])[CH:15]=1)[CH3:21]
Reactant: CO
Reactant: CCc1ccc2c(c1)CC(=O)N2c1c(F)c(F)cc(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1ccc(Nc2c(F)c(F)cc(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(2,3,5,6-tetrafluorophenyl)-5-ethyloxindole (72.67 g; 0.235 mol, is slurried in water containing a little methanol (10% v/v; 253 ml), and sodium hydroxide solution (50 wt %; 16.1 ml) is added. The mixture is stirred at 80-85° for 2-4 hours, then cooled to ambient temperature. The reaction solution is partially concentrated under reduced pressure (25-30 mm). After removal of 50 ml of the solvent, the mixture is diluted with water (150 ml) and t-butyl methyl ether (250 ml). The cooled mixture is acidified to pH 6.5-7.0 with aqueous HCl (12.1 N; 19.5 ml), keeping the temperature at 0-5°. The aqueous layer is discarded and the organic layer is washed with water (250 ml). The organic layer is concentrated under reduced pressure (20-100 mm) while exchanging the solvent to toluene. After the more volatile components have been removed, the batch volume is adjusted to 400-450 ml. This mixture is warmed to 70°, clarified, concentrated to one-half volume, and cooled to 0°. After stirring at this temperature for 2 hours, the product is collected and is washed with toluene/heptane (10:90; 100 ml). The resulting solid is dried under reduced pressure at 50-60° for 4-8 hours to give 5-ethyl-2-(2′,3′,5′,6′-tetrafluoroanilino)phenylacetic acid of Example 3.
Reaction SMILES: Cl[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15].[CH3:21][NH:22][CH3:23]>C(COC)OC>[CH3:21][N:22]([CH3:23])[C:2]1[C:3]([C:17]([F:20])([F:19])[F:18])=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:11][CH3:12])[C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CNC
Reactant: CCn1c(C)nc2cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c21
Solvent: COCCOC
Product: CCn1c(C)nc2cc(C(F)(F)F)c(N(C)C)c([N+](=O)[O-])c21
Temperature: 125 °C

Procedure:
A glass reaction tube was charged with 5.0g. (0.016 mole) of 6-chloro-1-ethyl-2-methyl-7-nitro-5-trifluoromethylbenzimidazole, 20 ml. of dimethoxyethane and 15 ml. of dimethylamine and then sealed. The sealed tube was maintained at 125°C. for 16 days and then opened. The contents were evaporated to dryness and the residue extracted with hot hexane, from which crystallized 3.1g. of the desired product m.p. 111°-115°C. after recrystallization from hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:15])([CH2:11][CH3:12])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: CCC(C#N)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C#N)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)butanenitrile (6.2 g, 35 mmol) in 50 mL DMF stirred at 0° C., was treated with NaH (0.99 g, 41 mmol). The mixture was stirred at 0° C. for 30 minutes, and was treated with MeI (7.3 g, 52 mmol). The mixture was stirred at 0° C. to room temperature for 2 hours, and was carefully quenched with H2O, and neutralized with 10% HCl to pH=5. The mixture was extracted with ether (3×50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10% EtOAc/hexane to give 6.5 g of the product as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:27][CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: NCCN1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCCCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (450 mg, 1.61 mmol) in 2-propanol (40 mL) was added 2-(piperidin-1-yl)ethanamine (227 mg, 1.77 mmol) followed by triethylamine (160 mg, 1.58 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-piperidin-1-yl-ethyl)-amine. (Yield 411 mg, crude).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH2:3]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C:19]2[O:20][C:21]([C:24](=[O:25])[NH:2][CH3:1])=[CH:22][CH:23]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=C(Cl)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.97 ml (5.94 mmol) of a 2 M solution of methylamine in THF were initially charged in 20 ml of THF, and a solution of 0.8 g (2.4 mmol) of 1-benzyl-3-(5-chlorocarbonyl-2-furyl)indazole in 10 ml of THF was added dropwise at RT. After 1 h, the mixture was poured into ice-water and the oil that separated off was extracted with ethyl acetate. The organic phase was washed with 1 N hydrochloric acid, dried and concentrated using a rotary evaporator. The crude product was recrystallized from isopropanol. This gave 0.44 g (55%) of the title compound. m.p.: 182-183° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([OH:18])[C:13]([O:15]CC)=[O:14])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.C(O)C.[OH-].[K+]>O1CCOCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH:12]([OH:18])[C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1
Reactant: CCOC(=O)C(O)c1ccc(-n2cccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)C(O)c1ccc(-n2cccc2)cc1
Temperature: 27 °C
Reaction time: 3 h
Yield: 43.7 %

