Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:22])[NH:20][CH:21]=2)[CH2:12][CH2:11]1.[CH3:23]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)(Cl)Cl.O>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:17]=[CH:18][C:19](=[O:22])[N:20]([CH3:23])[CH:21]=2)[CH2:12][CH2:11]1
Reactant: CN(C)C=O
Reactant: O=c1ccc(N2CCN(c3cccc(CO)c3F)CC2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cn1cc(N2CCN(c3cccc(CO)c3F)CC2)ccc1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5-{4-[2-Fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}pyridin-2(1H)-one (352 mg) and DMF (10 ml) were mixed, and potassium carbonate (240 mg) and methyl iodide (200 mg) were added thereto, followed by stirring at 60° C. overnight. Methyl iodide (49 mg) and potassium carbonate (48.1 mg) were added thereto, followed by stirring at 60° C. for 4 hours. The reaction mixture was cooled to room temperature, and water and CHCl3 were added thereto at 0° C. The organic layer was washed with water and saturated brine, and then dried over Na2SO4, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-{4-[2-fluoro-3-(hydroxymethyl)phenyl]piperazin-1-yl}-1-methylpyridin-2(1H)-one (256 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:8]=[C:7]([NH:9][C:10](=O)[CH3:11])[C:6]([CH3:13])=[N:5]1.ClC1C=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:19]([I:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=2)[C:6]([CH3:13])=[N:5]1
Reactant: FC(F)(F)c1cnc(Cl)cc1I
Reactant: CC(=O)Nc1cn(C)nc1C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
Sodium hydride (1.732 g, 41.13 mmol) was added to N-(1,3-dimethylpyrazol-4-yl)acetamide (6.3 g, 41.1 mmol) dissolved in THF (80 mL) under nitrogen. The resulting light suspension was stirred at room temperature for 15 minutes then at 35° C. for 15 minutes and then 2-chloro-4-iodo-5-(trifluoromethyl)pyridine (6.02 g, 19.6 mmol) was added. The mixture was stirred at 35° C. for 20 minutes then at 45° C. for 30 minutes, giving a light purple solution. The resulting mixture was allowed to cool to room temperature, quenched with water (30 mL) and lithium hydroxide hydrate (2.466 g, 58.75 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The mixture was extracted twice with DCM. The combined organic phases were washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product. The crude product was purified by flash chromatography on silica gel eluting with 0 to 50% EtOAc in DCM. The fractions containing pure product were evaporated to dryness, sonicated in petroleum ether then collected by filtration, washed with petroleum ether and dried to a constant weight to afford N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (3.5 g, 9.16 mmol, 46.8%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]O)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:16]([S:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][O:1][C:2]3[CH:15]=[CH:14][C:5]4[C@H:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][O:8][C:4]=4[CH:3]=3)[CH:30]=2)=[C:24]([CH3:37])[CH:23]=1)[CH3:17]
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: CCSCCOc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCSCCOc1cc(C)c(-c2cccc(COc3ccc4c(c3)OC[C@H]4CC(=O)OC)c2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution of methyl [(3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl]acetate (0.250 g, 1.20 mmol), {4′-[2-(ethylthio)ethoxy]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.380 g, 1.20 mmol) and tributylphosphine (0.388 g, 1.92 mmol) in toluene (20 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.484 g, 1.92 mmol) was added, and the mixture was stirred at room temperature for 1 hr under nitrogen atmosphere. Hexane (10 mL) was added to the reaction mixture, the precipitated insoluble substance was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-40:60) to give the title compound (0.363 g, yield 60%) as a pale-yellow oil.
