Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([OH:13])=O)=[C:4]([CH2:14][CH3:15])[CH:3]=1.CCN(CC)CC.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[N:45]1([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:48]2[CH2:47][CH2:46][N:45]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:50][CH2:49]2)=[O:13])=[C:4]([CH2:14][CH3:15])[CH:3]=1
Reactant: CCc1cc(Cl)c(Cl)cc1NCC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(Cl)c(Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.5 %

Procedure:
To a stirred mixture of 2-(4,5-dichloro-2-ethylphenylamino)acetic acid (100 mg, 0.403 mmol), Et3N (122 mg, 1.21 mmol) in DCM (3 mL) at 0° C., EDCI.HCl (123 mg, 0.604 mmol) and HOBt (8 2 mg, 0.604 mmol) were added. The resulting mixture was stirred at 0° C. for 30 min, and then tert-butyl piperazine-1-carboxylate (90 mg, 0.483 mmol) was added. The mixture was stirred at room temperature for 16 h and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=5:1) to afford the desired product (120 mg, 71.5% yield) as an off-white solid. ESI-MS m/z: 414.3 [M−H]−.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH:36]([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH2:40]([O:39][C:37]([CH:36]([O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)[CH3:42])=[O:38])[CH3:41]
Reactant: CCOC(=O)C(C)Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: CCOC(=O)C(C)OC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Method D, 0.5 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.15 ml of ethyl 2-bromopropionate are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.40 (1:1 EtOAc-heptane); Rt=5.93/6.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16]Cl.O>CS(C)=O>[Cl:13][C:14]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:15]=1[CH2:16][N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6]
Reactant: O=C1NCCN1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1Cc1ccc(Cl)cc1Cl
Reaction time: 0.3 h
Yield: 77 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 200 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 48.9 g (0.25 mole) of 2,4-dichlorobenzyl chloride. The reaction mixture was heated with stirring to 105° over 0.3 hours, held at 105° for 1.8 hours, and poured with rapid stirring into 1.5 l of water. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 580 ml of water, dried over MgSO4 overnight and filtered. The filtrate was concentrated under reduced pressure leaving 47 g (77%) of a light yellow oil. The oil was crystallized with 125 ml of ether, filtered, air dried, and dried to a constant weight at 60° to give 19 g (31%) of a white solid, m.p. 116°-118°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1.[S:32](N)([NH2:35])(=[O:34])=[O:33]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:26][CH2:27][N:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:4]([CH3:31])[CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCNCC3)cc2)c2ccc(Cl)cc2C)ccn1
Solvent: C1COCCO1
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(S(N)(=O)=O)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Yield: 82.3 %

Procedure:
A solution of (R)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)-3-(4-(piperidin-4-yl)phenyl)propan-1-one (60 mg, 0.14 mmol) and sulfamide (20 mg, 0.21 mmol) in 1,4-dioxane (5 mL) was stirred for 17 h at 108° C., then partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Flash chromatography (silica gel, 50% to 100% EtOAc in heptane) afforded the title compound (59 mg, 83%). White foam, MS (ESI+): m/z=512.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([CH:17]=O)=[CH:10][CH:9]=2)=[O:4].[OH:19][CH2:20][C@H:21]([NH:28][C:29]1[S:30][CH2:31][C:32](=[O:34])[N:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11](/[CH:17]=[C:31]1/[C:32](=[O:34])[N:33]=[C:29]([NH:28][C@H:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][OH:19])[S:30]/1)=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C1CSC(N[C@@H](CO)c2ccccc2)=N1
Reactant: COC(=O)c1cnc2ccc(C=O)cc2c1OC
Product: COC(=O)c1cnc2ccc(/C=C3\SC(N[C@@H](CO)c4ccccc4)=NC3=O)cc2c1OC

Procedure:
Similar procedure as described in example 1g was used, starting from 6-formyl-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1e) and 2-((R)-2-hydroxy-1-phenyl-ethylamino)-thiazol-4-one (example 3a) to give 6-[2-((R)-2-hydroxy-1-phenyl-ethylamino)-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-methoxy-quinoline-3-carboxylic acid methyl ester. LC-MS m/e 464 (MH+).
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.COC1C=C([Mg]Br)C=CC=1OC.[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]=1.Cl>O1CCCC1>[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](=[O:31])[C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([O:11][CH3:12])[CH:4]=2)=[CH:28][N:27]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COc1ccc(Br)cc1OC
Agent: COc1ccc([Mg]Br)cc1OC
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Cl)nc2)cc1OC
Yield: 67.3 %

