Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16](O)=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH3:29]>ClCCl.O1CCOCC1>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:9]([O:19][CH3:20])=[N:10][N:11]([CH2:15][C:16]([NH2:29])=[O:17])[C:12]=2[CH2:13][CH3:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(=O)O
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1c(Oc2ccc(C#N)cc2)c(OC)nn1CC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 17 %

Procedure:
The acid of step (b) above (180 mg, 0.6 mmol) was suspended in dichloromethane (5 ml), and oxalyl chloride (150 μl, 1.72 mmol) was added, resulting in gas evolution. The reaction mixture was stirred at room temperature for 1 hour, under nitrogen. The solvent was then evaporated under reduced pressure and the residue was azeotroped with toluene 3 times. The crude intermediate acid chloride was carried straight through to the next step. It was dissolved in tetrahydrofuran (2 ml), and ammonia 0.5M in dioxane (10 ml) was added. After stirring overnight at room temperature, analysis by TLC showed little product had formed. A further portion of fresh 0.5M ammonia in dioxane (10 ml) was added to the reaction mixture and stirring was continued for another overnight period. The reaction mixture was evaporated and the residue was partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate (10 ml). The organic layer was separated and the aqueous layer was extracted 3 times with dichloromethane (10 ml). The organic extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate to provide the title compound (20 mg, 17%).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].[NH2:10][C:11]1[NH:15][N:14]=[C:13]([CH2:16][CH2:17][CH2:18][N:19]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:20][CH2:21][OH:22])[N:12]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.CO.C(O)(=O)C>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[N:15]2[N:14]=[C:13]([CH2:16][CH2:17][CH2:18][N:19]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:20][CH2:21][OH:22])[N:12]=[C:11]2[N:10]=1)[CH3:1]
Reactant: Nc1nc(CCCN(CCO)c2ccc(F)cc2)n[nH]1
Reactant: CCC(=O)CC(=O)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(=O)O
Product: CCc1cc(CC)n2nc(CCCN(CCO)c3ccc(F)cc3)nc2n1
Temperature: 125 °C
Yield: 72.1 %

Procedure:
A mixture of 3,5-heptanedione (216 mg, 1.68 mmol), 2-{[3-(5-amino-1H-1,2,4-triazol-3-yl)propyl](4-fluorophenyl)amino}ethan-1-ol (470 mg, 1.68 mmol), and pyridine (3 mL) was added to a 50 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 125° C. Progress of the reaction was monitored by TLC using chloroform:methanol:acetic acid (9:1:0.2) (Rf starting material=0.1, Rf product=0.7). The solution was heated for 17 hours, and an additional portion of 3,5-heptanedione (95 mg, 0.74 mmol) was added. After an additional 6 hours of heating, the reaction was complete by TLC disappearance of the starting material. The mixture was allowed to cool to room temperature, concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography using a gradient elution of 65-100% ethyl acetate in hexanes to afford the title compound as an oil (450 mg, 72% yield). 1H NMR (DMSO-d6, 400 MHz) δ ppm: 7.11 (s, 1H), 6.95 (m, 2H), 6.70 (m, 2H), 4.66 (t, 1H), 3.50 (q, 2H), 3.40 (t, 2H), 3.35 (m, 2H), 3.09 (q, 2H), 2.86 (q, 4H), 1.99 (m, 2H), 1.34 (t, 3H), 1.28 (t, 3H). EM (calc.): 371.2; MS (ESI) m/e: 372.3 (M+H)+.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1.O(Cl)Cl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:13]([Cl:17])([Cl:15])[Cl:14])=[CH:2][CH:3]=1)#[N:8]
Reactant: Cc1ccc(C#N)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: ClOCl
Product: N#Cc1ccc(C(Cl)(Cl)Cl)cc1
Reaction time: 96 h
Yield: 100 %

