Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C4C=CC([N+]([O-])=O)=CC=4)[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:44]([C:47]1[CH:51]=[C:50]([CH2:52][OH:53])[O:49][N:48]=1)(=[O:46])[NH2:45]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH2:15][CH2:16][CH:17]([CH2:20][CH2:21][NH:22][C:23](=[O:24])[O:53][CH2:52][C:50]4[O:49][N:48]=[C:47]([C:44](=[O:46])[NH2:45])[CH:51]=4)[CH2:18][CH2:19]3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(CO)on1
Reactant: O=C(NCCC1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(COC(=O)NCCC2CCN(c3ccc(-c4ccc(F)cc4)cn3)CC2)on1

Procedure:
A solution of 0.25 g (0.54 mmol) of 4-nitrophenyl 2-[5′-(4-fluorophenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-ethylcarbamate, prepared in step 1.5., 0.139 g (1.08 mmol) of N,N-diisopropylethylamine, 0.033 g (0.27 mmol) of N,N-dimethylaminopyridine and 0.084 g (0.59 mmol) of 3-carbamoylisoxazol-5-ylmethanol in 5 mL of 1,2-dichloroethane is heated in a sealed tube at 90° C. for 12 hours.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:15])[F:14])[NH:6]2.[C:16]([O:20][C:21](=[O:25])[CH:22](Br)[CH3:23])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH:13]([F:14])[F:15])[N:6]2[CH:22]([CH3:23])[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:25]
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1Cl
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C(=O)OC(C)(C)C)n1c(C(F)F)cc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-chloro-2-(difluoromethyl)-1H-indole-5-carbonitrile, 2-bromopropionic acid t-butyl ester (1.5 eq) and Cs2CO3 (1.5 eq): MS (ES) m/z 355 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:15].[Na+].C(Cl)(Cl)Cl>C(O)C>[O:1]([C:8]1[C:9]2[CH:4]=[C:3]([C:2]([OH:1])=[O:15])[O:14][C:10]=2[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: O=C(O)c1cc2c(Oc3ccccc3)cccc2o1
Reaction time: 2 h

Procedure:
14.0 g of meta-phenoxyphenol was dissolved in 700 ml of 95% ethanol. 468 g of sodium hydroxide was then added rapidly. The resulting suspension was heated to 70°-80° C. Then 558.7 g of chloroform was added, at such a rate that gentle reflux was maintained; the addition required 10 hours. The mixture then was stirred for 2 hours at 75°-80° C., held at room temperature overnight and filtered. The solid product was dissolved in 1000 ml of water. The solution was acidified to pH=2 with concentrated hydrochloric acid, then was extracted with ether. The ether layer was dried (MgSO4) and concentrated. The residue was extracted with hot petroleum ether. The extract was dried (Na2SO4) and concentrated to give an oil, which was wet column chromatographed over silica gel, using first a 9/1 v/v mixture, then a 4/1 v/v mixture of petroleum ether and ether as eluent. The fourth fraction obtained, after removal of the solvents, was identified as 2-hydroxy-6-phenoxybenzaldehyde.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+].O>C(O)C>[CH:1](=[C:10]1[CH2:11][CH2:12][CH2:13][C:14](=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C(=Cc2ccccc2)CCCC1=Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
Benzaldehyde (1b, 1.00 ml, 9.8 mmol) and cyclohexanone (37, 0.51 ml, 4.9 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 0.99 g (73%) of yellow crystals: mp 118-119° C. [expected mp 117° C.]; 1H NMR: δ 1.77 (m, 2H), 2.92 (t, 4H, J=5.2 Hz), 7.39 (m, 10H), 7.80 (s, 2H); 13C NMR: δ 23.1, 28.5, 128.3, 128.5, 130.2, 135.9, 136.1, 136.8, 190.1.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[CH:2][C:1]([OH:4])=[O:3]
Reactant: O=Cc1ccccc1Cl
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1Cl
Temperature: 145 °C
Reaction time: 18 h