Procedure:
To 200 ml of tetrahydrofuran were added metallic magnesium (5.35 g) and 4-bromoveratrole (47.8 g), and the mixture was heated for 3 hours under reflux to prepare a 3,4-dimethoxyphenyl magnesium bromide solution. This solution was added, while stirring, dropwise at temperatures ranging from -50° C. to -60° C. to a solution of 6-chloronicotinic acid chloride (21.2 g) in tetrahydrofuran (200 ml) (the time required for the addition: one hour). The resultant mixture was stirred at the same temperature for 2 hours and 40 minutes, and there was then added 2N hydrochloric acid (100 ml). Precipitating crystals were collected by filtration, washed with water and dried to afford 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine (22.5 g), m.p. 158° to 159° C.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[N:12]=[C:13]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[N:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[C:15]=12.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[CH:48](O)=[O:49]>C(Cl)Cl>[NH2:20][C:16]1[C:15]2[N:14]([C:13]([CH:21]3[CH2:26][CH2:25][N:24]([CH:48]=[O:49])[CH2:23][CH2:22]3)=[N:12][C:11]=2[C:3]2[NH:2][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:19]=[CH:18][N:17]=1
Reactant: Nc1nccn2c(C3CCNCC3)nc(-c3cc4ccccc4[nH]3)c12
Reactant: O=CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccn2c(C3CCN(C=O)CC3)nc(-c3cc4ccccc4[nH]3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 432.5 %

Procedure:
To a solution of 1-(1H-Indol-2-yl)-3-piperidin-4-ylimidazo[1,5-a]pyrazin-8-amine hydrochloride (30.00 mg, 0.0068 mmol) in DCM (0.5 mL, 0.008 mol) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0195 g, 0.102 mmol), N,N-diisopropylethylamine (0.047 mL), 1-hydroxbenzotriaxole hydrate (0.0104 g, 0.0679 mmol) and formic acid (4.7 mg, 0.10 mmol). The reaction was stirred at rt overnight then diluted with DCM, washed with saturated NaHCO3 (2×25 mL) and brine (2×25), then dried over Na2SO4 and concentrated in vacuo. The material thus isolated was crystallized from EtOAc to afford 10.6 mg of desired product. 1H NMR (400 MHz, CDCl3): δ 2.04-2.12 (m, 4H), 2.99-3.00 (m, 1H), 3.27-3.32 (m, 2H), 3.85 (m, 1H), 4.49 (m, 1H), 5.70 (br, 2H), 6.80 (s, 1H), 7.13-7.24 (m, 4H), 7.45 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 8.97 (br, 1H). MS (ES+): m/z 361.16 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH:16]([CH:19]=O)[CH:17]=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH2:21][NH2:22].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:19]=[N:21][NH:22][CH:17]=1
Reactant: O=CC(C=O)C(c1ccccc1)c1ccc(Cl)cc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: Clc1ccc(C(c2ccccc2)c2cn[nH]c2)c(Cl)c1

