Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C@H:12]([O:14]S(C)(=O)=O)[CH2:11][CH2:10][N:9]2[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[C:26]([O:14][C@@H:12]1[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:13]1)(=[O:28])[CH3:27]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C[C@H]1c1ccc(F)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)O[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H](c2ccc(F)cc2)C1
Yield: 55.6 %

Procedure:
A solution of (±)-(2S,4R)-tert-butyl 2-(4-fluorophenyl)-4-(methylsulfonyloxy)piperidine-1-carboxylate (0.30 g, 0.80 mmol) and sodium acetate (0.33 g, 4.0 mmol) in dimethylsulfoxide (15 mL) was heated to 90° C. for 2.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (40 mL), and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexanes 1:10) to give (±)-(2R,4R)-tert-butyl 4-acetoxy-2-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO): 7.24 (m, 4H), 5.14 (br s, 1H), 4.63 (m, 1H), 4.00 (br d, 1H), 2.72 (m, 1H), 2.56 (br d, 1H), 1.88 (s, 3H), 1.84 (br d 1H), 1.78 (m, 1H), 1.44 (m, 1H), 1.39 (s, 9H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15].[CH3:22]I.Cl>CCCCCC.CS(C)=O>[OH:3][C:4]1[C:13]([O:14][CH3:22])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][C:9]2=[O:15]
Reactant: O=C1CC(c2ccccc2)Cc2c1ccc(O)c2O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: COc1ccc2c(c1O)CC(c1ccccc1)CC2=O
Yield: 43 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.39 g, 9.8 mmol) was washed with hexane and the hexane was decanted. DMSO (15 mL) was added to the sodium hydride and the resultant suspension was stirred vigorously. To the suspension was added a solution of 2.5 g (9.8 mmol) of 5,6-dihydroxy-3-phenyl-1,2,3,4-tetrahydro-1-naphthalenone, from Step 1, in 10 mL of DMSO. The mixture was stirred at ambient temperature for 80 min and 0.61 mL (9.8 mmol) of methyl iodide was added in one portion. The reaction mixture was stirred at ambient temperature overnight and then made acidic with 5% aqueous hydrochloric acid solution. The mixture was stirred for 30 min and then filtered. The filter cake was dissolved in 20% ethyl acetate in hexane and chromatographed on a silica gel column eluted with 20% ethyl acetate in hexane and 50% ethyl acetate in hexane to give a brown solid. The solid was crystallized from ethyl acetate to give 1.13 g (43% yield) of the title compound as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.C(C(CC)=O)C.[Na+].[Cl-]>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:9]#[C:10][CH3:11])[CH2:12][C:13]([OH:21])=[O:14])=[CH:6][CH:7]=1
Reactant: CC#CC(c1ccc(O)cc1)C1C(=O)OC(C)(C)OC1=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCC(=O)CC
Product: CC#CC(CC(=O)O)c1ccc(O)cc1
Yield: 77.5 %

Procedure:
A 1 L RB flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48 h. After cooling, the aqueous layer was saturated with NaCl(s) and separated. The organic layer was dried over MgSO4, filtered, and concentrated to a light brown oil which was crystallized from hot ethyl acetate:hexanes (1:2). After collecting and drying, the product was obtained as an off-white powder (20.3 g, 77%). 1H NMR (500 MHz)(DMSO-d6) δ 12.2 (s, 1H); 9.27 (s, 1H); 7.12 (d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, 1H); 2.54 (m, 2H); 1.82 (d, 3H, J=2.4 Hz). MS ESI (pos.) m/e: 205.1 (M+H); 227.1 (M+Na).
Reaction SMILES: Cl[C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[NH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>>[CH:7]1[CH:6]=[C:5]2[C:4]([N:33]([CH2:32][C:31]3[CH:34]=[CH:35][C:28]([C:27]#[N:26])=[CH:29][CH:30]=3)[C:2]([OH:3])([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:10]2=[CH:9][CH:8]=1)=[O:11]
Reactant: N#Cc1ccc(CN)cc1
Reactant: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2C(=O)c3ccccc3C2(O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 47.7 %