Procedure:
A mixture of 18.4 g (0.19 mol) of potassium acetate in 70.3 g (0.5 mol) 2-chlorobenzaldehyde is heated to 145° C. Next 76.5 g (0.75 mol) of acetic anhydride is added in 1 hour. After dosing of 0.50 mol of acetic anhydride the mixture became clear. The mixture is stirred at 145° C. during 18 hours. The hot reaction mixture is poured into a mixture of 670 g of 6.4 w/w % aqueous NaOH (1.1 mol, 2.1 eq based on 2-chlorobenzaldehyde) and 200 mL toluene at 80° C. The final pH was 7.4. After separation of the organic phase, the water layer is again extracted with 100 mL of toluene at 80° C. The combined water phases are acidified with 380 g of 25 w/w % H2SO4 to pH 4.6. Crystallization starts at pH 6.4. The mixture is cooled to 25° C. and the product is isolated by filtration, washed with 100 mL of water and dried (vacuo, 50° C.). 3-(2-chloro-phenyl)-acrylic acid was obtained as an off white solid (100.2 g, 0.55 mol, yield 55%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([OH:26])=[C:21]([Cl:27])[CH:20]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:25][C:23]1[CH:24]=[C:19]([NH:18][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:20]=[C:21]([Cl:27])[C:22]=1[OH:26]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cc(Cl)c(O)c(Cl)c3)c2cc1OC

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 213.6 mg (1.2 mmol) of 4-amino-2,6-dichlorophenol and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 1 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether/ethyl acetate (1:1). After drying in vacuo, this yielded 346.7 mg (88.8%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 389.8, 391.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: ClCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2ccccn2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (35.0 mg, 0.074 mmol), 2-(chloromethyl)pyridine (13.3 mg, 0.082 mmol, 1.05 equiv), and cesium carbonate (72.3 mg, 0.22 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 35.2 mg (77%). Mass spec.: 563.3 (MH)+.
Reaction SMILES: C(O)(=O)C.[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH2:18])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[C:5]([N:8]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:13][C:12]=2[C:11]2[N:19]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)[N:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:10]=2[CH2:9]1)(=[O:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(N)ccc21
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)N1Cc2c(C(N)=O)nn(-c3ccc4c(c3)OCO4)c2-c2cc(NS(C)(=O)=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25 %

Procedure:
The title material from Example 17 step 6 (300 mg, 0.000767 mol) was dissolved in pyridine (5 mL), and to this solution was added methane sulfonyl chloride (88 mg, 0.000767 mol). The resulting solution was stirred at room temperature for 18 hours. The reaction was then concentrated in vacuo, and the resulting solids were triturated with water and the product was isolated by vacuum filtration. 88 mg. (MW=469.48, 25% yield). LC/MS m/z=470.3 (m+1).
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3].[OH:25][CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=O)[O:27]1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([Cl:20])=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH:28]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:26](=[O:25])[O:27]4)[CH2:16][CH2:15]3)[CH:12]=2)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]1)[CH3:3]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCNCC3)cc21
Reactant: O=C1OC(O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(Cl)c(N3CCN(C4OC(=O)c5ccccc54)CC3)cc21
Yield: 76.9 %

Procedure:
A mixture of 1-ethyl-6-chloro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride 1.9 g (0.005 mole), 3-hydroxyphthalide 0.75 g (0.005 mole), triethylamine 0.5 g (0.005 mole) and DMF 10 ml was heated at 100°-110° C. for 8 hours under stirring. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in dichloromethane, washed with water and dried with anhydrous Na2SO4. After removing the solvent, the residue was recrystallized from a mixed solvent of DMF and ethanol to obtain 1.8 g (78%) of 1-ethyl-6-chloro-7-(4-phthalidyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. Colorless powders.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH2:53])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:32][CH2:31]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>ClCCl>[CH2:15]([NH:22][C:23](=[O:54])[NH:24][C:25]1[CH:52]=[CH:51][C:50]([NH:53][C:12](=[O:14])[CH3:13])=[CH:49][C:26]=1[C:27]([NH:29][CH:30]1[CH2:31][CH2:32][N:33]([CH:36]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:34][CH2:35]1)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCNC(=O)Nc1ccc(N)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)Nc1ccc(NC(C)=O)cc1C(=O)NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 24 h
Yield: 807.6 %