Reaction SMILES: N[C:2]1[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[N:6]2[CH3:19].C([OH:30])C=C.[OH-].[Na+]>C1COCC1>[F:26][C:22]1[CH:21]=[C:20]([C:5]2[N:6]([CH3:19])[C:7]3[C:3]([N:4]=2)=[C:2]([OH:30])[N:10]=[C:9]([C:11]#[C:12][C:13]2([OH:18])[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=3)[CH:25]=[CH:24][CH:23]=1
Reactant: C=CCO
Reactant: Cn1c(-c2cccc(F)c2)nc2c(N)nc(C#CC3(O)CCCC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(F)c2)nc2c(O)nc(C#CC3(O)CCCC3)nc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To 50 mg of 1-{2-[6-amino-8-(3-fluorophenyl)-9-methyl-9H-2-purinyl]-1-ethynyl}-1-cyclopentanol were added 3.0 ml of allyl alcohol and 1.0 ml of 5M NaOH, the mixture was stirred at room temperature for 10 minutes, 1.0 ml of THF was added thereto and the mixture was stirred again at room temperature for 15 hours and 40 minutes. The solvent was evaporated and then 200 ml of ethyl acetate and water (1:1) were added and an extraction was carried out. The aqueous lyaer was extracted with 100 ml of ethyl acetate again and the all organic layers were combined and washed with water and with brine once each. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The resulting residue was purified by a p-TLC (CH2Cl2:MeOH=10:1), the resulting yellowish white crystals were suspended in diethyl ether and the suspenion was filtered to give 217 mg of the title compound as white crystals. The yield was 36%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:14])([CH3:13])[C:7](=[O:15])[C:6]([C:16](OCC)=[O:17])=[C:5]2[OH:21].C(N(C(C)C)C(C)C)C.Cl.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([CH3:13])([CH3:14])[C:7](=[O:15])[C:6]([C:16]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:17])=[C:5]2[OH:21]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
Ethyl 6,7-dichloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (325 mg, 987 μmol) was dissolved in 1,4-dioxane (987 μL) and N-ethyl-N-isopropylpropan-2-amine (516 μL, 2962 μmol). tert-Butyl 2-aminoacetate hydrochloride (248 mg, 1481 μmol) was added, and the reaction was stirred at 80° C. for 4 hours. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 20 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (235 mg) as an off-white solid after purification via preparatory LC. MS (m/z)=358(M+H-tBu)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][OH:11])[CH2:5][CH2:4]1.[Br:12][C:13]1[CH:14]=[N:15][C:16](Cl)=[N:17][CH:18]=1.[Cl-].[NH4+].C([O-])(O)=O.[Na+]>O1CCCC1.O>[Br:12][C:13]1[CH:14]=[N:15][C:16]([O:11][CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:17][CH:18]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCCN1CCOCC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Brc1cnc(OCCN2CCOCC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
NaH (1.0 g, 25.0 mmol, 60% in oil) suspended in anhydrous tetrahydrofuran is cooled at 0° C. in an ice bath under argon, and then 2-morpholinoethanol (2.7 g, 20.7 mmol) is added dropwise. The ice bath is withdrawn and the suspension is stirred for 1 hour at ambient temperature. 5-Bromo-2-chloro-pyrimidine (4.0 g, 20.7 mmol) is then added at ambient temperature and the reaction mixture is stirred for 16 hours at ambient temperature. Saturated aqueous ammonium chloride solution (10 mL) and water (10 mL) are added to the reaction mixture; the pH is adjusted to 9 by adding saturated aqueous NaHCO3 solution. The resulting solution is extracted 3 times with ethyl acetate, the organic phase is then washed with brine, dried over MgSO4, and then evaporated to dryness. The expected compound precipitates out by means of the addition of petroleum ether.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37](=O)[CH3:38])=[CH:31][CH:30]=1.CC(O)=O>C1COCC1>[CH3:38][C:37](=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:36][CH2:35][C:32]1[CH:31]=[CH:30][C:29]([OH:28])=[CH:34][CH:33]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)CCc1ccc(O)cc1