Procedure:
A mixture of ethyl 4-(1-pyrrolyl)phenylglycolate (0.49 g, 0.002 mole), ethanol (10 ml), dioxane (1.2 ml) and 2 M aqueous KOH (1.5 ml) was stirred at 27° C. for 3 hrs., and then evaporated to dryness. The residue was dissolved in H2O. The solution was acidified with acetic acid and extracted with ethyl acetate (3×15 ml). The combined extracts after washing with H2O and drying (MgSO4), evaporation and recrystallization of the residue from H2O gave 0.19 g (44%) of 4-(1-pyrrolyl)phenylglycolic acid, m.p. 168°-168.5° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:11])=[N:6][C:7]([NH2:10])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:2]/[C:1]([C:4]1[C:5]([CH3:11])=[N:6][C:7]([N:10]=[CH:12][N:13]([CH3:15])[CH3:14])=[N:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cnc(N)nc1C
Product: Cc1nc(N=CN(C)C)ncc1C(=O)/C=C/N(C)C
Yield: 61 %

Procedure:
A solution of 5-acetyl-2-Amino-4-methypyrimidine (Alfa Aesar) (1.00 g, 6.62 mmol) in DMF-DMA (35.4 mL, 265 mmol) was heated at 120° C. for 18 hours. The reaction mixture was concentrated in vacuo, then was purified by Biotage™ silica gel chromatography [50 g SNAP column, 2-10% MeOH/DCM] to obtain a pale yellow solid as the desired product, which was dried over high vacuum for 1 hour (1.06 g, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 2.86 (br. s., 3 H) 3.03 (s, 3 H) 3.10 (br. s., 3 H) 3.13 (s, 3 H) 5.40 (d, J=12.63 Hz, 1 H) 7.50 (d, J=12.63 Hz, 1 H) 8.48 (s, 1 H) 8.64 (s, 1 H).
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:13](=[O:24])[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1.[H-].[Na+].F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>O>[C:30]([C:29]1[CH:32]=[CH:33][CH:34]=[CH:35][C:28]=1[N:14]1[CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]=2)[C:13]1=[O:24])#[N:31]
Reactant: O=c1[nH]cc(-c2ccccc2)cc1-c1ccccn1
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-n1cc(-c2ccccc2)cc(-c2ccccn2)c1=O
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
5 ml of a dimethylformamide solution containing 0.26 g of 3-(2-pyridyl)-5-phenyl-2 (1H)-pyridone was incorporated with 0.04 g of sodium hydride. After 15 minutes, the solution was further incorporated with 0.15 g of 2-fluorobenzonitrile and 0.10 g of cuprous iodide, and vigorously stirred at 100° C. for 2 hours. The solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then saturated saline water, and dried by magnesium sulfate anhydride. The solvent was distilled off under a vacuum. The residue was refined by silica gel chromatography (ethyl acetate/hexane=1:2), to obtain 0.03 g of the light yellow, powdery subject compound.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:15])(=O)[C:6]1[NH:13][C:11](=[O:12])[NH:10][C:8](=[O:9])[CH:7]=1>O>[O:12]=[C:11]1[NH:13][C:6]([C:5]([Br:3])=[O:15])=[CH:7][C:8](=[O:9])[NH:10]1
Reactant: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Reactant: O=S(Br)Br
Solvent: O
Product: O=C(Br)c1cc(=O)[nH]c(=O)[nH]1
Temperature: 45 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 10.07 mL (130 mmol) of thionyl bromide, and a water condenser, is placed 15.61 g (100 mmol) of orotic acid. Addition of the thionyl bromide is completed with heating to about 45° C. over the course of about 80 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carbonyl bromide (orotoyl bromide). This acyl bromide, 6.57 g (30 mmol), is put into a dry separatory funnel and combined with 25 mL of dry DCM for use in the next step of the reaction.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[CH2:21][C@H:22]2[CH2:26][CH2:25][CH2:24][N:23]2[CH3:27])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.CS(O)(=O)=O>[Pd].O>[CH3:27][N:23]1[CH2:24][CH2:25][CH2:26][C@@H:22]1[CH2:21][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([CH2:11][CH2:10][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:8])=[O:9])[CH:13]=2)[NH:17][CH:16]=1
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(C=CS(=O)(=O)c3ccccc3)cc12
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC(C)=O
Product: CN1CCC[C@@H]1Cc1c[nH]c2ccc(CCS(=O)(=O)c3ccccc3)cc12
Yield: 109.4 %