Procedure:
Two grams of [(2,4-dichlorophenyl)phenylmethyl]malonaldehyde in 10 ml of ethanol were heated with 3 ml of anhydrous hydrazine on a steam bath for two hours. The reaction mixture was poured into water and extracted with ether. The ether extract was dried, filtered, and evaporated. The residue was crystallized twice from Skelley B/acetone to provide 1.2 g of the desired title product, m.p. 131° C.
Reaction SMILES: [C:1]([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:16][CH:17]([C:25]([F:28])([F:27])[F:26])[C:18]([F:24])([F:23])[S:19]([O-:22])(=[O:21])=[O:20].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:24][C:18]([F:23])([S:19]([O-:22])(=[O:21])=[O:20])[CH:17]([O:16][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:15][CH:14]=1)[C:25]([F:28])([F:26])[F:27].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: C=C(C)C(=O)Oc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 2.4 g (11 mmol) of the resulting 4-methacryloyloxybenzoic chloride were added 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11 and 20 g of methylene chloride, which was ice cooled. To the solution, a solution of 1.1 g (11 mmol) of triethylamine and 0.2 g (2 mmol) of N,N-dimethylaminopyridiene in 5 g of methylene chloride was added such that the temperature might not exceed 5° C., followed by stirring at room temperature for 3 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. The residue was washed with diisopropyl ether and purified by silica gel chromatography. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-methacryloyloxy-benzoyloxy)-propane-1-sulfonate was obtained as colorless oil (6.0 g, yield 88%). The compound has the following structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10]Br.[OH:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1>>[F:7][C:8]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:9]=1[CH2:10][O:17][C:18]1[N:19]=[C:20]([S:36][CH3:37])[N:21]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=2[CH3:35])[C:28]([O:30][CH3:31])=[O:29])[C:22](=[O:24])[CH:23]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(SC)nc(O)cc2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(C)c(-n2c(SC)nc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
To a solution of methyl 3-[4-hydroxy-2-(methylthio)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (1.0 g, 0.0033 mol) in DMF (10.0 mL) obtained from step 2, was added potassium carbonate (0.7 g, 0.005 mol) followed by the addition of 2,4difluorobenzyl bromide (0.8 g, 0.0039 mol) and stirred at 0° C. for 15 min. After stirring at room temperature for 30 min, DMF was distilled in vacuo and the residue was portioned between EtOAc (25 mL) and water (25 mL). The organic phase was washed with water, (2×20 mL), dried (Na2SO4) and concentrated. The resulting material was purified by flash chromatography using EtOAc/hexane (1:1 v/v) to afford the title compound (0.9 g, 64%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.08 (dd, 1H, J=8.4 Hz, & 1.6 Hz), 7.83 (d, 1H, J=1.6 Hz), 7.55 (m, 2H), 6.99 (m 2H), 5.64 (s, 1H), 5.48 (s, 2H), 3.89 (s, 3H), 2.50 (s, 3H), and 2.15 (s, 3H); ES-HRMS m/z 433.1016 (M+H calcd for C21H19N2O4SF2 requires 433.1028).
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:24][O:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:10]([CH2:11][CH2:12][CH3:13])[C:5]=2[O:4][N:3]=1
Reactant: CCCc1c(OCc2ccccc2)ccc2c(O)noc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCc1c(OCc2ccccc2)ccc2c(OC)noc12

Procedure:
A solution of 3-hydroxy-6-benzyloxy-7-propyl benz[4,5]isoxazole (195 mg) in acetone (3 mL) was treated with methyl iodide (0.067 mL) and potassium carbonate (100 mg). The mixture was refluxed for 8 hours. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was dried over magnesium sulfate, filtered and concentrated to a solid, which was chromatographed over silica gel to afford the product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>ClCCl>[C:1]([O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCCCCCOc1ccccc1O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCOc1ccccc1OC(C)=O
Reaction time: 1 h
Yield: 94.8 %

Procedure:
Acetyl chloride (2.4 g, 30.1 mmol) was added dropwise to vigorously stirred mixture of 2-hexyloxyphenol (5.0 g, 25.8 mmol) and pyridine (5 ml) in dichloromethane (50 ml). The mixture was stirred for 1 hour and poured onto water. The organic layer was separated, dried (MgSO4), concentrated to give crude product which was purified by column chromatography on silica gel using dichloromethane petroleum spirit (1:3) as eluent to give title compound as a colourless oil (5.78 g, 95%). Found: C, 71.00; H, 8.35. C14H20O3 requires C, 71.19; H, 8.47. δH (CHCl3) 7.21-7.15 (m, 1H, ArH), 7.05-7.01 (m, 1H, ArH), 6.97-6.89 (m, 2H, ArH), 3.97 (t, J 6.5, 2H, OCH2), 2.30 (s, 3H, COCH3), 1.78-1.71 (m, 2H, ArOCH2CH2), 1.57-1.30 (m, 6H, CH2), 0.90 (t, J 6.9, 3H, CH2CH3). MS (FAB), 236 (M+, 53%), 194 (100%), 153 (27%), 110 (34%), 85 (7%), 55 (7%).
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12](=[O:36])[NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([NH:25][C:26]2[C:27]([CH3:35])=[CH:28][N:29]3[C:34]=2[CH:33]=[CH:32][CH:31]=[CH:30]3)=[O:24])[CH:18]=1)([CH3:10])([CH3:9])[CH3:8].Cl[C:38]([C:40]1[CH:41]=[CH:42][C:43]([NH:56][C:57](=[O:62])[C:58]([F:61])([F:60])[F:59])=[C:44]([CH:55]=1)[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=[O:39]>ClCCl>[C:7]([O:11][C:12]([NH:13][CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[C:23]([NH:25][C:26]1[C:27]([CH3:35])=[C:28]([C:38]([C:40]2[CH:41]=[CH:42][C:43]([NH:56][C:57](=[O:62])[C:58]([F:61])([F:59])[F:60])=[C:44]([CH:55]=2)[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[O:39])[N:29]2[C:34]=1[CH:33]=[CH:32][CH:31]=[CH:30]2)=[O:24])=[O:36])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Reactant: Cc1cn2ccccc2c1NC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)OC(C)(C)C)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
4.43 ml (43.7 mmol) of pyridine and 8.95 g (21.9 mmol) of tert-butyl[2-(3-{[(2-methylindolizin-1-yl)amino]-carbonyl}phenoxy)ethyl]carbamate are added to the suspension of 9.27 g (24.0 mmol) of benzyl 5-(chlorocarbonyl)-2-[(trifluoroacetyl)amino]benzoate in 180 ml of dichloromethane. The reaction medium that has turned greenish is stirred at ambient temperature for 16 hours. It is concentrated to dryness and the residue is taken up in diisopropyl ether and ethanol. The solid in suspension is filtered, washed with diisopropyl ether and dried. 6.29 g (38%) of a yellow powder are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:45][CH2:44][CH:43]([CH2:46][OH:47])[CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OCC1CCNCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC(CO)CC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 78.8 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (97.6 mg, 0.170 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was treated with 4-piperidine methanol (0.196 mL, 1.70 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[3-(4-hydroxymethylpiperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (87.2 mg, yield 79%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:23]=2)[N:6]=1)(=O)=O.[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[OH:49])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[O:49][C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([N+:18]([O-:20])=[O:19])=[C:7]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])[CH:23]=2)[N:6]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N#Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CCOC(=O)COc1nc(S(C)(=O)=O)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]
Product: CCOC(=O)COc1nc(Oc2cc(C#N)ccc2OCc2ccccc2)nc(Oc2cccc(C(=O)N(C)C)c2)c1[N+](=O)[O-]