Procedure:
Distilled THF (25 mL) was added to 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one (1.071 g, 3.84 mmol) followed by triethylamine (777.14 mg, 7.68 mmol, 1.07 mL) and 4-(aminomethyl)benzonitrile (507.6 mg, 3.84 mmol). The mixture was stirred at room temperature under nitrogen for 4 hours and monitored by TLC. Upon completion the mixture was then extracted with EtOAc (15 mL) and washed with saturated sodium bicarbonate (3×10 mL), water (3×10 mL) and dried (Na2SO4). Removal of solvent after washing produced a viscous orange oil. Trituration under petrol yielded a yellow/orange solid which was recrystallised from a minimum amount of boiling ethyl acetate and excess petrol to produce the title product as a fine pale yellow crystalline solid (665 mg, 1.83 mmol, 50%). 1H NMR: (300 MHz, DMSO) δ ppm 4.31 (d, 2H, J=16.12 Hz, H9), 4.55 (d, 2H J=16.15 Hz, H9′), 7.26 (m, 5H, H1-H5), 7.37 (d, 2H J=8.29 Hz, H10, H13), 7.58 (m, 2H, H6-H7), 7.64 (d, 2H J=8.26 Hz, H11-H12), 7.77 (d, 1H, H8). 13C NMR: (75 Hz, DMSO); δ 42.51 (N—CH2), 60.02 (CN) 90.57 (O—C—N), 109.82, 119.08, 123.06, 123.25, 128.40, 128.62, 129.16, 129.83, 130.54, 132.03, 133.19, 133.26, 133.52, 139.19, 144.24, 149.48 (Ar), 167.23 (C═O). IR: 1397, 1655, 2227 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[CH2:6]2.[C:15]([O:18][C:19](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][O:18][CH3:19]
Reactant: COc1ccc2c(c1)CC(=O)NC2=O
Reactant: CC(=O)OC(C)=O
Solvent: COC(OC)OC
Solvent: CN(C)C=O
Product: COC=C1C(=O)NC(=O)c2ccc(OC)cc21

Procedure:
A mixture of 6-methoxy-4H-isoquinoline-1,3-dione (400 mg, 2.1 mmole), 8 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.7 mL, 15.5 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed, the residue treated with hexane-ethyl acetate, the solid collected by filtration, washed with fresh hexane-ethyl acetate and dried to give a yellow solid, 317 mg, (65%), mp 245-7° C., MS (ESI): m/z 234.1 (M+H).
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21]>>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1
Reactant: COCCOCCO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [Na]
Product: COCCOCCOc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of sodium (210 mg, 9 mmol) in 2-(2-methoxyethoxy)ethanol (10 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (590 mg, 3 mmol). The mixture was stirred at 50° C. for 4 h and evaporated. The residue was dissolved in water and extracted with ether. The combined organic phases were dried and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:13]([OH:17])[CH2:14][CH2:15][CH3:16])=[C:9]([CH2:11][CH3:12])[N:10]=2)[CH:5]=[CH:6][N:7]=1.I[CH2:19][CH3:20].[H-].[Na+].O>CN(C)C=O>[CH2:19]([O:17][CH:13]([C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]2=[N:10][C:9]=1[CH2:11][CH3:12])[CH2:14][CH2:15][CH3:16])[CH3:20]
Reactant: CCCC(O)c1c(CC)nc2c(Cl)nccn12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(OCC)c1c(CC)nc2c(Cl)nccn12
Reaction time: 3 h

Procedure:
The resulting 1-(8-chloro-2-ethylimidazo[1,2-a]pyrazin-3-yl)-1-butanol was dissolved in N,N-dimethylformamide (2.2 mL), then iodoethane (0.079 mL, 0.99 mmol) and sodium hydride (65% in oil; 49 mg, 1.32 mmol) were added thereto under ice-cooling, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (55 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH:18]2[CH2:35][CH2:34][C:21]3([CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>ClCCl>[CH2:22]1[C:21]2([CH2:34][CH2:35][CH:18]([NH:17][C:3]3[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=4)[N:4]=3)[CH2:19][CH2:20]2)[CH2:26][CH2:25][NH:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Nc3nc(Nc4cnn(CCO)c4)ncc3Cl)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OCCn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (500 mg, 0.99 mmol) in dichloromethane (20 mL) was added a solution of HCl in EtOAc (5 mL, 20 mmol). The mixture was stirred at room temperature for 2 h and then concentrated in vacuo. The residue was dissolved in methanol (2 mL) and adjust to pH=7-8 with the solution of NaHCO3 and extracted with DCM (100 mL×3) The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with a silica gel column chromatography (MeOH/DCM (v/v)=1/10 to 1/7) to give the product as a light yellow solid (340 mg, 84.77%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[NH:4][N:3]=1.[H-].[Na+].[CH3:19][CH:20]([CH3:23])[CH2:21]Br>CN(C=O)C.O>[CH3:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:12])=[O:13])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH2:19][CH:20]([CH3:23])[CH3:21])[N:3]=1
Reactant: CC(C)CBr
Reactant: CC1=NNS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1=NN(CC(C)C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56.2 %