Procedure:
Triethylamine (0.098 ml, 0.65 mmol) and acetic anhydride (0.067 ml, 0.07 mmol) were added to a solution of the 2-(N'-n-heptylureido)-5-amino-N-(1-diphenylmethylpiperidin-4-yl)-benzamide (0.32 g, 0.59 mmol) in dichloromethane (3 ml) at room temperature. The mixture was stirred for 24 hours and then concentrated. The residue was purified by column chromatography on silica gel (50% ethyl acetate in cyclohexane) to give 2-(N'-n-heptylureido)-5acetylamino-N-(1-diphenylmethylpiperidin-4-yl)benzamide (0.33 g, 96.0%): mp 113°-115° C., 1H NMR (CDCl3)ppm: 0.86 (3H, t), 1.27 (8H, m), 1.49-1.69 (4H, m), 1.92-2.08 (4H, m), 2.17 (3H, s), 2.85 (2H, m), 3.22 (2H, q), 3.90 (1H, m), 4.28 (1H, s), 4.57 (1H, t), 6.40 (1H, d), 7.03 (1H, dd), 7.15-7.40 (11H, m), 8.06 (1H, d), 8.30 (1H, d), 10.10 (1H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:5][N:4]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]2[N:19]=[C:20]([SH:22])[NH:21][C:17]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:9][C:8]1[C:3]([CH2:2][S:22][C:20]2[NH:21][C:17]3[CH:16]=[C:15]([C:14]([F:26])([F:25])[F:13])[CH:24]=[CH:23][C:18]=3[N:19]=2)=[N:4][CH:5]=[CH:6][C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1c([N+](=O)[O-])ccnc1CCl
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c([N+](=O)[O-])ccnc1CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.4 g of 2-(chloromethyl)-3-methyl-4-nitropyridine and 10 g of 5-(trifluoromethyl)-2-benzimidazolethiol in 260 ml of abs. acetone was treated with 3 g of finely ground potassium carbonate and stirred at room temperature under argon for 18 hours. 180 ml of acetone were distilled off in a vacuum, whereupon the remaining portion of the reaction mixture was poured on to ice. The crystallized-out product was filtered off and dried at 35° in a drying oven By recrystallization from ethyl acetate/n-hexane there was obtained 2-[[(3-methyl-4-nitro 2-pyridyl)methyl]thio]-5-(trifluoromethyl)benzimidazole of melting point 192°-193°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=1.[Li]CCCC.[C:16](=[O:18])=[O:17]>C1COCC1>[C:7]([N:5]1[CH:6]=[C:2]([C:16]([OH:18])=[O:17])[CH:3]=[N:4]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C=O
Reactant: CC(C)(C)n1cc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)n1cc(C(=O)O)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a −78° C. solution of 4-bromo-1-t-butyl-1H-pyrazole (15 g, 74.3 mmol) in anhydrous THF (100 mL) was added n-BuLi (2.5 M in hexane, 53 mL, 132 mmol) under N2, and the resulting mixture was stirred at −78° C. for 30 min. Excess dry ice was added at −78° C., and the mixture was warmed slowly to RT and stirred overnight. The reaction was concentrated in vacuo, water was added and the pH was adjusted to pH 3 by the addition of 2N aq HCl. The aqueous solution was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was recrystallized (EtOAc-pet. ether) to give 1-t-butyl-1H-pyrazole-4-carboxylic acid (8.0 g, 67% yield). 1H NMR (300 MHz, CDCl3): δ 8.10 (s, 1 H), 8.03 (s, 1 H), 1.64 (s, 9 H); MS (ESI) m/z: 168.9 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH:31]([C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[N:23]1([CH2:22][CH2:21][N:20]([CH2:31][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:19][CH2:18][O:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:9]3[CH:10]=[CH:11][C:6]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[CH:7][CH:8]=3)=[CH:30][CH:29]=2)[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: c1coc(-c2ccc(Cc3ccc(OCCNCCN4CCOCC4)cc3)cc2)n1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CN(CCOc2ccc(Cc3ccc(-c4ncco4)cc3)cc2)CCN2CCOCC2)cc1
Reaction time: 17 h
Yield: 84 %

Procedure:
A solution of N-[2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]-4-morpholineethanamine (0.25 g, 0.6 mmol) and methyl 4-formylbenzoate (0.11 g, 0.66 mmol) in dichloroethane (5 mL) was stirred as sodium triacetoxyborohydride (0.16 g, 0.74 mmol) was added and stirred for 17 h. The reaction was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried and concentrated. Purification by chromatography on silica gel using a gradient of methanol in dichloromethane gave 0.28 g of methyl 4-[[[2-(4-morpholinyl)ethyl][2-[4-[[4-(2-oxazolyl)phenyl]methyl]phenoxy]ethyl]amino]-methyl]benzoate; 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 4H), 7.68 (s, 1H), 7.42 (d, 2H), 7.27 (d, 2H), 7.21 (s, 1H), 7.08 (d, 2H), 6.78 (d, 2H), 4.03 (t, 2H), 3.96 (s, 2H), 3.92 (s, 3H), 3.79 (s, 2H), 3.66 (m, 4H), 2.92 (t, 2H), 2.73 (t, 2H), 2.47 (m, 2H) 2.42 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[C:43]1([CH3:52])[C:44]([N:49]=[C:50]=[S:51])=[CH:45][CH:46]=[CH:47][CH:48]=1>CN(C=O)C>[C:43]1([CH3:52])[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[NH:49][C:50]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[S:51]
Reactant: Cc1ccccc1N=C=S
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=S)Nc3ccccc3C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 131.4 %