Agent: [Br-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=Cc1ccccc1)CCc1ccc(O)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
To a suspension of benzyltriphenylphosphonium bromide (10.9 g, 25.1 mmol, 1.2 equiv.) in THF (35 mL), was added potassium-t-amylat (1.7 M in toluene, 20 mL, 34.0 mmol, 1.7 equiv.) at 25° C. 4-(4-Hydroxyphenyl)butan-2-one (3.3 g, 20.1 mmol, 1.0 equiv.) in THF (5 mL) was added to the red suspension, and the mixture was stirred at 70° C. for 30 min. After addition of 20% aq. AcOH-solution (10 mL) at 25° C., the aqueous layer was diluted with hexanes (50 mL). The organic phase was washed with H2O (2×30 mL) and MeOH/H2O (8:2, 2×20 mL) and concentrated. The residue was purified by flash chromatography on SiO2 to yield 2.10 g (44%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([F:1])[CH:3]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:5]=2[O:9]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccccc1-c1cc(F)cc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1cc(F)cc2c1OC(CNC(=O)OCc1ccccc1)C2

Procedure:
Treatment of (±)-1-[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (3.11 g, 12.1 mmol) with diisopropylethylamine (2.34 g, 18.1 mmol) and benzyl chloroformate (2.27 g, 13.3 mmol) generally according to the procedure described for Intermediate 12 gave 4.35 (92%) of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.83 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C24H22FO3.0.2H2O: C, 72.97; H, 5.72; N, 3.55. Found: C, 72.8; H, 5.72; N, 3.48. Chiral HPLC separation of (±)-benzyl[5-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OD, hexane:isopropanol 8:2) provided two fractions. Fraction 1 (Rt=7.269 min, Chiralcel OD, hexane:isopropanol 8:2); Fraction 2 (Rt=8.449 min, Chiralcel OD, hexane:isopropanol 8:2).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][C:6]=1Br.C(O)(=O)C>[Zn].O>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:8]#[N:9])[S:5][CH:6]=1
Reactant: Cc1c(C#N)sc(Br)c1Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)csc1C#N
Temperature: 102.5 °C
Yield: 96.2 %

Procedure:
A mixture of 0.400 g (1.42 mmol) of 4,5-dibromo-3-methyl-2-thiophenecarbonitrile, 0.186 g (2.85 mmol) of zinc dust, 4 mL of acetic acid and 1 mL of water was heated at 100-105° C. for 45 minutes. After cooling, the solvents were removed under reduced pressure and the residue was dissolved in 10 mL of ether and washed with water (2×5 mL) and dilute, aqueous sodium carbonate solution (1×5 mL). After drying (sodium sulfate), the ether was removed on the rotovap to afford 0.276 g (96%) of an off-white solid: mp 54-58° C.; 1H NMR (CDCl3) 7.47 (s, 1H, ring-H) and 2.42 (s, 3H, CH3); GC-MS (EI) 201/203 (M+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[C:17]([CH3:18])=[CH:16][C:15]([OH:19])=[CH:14][C:13]1=[O:20].N12CCCN=C1CCCCC2.[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35]Br.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:32][C:33]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:34]=1[CH2:35][O:19][C:15]1[CH:16]=[C:17]([CH3:18])[N:12]([C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=2[F:1])[C:6]([O:8][CH3:9])=[O:7])[C:13](=[O:20])[CH:14]=1
Reactant: COC(=O)c1ccc(F)c(-n2c(C)cc(O)cc2=O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Reaction time: 18 h

Procedure:
A 100 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with the product of Step 3 (14.4 g, 51.9 mmol) and N,N-dimethyl formamide (40 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (10.9 mL, 72.8 mmol) was added followed by 2,4-difluorobenzyl bromide (9.3 mL, 72.8 mmol). The reaction mixture was stirred at 65 C for 18 h, was poured into saturated aqueous NaHCO3 and was extracted with ethyl acetate. The organic layer was washed with brine, dried with Na2SO4 and concentrated in vacuo to give the title product, as an orange oil (21.59), which was carried on to the next reaction without further purification. 