Procedure:
p-Tolunitrile (4.10 g, 0.035 mole) and dichlorine monoxide (6.93 g, 0.074 mole) in carbon tetrachloride (97 ml) were added to a bottle under nitrogen. The bottle was capped and stored at room temperature for 4 days. The water layer was separated, the organic layer dried (MgSO4) and the solvent removed on a rotary evaporator to give p-cyanobenzotrichloride as an oil (7.87 g, yield 100%). The oil was combined with a similar run and distilled in a short path still to give a white crystalline solid which was recrystallized from petroleum ether to give substantially pure p-cyanobenzotrichloride (mp 40.5°-41.7°).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][NH:14][CH3:15]>>[Cl:1][C:2]1[N:11]=[C:10]([N:14]([CH3:15])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(C)c1nc(Cl)nc2ccccc12

Procedure:
Prepared as in Example 38 from 2,4-dichloroquinazoline and dimethylamine. 1H NMR (400 MHz, CDCl3) δ 3.42 (s, 6H), 7.42-7.39 (m, 1H), 7.72-7.70 (m, 1H), 7.79-7.77 (m, 1H), 8.03-8.01 (m, 1H). MS 208 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](=[O:10])[CH3:9])[CH:3]=1.[CH3:11][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:3]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1cc(Cl)ncn1
Solvent: C1CCOC1
Product: CC(C)(O)c1cc(Cl)ncn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a stirred solution of 1-(6-chloro-4-pyrimidinyl)ethanone (Intermediate 18, 500 mg, 3.19 mmol)) in THF (5 mL) was added methylmagnesium bromide (1.171 mL, 3.51 mmol), and the resulting mixture stirred under argon at 0° C. for 2 hrs. The reaction was quenched with water (25 mL) with stirring and extracted with ethyl acetate (50 mL). The combined organic layers were dried (MgSO4), filtered and evaporated to dryness to afford the crude residues. Crude residues were then purified on Biotage Isolera on a pre-packed silica cartaridge (25 g) eluting with 0-20% ethyl acetate-isohexane. The appropriate fractions were combined and evaporated in vacuo to give the required product as a yellow oil (218 mg).
Reaction SMILES: [Br:1][C:2]1[S:24][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[N:8]([CH2:11][CH2:12][CH2:13][O:14][Si](C(C)(C)C)(C)C)[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:25]>Cl.CO.C(Cl)Cl>[Br:1][C:2]1[S:24][C:5]2[N:6]([CH3:23])[C:7](=[O:22])[N:8]([CH2:11][CH2:12][CH2:13][OH:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:25]
Reactant: Cc1c(Br)sc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Cc1c(Br)sc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.2 %