Procedure:
The product from step B (0.9 g, 2.85 mmol) was dissolved in DMF (10 mL). Sodium hydride (0.17 g, 4.28 mmol of a 60% suspension in mineral oil) was added slowly at room temperature. The mixture was stirred for 15 min and then 2-methyl bromopropane (0.47 mL, 4.28 mmol) was added. The mixture was warmed to 80° C. and stirred for 2h. And then cooled to 0° C. and stirred for 12h. DMF was evaporated under high vacuum. The residue obtained was diluted with water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over MgSO4 and evaporated to provide an oil which was purified by flash column chromatography (silica, hexane-ethyl acetate gradient) to give the desired compound as a white solid (0.54 g, 50%). mp: 140°-142° C. 1H NMR (DMSO-d6): δ:0.89 (6H, d, 2CH3); 2.03 (1H, m, CH); 2.49 (3H, s, CH3); 3.64 (2H, δ, CH2); 7.94 (1H, s, CH); 8.21 (2H, s, NH2 exchangeable). Analysis calculated for C9H13N3O4S3 : C, 35.59; H, 4.78; N, 12.45 Found: C, 35.56; H, 4.44; N, 12.36.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:20]#[N:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][NH:30][OH:31].Cl>CCO>[OH:31][N:30]([C:20](=[NH:21])[CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:29]
Reactant: N#CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Reactant: CNO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(O)C(=N)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1-Benzyloxycarbonyl-2-cyanoindoline was added to a solution of triethylamine (2 eq.) and MeNHOH.HCl (2 eq.) in EtOH. After stirring overnight the reaction mixture was evaporated, dissolved in EtOAc, washed with water, dried over Na2SO4 and evaporated to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:19])=[O:18])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=O)=CC=1.[CH3:56][O:57][C:58]1[CH:59]=[CH:60][C:61]2[CH:65]=[C:64]([CH2:66]O)[S:63][C:62]=2[CH:68]=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([CH2:66][C:64]2[S:63][C:62]3[CH:68]=[C:58]([O:57][CH3:56])[CH:59]=[CH:60][C:61]=3[CH:65]=2)[NH:16][S:17]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: COc1ccc2cc(CO)sc2c1
Agent: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Product: COc1ccc2cc(CC(NS(=O)(=O)c3cccnc3)c3cccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n3)sc2c1
Yield: 77.7 %

Procedure:
Reaction was carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (69.4 mg, 0.145 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using (6-methoxybenzo[b]-thiophen-2-yl)methanol (see WO 2006/106711A, 33.9 mg, 0.175 mmol) in place of tert-butyl [tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extraction with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=3:1→1:1 (V/V)) and then to reversed phase column chromatography (column; Megabond Elut™ C18 (manufactured by Varian, Inc.), eluent; acetonitrile:water=1:1→1:0 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (73.8 mg) as a white foam. (Yield: 78%)
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8].CI.[CH2:25](Cl)Cl>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH3:25])[C:13]1[CH:22]=[CH:21][C:16]2[N:17]=[CH:18][N:19]([CH3:20])[C:15]=2[CH:14]=1)[C:7]#[N:8]
Reactant: Cn1cnc2ccc(Nc3ccc(C#N)cc3F)cc21
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(c1ccc2ncn(C)c2c1)c1ccc(C#N)cc1F
Reaction time: 0.5 h

Procedure:
NaH (7.14 mmol) was added to a solution of 3-fluoro-4-[(3-methylbenzimidazol-5-yl)amino]benzonitrile (2.38 mmol) in THF (10 mL) at 0° C. The mixture was stirred for 30 min. MeI (4.76 mmol) was added and the mixture was stirred at room temperature during 3 h. The mixture was diluted (DCM), washed (H2O) and concentrated. The residue was purified by prep HPLC to yield the desired product (Compound C).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH2:12][CH2:13][NH2:14].[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24]Br)[CH3:21].O>CN(C)C=O>[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[CH2:24][NH:14][CH2:13][CH2:12][C:11]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:9]([O:8][CH3:7])[CH:10]=1)[CH3:21]
Reactant: COc1ccc(CCN)cc1OC
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(CNCCc1ccc(OC)c(OC)c1)OCC
Reaction time: 1 h
Yield: 71 %

Procedure:
To a stirred suspension of anhydrous potassium carbonate (300 g) and 3,4-dimethoxyphenethylamine (148 g, 0.818 m) in dimethylformamide (750 ml) under N2 at 110° C. was added dropwise over 30 min bromoacetaldehyde diethylacetal (167.5 g, 0.850 m). During the addition, the temperature was allowed to rise to 130° C., maintained at 125°-130° C. for 1.5 hours, then the solution cooled. At ca 40° C., 70 ml of water were added, the mixture was stirred for 1 hour, then the inorganic salts were removed by filtration and the solvent evaporated. n-Hexane (750 ml) was added, the precipitated solid was filtered and the filtrate evaporated to an oil, 247 g. This material was vacuum-distilled to give three fractions: (1) b.p. 30°-154° C./0.1 mm, 17.0 g; (2) b.p. 154°-157° C./0.1 mm, 171.6 g; (3) b.p. 157°-174° C./0.1 mm, 37.3 g. Fraction (2) contained the product in 71% yield and 86% purity (GLC).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)([OH:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[NH2:31][C:32]1[N:37]=[CH:36][C:35]([C:2]2[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][C:15]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)([OH:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][N:33]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: OC1(c2ccccc2)CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(O)(c5ccccc5)CC4)cc3n2)cn1