Procedure:
In a similar manner, 2-methylsulfonyl-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (R), was treated with 2-benzyloxy-5-cyanophenol to yield 2-(2-benzyloxy-5-cyanophenoxy)-4-(ethoxycarbonyl)methoxy-5-nitro-6-(3-dimethylaminocarbonylphenoxy)pyrimidine, a compound of formula (S).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=1.[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1)([CH3:23])([CH3:22])[CH3:21].C(N(CC)C1C=CC=CC=1)C>ClCCl>[C:20]([O:24][C:25](=[O:38])[NH:26][C:27]([CH3:37])([CH3:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:2]2[C:7]([CH2:8][NH:9][C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[CH:6][N:5]=[C:4]([S:18][CH3:19])[N:3]=2)[CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(Cc1cccc(N)c1)NC(=O)OC(C)(C)C
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Cl)n1
Solvent: CCN(CC)c1ccccc1
Solvent: ClCCl
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CC(C)(C)NC(=O)OC(C)(C)C)c2)n1
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
A solution of 520 mg (1.6 mmol) of 4-chloro-5-(2,6-dichloroanilinomethyl)-2-methylthiopyrimidine, 420 mg (1.6 mmol) of (2-(3-aminophenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester and 250 mg (1.7 mmol) of N,N-diethylaniline in 5 ml of dichloromethane was heated at 80° C. until the solvent had evaporated and then to 120° C. for 30 minutes and then cooled. The product was purified by flash chromatography on silica gel eluting with diethyl ether/isohexane in a ratio 1:1 to give 350 mg (39%) of (2-(3-[5-[(2,6-dichlorophenylamino)-methyl]-2-methylthiopyrimidin-4-yl-amino]-phenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester as a white solid. [Mass spectrum (ESI) MH+ =562].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][NH:15][CH2:16][CH2:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]1[CH2:14][N:15]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:16][CH2:17][CH:18]=1
Reactant: Fc1ccc(CCCCCl)cc1
Reactant: COc1ccc2[nH]cc(CC3=CCCNC3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CC3=CCCN(CCCCc4ccc(F)cc4)C3)c2c1
Temperature: 25 °C

Procedure:
A mixture of compound of Description 5 [5-methoxy-3-(1,2,5,6-tetrahydro-pyridin-3-ylmethyl)-1H-indole] (1.4 g; 0.0058 mol), potassium carbonate (4 g; 0.0029 mol), a catalytic amount of potassium iodide (0.030 g) and compound of Description 9 [1-(4-chloro-butyl)-4-fluoro-benzene] (5.4 g; 0.029 mol) in dimethylformamide (40 ml) was heated at 80° C. for 6 hours. The reaction mixture was cool down to room temperature. quenched with water and then extracted with ethyl acetate. The organic extract was dried (MgSO4) and evaporated under vacuum. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0,5), the desired compound was obtained as an oil. A solution of this oil in methanol was saturated with gaseous hydrogen chloride. A solid was precipitated. The title compound hydrochloride was collected by filtration, washed with hexane and dried under vacuum (0.66 g).