Procedure:
6-bromo-3-(3-(tert-butyldimethylsilyloxy)propyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4 (1H,3H)-dione (2.4 g, 4.39 mmol) was dissolved in aq. 6N HCl (15 mL) and MeOH (15 mL). The reaction was stirred at RT for 30 min then diluted with DCM (20 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4 and concentrated to give 6-bromo-3-(3-hydroxypropyl)-1,5-dimethylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.7 g, 95.5% yield) as a white solid. LCMS: MH+ 334 and TR=1.049 min. Used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].CC(=CC)C.O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:26])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=P([O-])(O)O
Reactant: CCc1ccc(Oc2ccc(C=O)cc2)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CCc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
An oxidation reaction (which is the method disclosed in Tetrahedron, (1987), 43, 4767-4776) was conducted using 4-(4-ethylphenoxy)benzaldehyde (which is the compound disclosed in J. Med. Chem., (1996), 39, 3984-3997, 500 mg, 2.21 mmol). 2-Methyl-2-butene (940 μL, 8.84 mmol), sodium dihydrogen phosphate dihydrate (338 mg, 2.16 mmol), and sodium chlorite (80%, 875 mg, 7.74 mmol) were added to a mixture solution of tert-butanol (3.6 mL) and water (1.0 mL) containing 4-(4-ethylphenoxy)benzaldehyde. The resulting mixture was stirred at room temperature, and the reaction was terminated with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 622 mg of 4-(4-ethylphenoxy)benzoic acid (white powder, yield: quantitative). Then, the same reaction as in Example 9 (9b) was conducted using all this 4-(4-ethylphenoxy)benzoic acid to give 437 mg of the title compound (pale red powder, yield: 66%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:38]1([C:44]([N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:49]3[CH2:48][CH2:47][N:46]([C:44]([N:38]4[CH2:39][CH2:40][O:41][CH2:42][CH2:43]4)=[O:45])[CH2:51][CH2:50]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(N1CCNCC1)N1CCOCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)N2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was coupled with morpholin-4-yl-piperazin-1-yl-methanone (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O4 [(M+H)+] 721.3031, observed 721.3031.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH2:35](O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:35]([N:1]([C:18]([O:20][CH2:21][CH:22]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29]2[C:34]1=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:19])[C@H:2]([C:15]([OH:17])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC[C@@H](C(=O)O)N(Cc1ccccc1)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a mixture of Fmoc-Lys(Boc)-OH (47, 2.0 g, 4.27 mmol) and benzyl alcohol (531 μL, 5.12 mmol) in CH2Cl2 (8.5 mL) at 0° C. was added DMAP (52 mg, 0.43 mmol) and DCC (1.06 g, 5.12 mmol). The mixture was stirred for 2 h at 0° C. and 3 h at room temperature, then filtered. Solids were washed with small portions of CH2Cl2 and the combined filtrates were concentrated, redissolved in EtOAc, washed with H2O, 0.5 N aqueous HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography on a Biotage™ flash chromatography system, using a gradient of 0-10% EtOAc in CH2Cl2 to furnish compound 48 (2.3 g, 96%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.25-1.39 (m, 2H), 1.40-1.52 (m, 2H), 1.43 (s, 9H), 1.66-1.75 (m, 1H), 1.82-1.90 (m, 1H), 3.02-3.11 (m, 2H), 4.20-4.24 (m, 1H), 4.35-4.52 (m, 4H), 5.16 (d, J=12.0 Hz, 1H), 5.22 (d, J=12.0 Hz, 1H), 5.39 (bd, J=8.0 Hz, 1H), 7.29-7.42 (m, 9H), 7.60 (d, J=7.5 Hz, 2H), 7.77 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][N:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[N:20][C:19]=12.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:29][N:27]1[CH:28]=[C:24]([C:22]2[CH:21]=[N:20][C:19]3[N:18]([N:17]=[CH:16][C:15]=3[C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:23]=2)[CH:25]=[N:26]1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: Cn1cc(-c2cnc3c(Br)cnn3c2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cnn3cc(-c4cnn(C)c4)cnc23)cc1
Temperature: 85 °C

Procedure:
[4-(Methoxycarbonyl)phenyl]boronic acid (0.5 g, 2.77 mmol) was added to 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (0.7 g, 2.52 mmol). DMF (12.5 mL) and 1M Na2CO3 (3.8 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.15 g, 0.13 mmol) was added in a counter flow of nitrogen. The reaction mixture was heated to 85° C. for 16 h, cooled, and poured into a 5-fold excess of water. The solids were filtered and dried to give crude methyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoate: LC/MS [M+H]=334.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc(NC(=O)Cl)cc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CCOc2ccc(N=C=O)cc2)cc1
Yield: 94.8 %

Procedure:
A solution of 4-[2-(4-methylphenyl)ethoxy]phenylcarbamyl chloride (IV) (14.4 g, 0.05 mole) in toluene (80 ml) was heated at 60° C. for 1 hour and distilled under reduced pressure to obtain 12 g of 4-[2-(4-methylphenyl)-ethoxy]phenyl isocyanate (III) as white crystals (yield, 94.9%). B.P., 170°-181° C./0.9 mmHg.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].ClCCCC(=O)C.C1(=O)NC(=O)C2=CC=CC=C12.[K].[C:38](=[S:41])([S-:40])[NH2:39].[NH4+]>C(O)C>[SH:41][C:38]1[S:40][CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][N:7]2[C:15](=[O:16])[C:14]3=[CH:13][CH:12]=[CH:11][CH:10]=[C:9]3[C:8]2=[O:17])[N:39]=1
Reactant: O=C(CBr)CCCN1C(=O)c2ccccc2C1=O
Reactant: NC(=S)[S-]
Agent: CC(=O)CCCCl
Agent: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CCCc1csc(S)n1
Yield: 57.8 %