Procedure:
1-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-4-phenylpiperidin-4-ol was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica gave 289, purity 95%. NMR (400 MHz 1H DMSO): 9.12 (s, 2H); 7.50 (d, 2H, J=7.26); 7.34 (d, 2H, J=11.96); 7.32 (d, 1H, J=15.36); 7.21 (t, 1H, J=7.28); 7.04 (s, 2H); 3.96 (t, 4H, J=4.70); 3.89 (s, 2H); 3.79 (t, 4H, J=4.67); 2.74 (d, 2H, J=10.55); 2.58 (t, 2H, J=10.65); 2.97 (m, 2H); 1.65, (d, 2H, J=12.40). LC-MS (m+1)=503.63
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1.IC1C2C(=O)N(COCC[Si](C)(C)C)N=CC=2N(COCC[Si](C)(C)C)C=1.[CH2:55](B(O)O)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>>[CH2:55]([C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:7]=[CH:6][C:5]=2[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[CH:3]=1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(Br)cn2COCC[Si](C)(C)C)c1=O
Reactant: OB(O)CCc1ccccc1
Agent: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Product: C[Si](C)(C)CCOCn1ncc2c(c(CCc3ccccc3)cn2COCC[Si](C)(C)C)c1=O
Yield: 77.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 18-(c) except for using 855 mg (1.80 mmol) of 3-bromo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 20-(a) in place of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 965 mg (6.43 mmol) of phenethylboronic acid in place of methylboronic acid, respectively, whereby 698 mg of the title compound was obtained as an orange oil. (Yield: 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C-]#N.[Na+].[C:13]([O:17][CH3:18])(=[O:16])[CH:14]=[CH2:15].O>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([CH2:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CC(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(Cl)cc1
Temperature: 35 °C
Yield: 86.2 %

Procedure:
A solution of 4-chlorobenzaldehyde (23.4 g) in dry dimethylformamide (DMF: 100 ml) was added over 10 minutes to a stirred mixture of sodium cyanide (4.0 g) and dry DMF (200 ml). After 5 minutes a solution of methyl acrylate (10.75 g) in dry DMF (100 ml) was added to the reaction mixture over 20 minutes. The temperature of the reaction mixture was maintained at 35° C. throughout both additions and then for a further 3 hours before it was poured into water and extracted with diethyl ether. The extracts were washed successively with water (several times), dilute sulphuric acid, aqueous sodium bicarbonate, and water, before drying over magnesium sulphate and concentration under reduced pressure to give methyl 3-(4-chlorobenzoyl)propanoate (24.4 g, 86%) as a yellow solid.
Reaction SMILES: [CH3:1][OH:2].[Na].Cl[C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1>C(O)(=O)C>[CH3:1][O:2][C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: CO
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Agent: [Na]
Solvent: CC(=O)O
Product: COc1nc2c(c3nc(-c4ccccc4F)cn13)CCCC2

Procedure:
To 10 mL anhydrous methanol was added 100 mg of sodium, and the mixture was stirred to ensure all the sodium had dissolved. Next, 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg) was added and the mixture refluxed for 1 h. To this mixture was added 2 mL of acetic acid and the solvent was then removed under reduced pressure. The resulting solid was recrystallized from ethanol and collected to yield 5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 37), m.p. 160-161° C.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][S:7][CH2:6][C@H:2]1[C:3]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CSC[C@H]1C(=O)O
Reactant: CC(C)(C)N
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
To a solution of 3.0 g (12.9 mmol) of Boc-Thz-OH and 2.15 ml (15.5 mmol) of triethylamine in 25 ml of DMF, 2.02 ml (15.5 mmol) of isobutyl chloroformate was added dropwise at -15° C. After stirring for 10 min at that temperature. 4.06 ml (38.7 mmol) of tert-butylamine was added. The reaction mixture was stirred for 10 min at that temperature and 100 min under ice cooling, concentrated under reduced pressure, diluted with 50 ml of ethyl acetate, washed with 5% NaHCO3 aqueous solution, 5% citric acid aqueous solution, and saturated NaCl aqueous solution successively, dried over Na2SO4, and evaporated under reduced pressure to give 3.13 g (Y. 84%) of Boc-Thz-NH-tBu which was convened to Qoa-Mta-AHPBA-Thz-NH-tBu by a similar method with processes 2-5 of Example 3.