1H NMR (400 MHz, CD3OD) δ 8.20 (dddd, J=2.2, 4.8, 7.2 and 8.8 Hz, 1H), 8.00 (dd, J=2.2 and 7.2 Hz, 1H), 7.56 (td, J=2.4, 6.4 and 9.2 Hz, 1H), 7.46 (t, J=9.2 Hz, 1H), 7.02 (m, 2H), 6.18 (dd, J=0.8 and 2.6 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 5.14 (s, 2H), 3.90 (s, 3H), 1.98 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ −111.34 (1F), −116.00 (1F), −117.35 (1F) ppm. ES-HRMS m/z 404.1104 (M+H calcd for C21H17F3NO4 requires 404.1104).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][N:16]=1.N>>[F:14][C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)=[CH:22][CH:23]=1
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(O)c1ccc(F)nc1
Agent: N
Product: Fc1ccc(-c2nc(-c3ccc4nccn4c3)no2)cn1

Procedure:
The title compound was prepared according to Method C using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 6-fluoronicotinic acid (Frontier). 1H NMR (300 MHz, DMSO-d6) δ 7.55 (ddd, J=8.5, 2.7, 0.7 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.73-7.86 (m, 2H), 8.20 (s, 1H), 8.75 (ddd, J=8.1, 2.5 Hz, 1H), 9.08 (dt, J=1.7, 0.8 Hz, 1H), 9.46 (dd, J=1.7, 1.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].[Br:29]N1C(=O)CCC1=O>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([CH3:27])([CH3:26])[CH3:28])=[CH:23][CH:24]=3)(=[O:17])=[O:18])=[CH:11][C:9]=2[C:10]=1[Br:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1sc2ccc(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)cc2c1Br
Yield: 94 %

Procedure:
According to Step 4, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-1-benzothiophene-2-carboxylic acid ethyl ester (5.34 mg, 12.79 mmol) from Example 1b) with N-bromosuccinimide (2.30 g, 12.7 mmol) followed by chromatographic purification (silica gel, hexane/ethyl acetate (0-70% ethyl acetate)), the desired compound is obtained at 94% yield (5.98 g).
Reaction SMILES: Br[C:2]1[C:11]2[NH:10][C:9]3[CH:12]=[N:13][N:14]([CH3:15])[C:8]=3[C:7](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)CCC.[Cl-].[Li+]>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>[CH3:15][N:14]1[C:8]2[C:7](=[O:16])[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:11]=3[NH:10][C:9]=2[CH:12]=[N:13]1
Reactant: Cn1ncc2[nH]c3c(Br)cccc3c(=O)c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cn1ncc2[nH]c3c(-c4ccccc4)cccc3c(=O)c21
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A mixture of 5-bromo-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one (EXAMPLE 5, 50 mg, 0.18 mmol), tributylphenyltin (0.12 ml, 0.36 mmol), tetrakis(triphenylphosphine)palladium (0) (62 mg, 0.054 mmol) and lithium chloride (19 mg, 0.45 mmol) in 1,4-dioxane (2 ml) was refluxed for 16 h. After cooling to room temperature, the mixture was evaporated, dissolved in ethyl acetate (20 ml) and the insoluble material was filtered off. The filtrate was concentrated in vacuo and purified by preparative thin layer chromatography developing with ethyl acetate/hexane (1/2). The obtained solid was recrystallized from diethyl ether to afford 17 mg (33%) of the title compound as a solid.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[C:9]([Si](C)(C)C)[S:10][CH:11]=1.[C:16]([C:19]1[O:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=1)(=[O:18])[CH3:17]>C(OCC)C>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[CH:23]=[C:19]1[C:16]([C:11]1[S:10][CH:9]=[N:8][C:7]=1[CH3:6])([OH:18])[CH3:17]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: Cc1csc([Si](C)(C)C)n1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ncsc1C(C)(O)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1 equivalent) was added dropwise to a solution of 4-methyl-2-trimethylsilylthiazole (1 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylbenzofuran (1 equivalent) in diethyl ether was added. After 1 hour the mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work up in the normal fashion and column chromatography on silica gel then afforded the title compound.