Procedure:
2-(5-Bromo-4-oxopentyl)-isoindoline-1,3-dione (17.8 g) synthesized using 1-chloro-4-oxopentane and potassium phthalimide as starting materials and in reference to non-patent reference [Pharmazie, 47, 86 (1992)] and the like and ammonium dithiocarbamate (6.96 g) were suspended in ethanol (250 mL), and the suspension was refluxed for 6 hr. The precipitated crystals were collected by filtration and washed with ethanol to give the title compound (10.1 g) as white crystals.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9].[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[CH3:39])([CH3:30])[CH3:29])[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:24]([O:26][C:27](=[O:40])[C:28]([O:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:2][C:3]2[C:4]([CH2:20][CH2:21][O:22][CH3:23])=[N:5][C:6]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:7][C:8]=2[CH3:9])=[CH:34][C:33]=1[CH3:39])([CH3:29])[CH3:30])[CH3:25]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3ccc(C(F)(F)F)cc3)nc2CCOC)cc1C
Yield: 51.8 %

Procedure:
A solution of 350 mg (1 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 118G]), 235 mg (1 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 417 mg (1 mmol) cesium carbonate in 5 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 283 mg of pure 2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:5][C:6]=1[C:7]([O:9]C)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1>>[CH2:11]([C:4]1[S:3][C:2]2[N:1]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][N:21]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1cc(C(=O)OC)c(N)s1
Reactant: COC(=O)c1ccc(Cl)nc1
Product: CCCCc1cc2c(=O)n3cc(C(=O)OC)ccc3nc2s1
Yield: 42.1 %

Procedure:
From 5.1 g (0.024 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, methyl ester and 4.1 g (0.024 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company), following the procedure of Example 7, there is obtained 3.2 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester; mp 137°-138° C. after recrystallization from methanol.
Reaction SMILES: C([C:6]1[C:7]([S:17]([NH:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])(=[O:19])=[O:18])=[N:8][N:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[N:11][C:10]=12)(OCC)=O.Cl.O>CC(O)=O>[CH3:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]2[N:8]=[C:7]([S:17]([NH:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:18])=[O:19])[CH:6]=[C:10]2[N:11]=1
Reactant: CCOC(=O)c1c(S(=O)(=O)Nc2c(F)cccc2F)nn2c(C)cc(C)nc12
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(F)cccc3F)cc2n1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A slurry of 4.8 g (10.8 mmole) of 3-carboethoxy-5,7-dimethyl-N-(2,6-difluorophenyl)pyrazolo[1,5-a]pyrimidine-2-sulfonamide in 30 ml glacial HOAc was stirred at room temperature with 1 ml concentrated HCl and 3 ml water for 2 hours. The mixture was then heated at 110° C. for 16 hours. A further 1 ml concentrated HCl and 5 ml water were added and the mixture stirred for 16 hours, then cooled to room temperature. The mixture was thrown onto ice and the resultant solid collected by filtration, washed with water and dried to give 2.34 g (64 percent) of the product as a brown powder, m.p. 201°-208° C. An analytical sample was recrystallized from CH3CN/EtOAc/CH3OH, m.p. 209°-211° C. (dec). 1H NMR (DMSO-d-6): 10.3 (s, 1H, NH), 7.37 (m, 1H, benzene), 7.10 (m including s, 3H, aromatic and H-3 or H-6), 6.82 (s, 1H, H-3 or H-6), 2.63 (s, 3H, CH3), 2.53 (s, 3H, CH3). IR (KBr): 3400, 3050, 2800, 1625, 1600, 1540, 1480, 1430, 1325, 1290, 1240, 1170, 1140, 1000. Analysis: Calculated for C14H12N4F2O2S: C, 49.70; H, 3.58; N, 16.56. Found: C, 48.68; H, 3.74, N, 15.98.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9]2=N)[CH2:3][CH2:2]1.[OH-:20].[Na+]>Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH:8]2[CH2:12][N:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][C:9]2=[O:20])[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N=C1NN(c2ccccc2)CC1CN1CCOCC1
Agent: Cl
Agent: [Na+]
Product: O=C1NN(c2ccccc2)CC1CN1CCOCC1