Procedure:
(R)-5-(2-Phenylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (200 kg dry equivalent) and acetone (1186.5 kg) were charged to a dry, glass lined vessel. De-ionised water (300 kg), further acetone (237 kg), methanesulphonic acid (55 kg) and a slurry of palladium on carbon (22.4 kg dry equivalent) in de-ionised water (200 kg) were added and the mixture was hydrogenated under an atmosphere of hydrogen gas. The reaction slurry was filtered to remove the catalyst. De-ionised water (1300 kg) and 48% aqueous sodium hydroxide solution (60 kg) were added to precipitate the product, which was isolated by filtration and washed with a mix of de-ionised water (210 kg), acetone (83 kg) and further de-ionised water (710 kg) to yield 3-{[1-methylpyrrolidin-2(R)-yl]methyl}-5-(2-phenylsulphonylethyl)-1H-indole (220 kg wet, 157.65 kg when dry, 78.41%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.F[C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=1.C(=O)(O)[O-].[K+]>CS(C)=O>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry DMSO, 51.2 mg (0.31 mmol) of 2-fluoro-5-(trifluoromethyl)pyridine and 31.1 mg (0.31 mmol) of potassium bicarbonate are added, and the mixture is heated at 130° C. under argon for 16 h. Purification by preparative HPLC results in 22 mg (30% of theory) of the product as a solid.
Reaction SMILES: C(OC([N:11]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1)[CH2:12][C:13]([NH:15]CC(N)=O)=O)=O)C1C=CC=CC=1.C[OH:29]>[Pd]>[CH3:26][C:24]1[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([NH:11][C:12](=[O:29])[CH2:13][NH2:15])[CH:25]=1
Reactant: Cc1cc(C)nc(N(CC(=O)NCC(N)=O)C(=O)OCc2ccccc2)c1
Reactant: CO
Agent: [Pd]
Product: Cc1cc(C)nc(NC(=O)CN)c1

Procedure:
1 g (2.6 mmol) of the product of Example 24 is dissolved in 60 ml of methanol. Palladium-on-carbon is added and the whole is stirred under a hydrogen atmosphere. Filtration is then carried out, the methanol is evaporated and the title product is recovered.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[F:34])=[N:21][CH:22]=[N:23]3)=[CH:18][C:17]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:34][C:28]1[CH:29]=[C:30]([CH3:33])[CH:31]=[CH:32][C:27]=1[NH:26][C:20]1[C:19]2[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[C:17]([O:35][CH3:36])[CH:18]=2)[N:23]=[CH:22][N:21]=1
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A suspension of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline (318 mg, 0.64 mmol) in methylene chloride (5 ml) containing TFA (2.5 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH 10–11. The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation to give 4-(2-fluoro-4-methylanilino)-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (220 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Cl[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:17][CH:18]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: COC(=O)c1cccc(Cc2ccc(O)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(Cc2ccc(OCc3ccc4ccccc4n3)cc2)c1

Procedure:
A mixture of methyl 3-(4-hydroxybenzyl)benzoate (0.08 mol), 2-chloromethylquinoline (0.10 mol) and potassium carbonate (anhydrous, 0.10 mol) are heated at reflux in a 7:1 mixture of acetone:dimethylformamide (600 ml) until all the benzoate starting material is consumed. The reaction is then filtered, evaporated and the residue diluted with water and extracted with ethyl acetate. The ethyl acetate extracts are dried (magnesium sulfate), evaporated and then applied to a silica gel column. Elution with ethyl acetate:petroleum ether gives methyl 3-(4-(2-quinolinylmethyloxy)benzyl)benzoate.