Procedure:
To a DMF solution (2 ml) of ice-cooled bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol), 60% oily NaH (18 mg) was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, o-tolyl isothiocyanate (59.8 μl, 0.445 mmol) was added, followed by further stirring for 2 hours. The reaction mixture was ice-cooled, and quenched with water (1 ml). This was diluted with dichloromethane (10 ml), and washed with water (10 ml×2). After the organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carbothioic acid o-tolylamide as a brown solid (134 mg). The PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-210) as a yellow powder (35.9 mg, 54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: Fc1cnc2[nH]nc(I)c2c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12.1 g (39.65 mmol) of the compound from Example 6A were initially charged in DMF (217 ml), and 8.25 g (43.62 mmol) of 2-fluorobenzyl bromide and 14.21 g (43.62 mmol) of cesium carbonate were then added. The mixture was stirred at RT for two hours. The reaction mixture was then poured onto water (1.17 l) and extracted twice with ethyl acetate (502 ml). The collected organic phases were washed with saturated aqueous sodium chloride solution (335 ml), dried, filtered and concentrated. The residue was chromatographed on silica gel (eluent: 97:3 petroleum ether/ethyl acetate) and the product fractions were concentrated. This gave 9.0 g (61% of theory) of the desired compound in solid form. The solid was taken up in ethyl acetate and washed with 10% aqueous sodium thiosulfate solution and then with saturated aqueous sodium chloride solution, dried and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:13])=[CH:10]/[CH2:11][OH:12])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:14]([O:16][C@@H:17]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:15]>>[Br:1][C:2]1[CH:3]=[C:4](/[C:9](/[CH3:13])=[CH:10]/[CH2:11][O:12][C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C@H:17]([O:16][CH2:14][CH3:15])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:29][CH:28]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: C/C(=C\CO)c1cc(Br)cc(Br)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2cc(Br)cc(Br)c2)cc1)OCC
Yield: 80.9 %

Procedure:
The title compound (851 mg, 81%) was prepared from (E)-3-(3,5-dibromo-phenyl)-but-2-en-1-ol (612 mg, 2.0 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (500 mg, 2.10 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: Br[CH:2]([CH:7](Br)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[C:11]2[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[C:3]([O:5][CH3:6])=[O:4].[OH-].[K+].[CH2:27](O)C>>[N:21]1[CH:22]=[CH:23][C:18]([C:11]2[C:10]3[C:15](=[CH:16][CH:17]=[C:8]([C:7]#[C:2][C:3]([O:5][CH2:6][CH3:27])=[O:4])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)C(Br)C(Br)c1ccc2nccc(-c3ccncc3)c2c1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOC(=O)C#Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 95 °C
Yield: 60 %

Procedure:
A slurry of methyl 2,3-dibromo-3-[4-(4-pyridinyl)-6-quinolinyl]propanoate (4.20 g, 9.33 mmol) in ethanol (120 ml) was treated with solid potassium hydroxide pellets in one portion then heated at 95° C. for 2 hours. The reaction was cooled to room temperature then evaporated under reduced pressure. The resulting residue was diluted with ethanol (90 ml) and concentrated H2SO4 (3 ml) then heated at 95° C. for 3.5 hours. Cooled to room temperature then concentrated under reduced pressure. The resulting wet residue was taken into a minimum of water then made neutral with the addition of saturated aqueous NaHCO3 solution. This solution was extracted with EtOAc and the extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (EtOAc) to give the title compound (1.68 g, 60%) as a pale yellow solid. MS(ES)+ m/e 303 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[C:34]([CH2:35]OS(C)(=O)=O)=[C:33]([CH3:41])[O:32][N:31]=1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:35][C:34]2[C:30]([CH3:29])=[N:31][O:32][C:33]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Reactant: Cc1noc(C)c1COS(C)(=O)=O
Solvent: CO
Product: Cc1noc(C)c1Cn1cc(C(=O)N2CCC3(CC2)OC(=O)c2cc(F)ccc23)c2ccc(Cl)cc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19 above) with methanesulfonic acid 3,5-dimethyl-isoxazol-4-ylmethyl ester (prepared by mesylation of the commercially available 1,5-dimethyl-1H-pyrazol-3-yl)-methanol) gave the title compound. ES-MS m/e (%): 508.2 (M+H+).