Procedure:
A solution of 4-morpholinomethyl-1-phenylpyrazolidin-3-imine (29g) in dilute hydrochloric acid (120 ml of 2N) was boiled under reflux for 4 hours. The solution was cooled, neutralised with sodium hydroxide and extracted with chloroform. The chloroform extract was dried and evaporated to dryness. The solid residue was recrystallized from petroleum ether (boiling point 100°-120° C) as colourless plates (melting point 143°-144° C).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[C@@H:10]([OH:14])[C:11]([NH2:13])=[O:12].CS(O)(=O)=O>C1(C)C(C)=CC=CC=1>[OH:14][C@H:10]1[C:11](=[O:12])[NH:13][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][C@H:9]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc([C@H](Sc2ccccc2N)[C@@H](O)C(N)=O)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1C
Product: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of (2S,3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propioamide (1.59 g), xylene (8 ml) and methanesulfonic acid (24 ml) is refluxed for 11 hours. The reaction solution is allowed to cool to room temperature with stirring. The precipitated crystals are collected by filtration, washed with cold methanol, and dried at 50° C. to give (2S,3S)-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5H)-one (1.41 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].C(Cl)(=O)C(Cl)=O.N1C=C[CH:20]=[CH:19][CH:18]=1.C(O)(C)C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH:19]([CH3:20])[CH3:18])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1sc(C(=O)O)cc1Br
Reactant: c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClCCl
Product: Cc1sc(C(=O)OC(C)C)cc1Br
Reaction time: 0.5 h
Yield: 32.1 %

Procedure:
A solution of 5 g (22.6 mmol) of 4-bromo-5-methylthiophene-2-carboxylic acid was dissolved in dry dichloromethane (200 mL) and reacted with oxalyl chloride (2 mL, 22.6 mmol) and dimethylformamide (100 μL) stirring on an ice bath for 30 min and then at room temperature for 2.5 h. The solvents were removed in vacuo and the residue was passed through silica gel, eluting off with hexanes:ethyl acetate 7/3 (v:v), ethyl acetate, and dichloromethane. The solvents were removed in vacuo and the resulting oil dissolved in dry dichloromethane (100 mL). This solution was reacted with dry pyridine (9 mL, 113 mmol) and dry isopropanol (40 mL, 522 mmol) for 88 h. The solvents were removed in vacuo and the residue partitioned between sodium bicarbonate (150 mL) and dichloromethane (75 mL). The aqueous layers were extracted with dichloromethane (2×20 mL), and the combined organic layers were washed with sodium bicarbonate (30 mL), brine (30 mL), and dried over anhydrous sodium sulfate. The solvents were removed in vacuo. The residue was purified by column chromatography eluting with hexanes:ethyl acetate 9/1 (v:v) to give isopropyl 4-bromo-5-methylthiophene-2-carboxylate (1.91 g, 32%) as a pale yellow oil. 1H-NMR NMR (DMSO-d6; 300 MHz) δ7.66 (s, 1H), 5.07 (septet, 1H, J=6.2 Hz), 2.42 (s, 3H), 1.29 (d, 6H, J=6.2 Hz). Mass spectrum (ESI, m/z): Calcd. for C9H11O2SBr 264.2 (M+H), found 264.8.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH2:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCn1ccnc1
Product: O=S(=O)(NCCn1ccnc1)c1ccc(Br)cc1

Procedure:
When 1H-imidazole-1-ethanamine was treated with 4-bromobenzenesulfonyl chloride by the procedure of Example 20, the compound of this example, mp 165°-167° C., was obtained.