Reaction SMILES: ClC1C(NC2C=C(C3CC3)NN=2)=NC(C2SC(C(O)C(OCC)=O)=CC=2)=NC=1.[C:29]([O:32][CH2:33][CH2:34][CH:35]([C:44]1[S:45][C:46](Br)=[CH:47][CH:48]=1)[O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])(=[O:31])[CH3:30].C(OCCC(C1SC(B(O)O)=CC=1)O[Si](C(C)(C)C)(C)C)(=O)C.Br[C:74]1[N:79]=[C:78]([NH:80][C:81]2[CH:85]=[C:84]([CH:86]3[CH2:88][CH2:87]3)[NH:83][N:82]=2)[C:77]([C:89]#[C:90][Si](C)(C)C)=[CH:76][N:75]=1>>[C:29]([O:32][CH2:33][CH2:34][CH:35]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:44]1[S:45][C:46]([C:74]2[N:79]=[C:78]([NH:80][C:81]3[CH:85]=[C:84]([CH:86]4[CH2:88][CH2:87]4)[NH:83][N:82]=3)[C:77]([C:89]#[CH:90])=[CH:76][N:75]=2)=[CH:47][CH:48]=1)(=[O:31])[CH3:30]
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(=O)OCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)s1
Agent: CC(=O)OCCC(O[Si](C)(C)C(C)(C)C)c1ccc(B(O)O)s1
Agent: CCOC(=O)C(O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Product: C#Cc1cnc(-c2ccc(C(CCOC(C)=O)O[Si](C)(C)C(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Yield: 50 %

Procedure:
Following procedure from Compound 191, 3-(5-Bromothiophen-2-yl)-3-(tert-butyldimethylsilyloxy)propyl acetate was converted to 5-(3-acetoxy-1-(tert-butyldimethylsilyloxy)propyl)thiophen-2-ylboronic acid (2.7 g, 94.5%) (LC-MS (m/z)=441.0 [M+H]+), which was condensed with 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine to produce 3-(tert-butyldimethylsilyloxy)-3-(5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynylpyrimidin-2-yl)thiophen-2-yl)propyl acetate (500 mg, 50.0%). LC-MS (m/z)=538.1 [M+H]+
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]2[N:21]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][N:5]4[C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=5[N:7]([CH3:14])[C:6]4=[O:15])[CH2:29][CH2:30]3)[C:22](=[O:24])[NH:23][C:19]=2[CH:18]=1
Reactant: Cn1c(=O)n(CCCI)c2ccccc21
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCCN2CCC(n3c(=O)[nH]c4cc(Cl)ccc43)CC2)c2ccccc21
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 5 parts of 1,3-dihydro-1-(3-iodopropyl)-3-methyl-2H-benzimidazol-2-one, 3.75 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 2.65 parts of sodium carbonate and 22.5 parts of N,N-dimethylformamide is stirred at 70°-80° C for 2 hours. The reaction mixture is cooled, poured onto water and the precipitated product is filtered off. It is dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. yielding 3 parts (43%) of 5-chloro-1-{1-[3-(1,3-dihydro-3-methyl-2-oxo-2H-benzimidazol-1-yl)propyl]-4-piperidinyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 166.5° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.S(Cl)(Cl)=O.[CH3:17]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:17])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: CO
Reactant: COc1cc(F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1OC
Yield: 70 %

Procedure:
To a solution of 4-fluoro-2-methoxybenzoic acid (1.7 g, 10 mmol) in methanol (100 mL) was added thionyl chloride (5.73 g, 48 mmol) at 0° C. The resultant mixture was stirred for 12 hours and then solvent was evaporated in vacuo. To the residue, saturated sodium bicarbonate aqueous solution (50 mL) was added and the mixture was extracted with ethyl acetate (100 mL×3). The organic phase was dried by sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo to give methyl 4-fluoro-2-methoxybenzoate (1.3 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][C:23]([CH3:25])=[O:24])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:19])[NH:12][C:11]([CH2:20][O:21][CH2:22][CH:23]([OH:24])[CH3:25])=[C:10]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(COCC(C)=O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C(COCC(C)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 43.3 %

Procedure:
A solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}acetone (0.46 g) and sodium borohydride (0.10 g) in ethanol (40 ml) was stirred at room temperature for 5 hours. The solution was evaporated and the residue was dissolved in ethyl acetate and washed three times with water. The organic layer was dried over MgSO4 and evaporated. The residue was crystallised from diethyl ether/hexane to give the title compound (0.20 g), m.p. 110°-113°.