Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([O:12][C:13]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)=[O:14])[CH3:11].C(=O)([O-])[O-].[Ca+2]>CS(C)=O>[CH2:10]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:19][CH2:20]1)=[O:14])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CS(C)=O
Product: CCOC(=O)N1CCN(c2ccccc2C=O)CC1
Yield: 68 %

Procedure:
2-Fluorobenzaldehyde (3.0 g, 24.2 mmol), 1-(ethoxycarbonyl)piperazine (4.2 ml, 28.7 ml), and calcium carbonate (2.46 g, 24.6 mmol) were reacted at 120° C. for 7.5 hours in dimethylsulfoxide (12 ml). After the reaction was completed, the insolubles were filtered off and the resulting filtrate was extracted by adding water and ethyl acetate thereto. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give oily substances. The resulting oily substances were purified by silica gel column chromatography (eluent: from hexane/ethyl acetate=4/1 to hexane/ethyl acetate=1/1) to give the title compound (4.29 g, 68%).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2O)[CH:3]=[CH:2]1.S(Cl)([Cl:13])=O.CN(C=O)C>C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Cl:13][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:3]=[CH:2][S:1][C:9]=12
Reactant: Oc1ccnc2ccsc12
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccnc2ccsc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Thieno[3,2,b]pyridin-7-ol (200 mg; 1.32 mmol) was added to thionyl chloride (1.57 g; 13.2 mmol), followed by a drop of DMF. The solution was stirred at 80° C. for 4 hours. The cooled solution was diluted with ethyl acetate and neutralised to pH 7 with a saturated solution of sodium hydrogen carbonate (25 ml). The organic layer was washed with brine, dried and concentrated to yield the title compound (112 mg; 50%); Mass Spectrum: M+H+ 170.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.[F:45][C:46]([F:52])([F:51])[S:47]([OH:50])(=[O:49])=[O:48]>C1(OC)C=CC=CC=1>[F:45][C:46]([F:52])([F:51])[S:47]([OH:50])(=[O:49])=[O:48].[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
305 mg of (2S,4S)-4-(4-methoxybenzylthio)-2-(4-methyl-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 1) were suspended in 627 μl of anisole, and then the suspension was placed over an ice bath. 3.14 ml of trifluoroacetic acid and 56 μl of trifluoromethanesulfonic acid were then added to the suspension, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the solvent was removed by distillation under reduced pressure. The residue was washed with diethyl ether by repeated decantation, after which it was dried under reduced pressure to obtain 318 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:10]([NH:12][CH:13]1[C:30](=[O:31])[N:15]2[CH:16]([C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])[C:17]([CH3:21])([CH3:20])[S:18](=[O:19])[C@H:14]12)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:38]N1C(=O)CCC1=O>>[CH3:20][C:17](=[CH2:21])[CH:16]([N:15]1[C:30](=[O:31])[CH:13]([NH:12][C:10](=[O:11])[CH:9]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:14]1[S:18]([Cl:38])=[O:19])[C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)NC(C(=O)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(C)(C)S(=O)[C@H]12)c1ccccc1
Product: C=C(C)C(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1S(=O)Cl
Temperature: 25 °C

Procedure:
A solution of 2.85 g. (5 mmol) of 2,2,2-trichloroethyl 6-(α-t-butyloxycarbonylaminophenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide in 175 ml. of toluene was dried azeotropically by distillation of about 50 ml. of toluene from the mixture. To the dried solution was added 0.685 g. (5.5 mmol.) of N-chlorosuccinimide. The resulting mixture was refluxed for 70 minutes. The mixture was allowed to cool to room temperature and then was filtered and evaporated in vacuo to dryness to provide the title product (contaminated with succinimide).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=O)[C:3]=1[N+:10]([O-:12])=[O:11].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:4]1[C:3]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(C)c([N+](=O)[O-])c(=O)[nH]1
Product: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 180.4 %

Procedure:
A mixture of 4,6-dimethyl-3-nitro-2(1H)-pyridinone (step 1, 10.0 g, 29.7 mmol) in phosphorus oxychloride (35 mL, 187.3 mmol) was stirred at 95° C. for 3 h, then cooled to 45° C. The excess amount of phosphorus oxychloride was removed by distillation under reduced pressure at 45° C. The residue was cooled to room temperature, and diluted with dichloromethane (75 mL). The resulting solution was cooled to 0° C., and 2N hydrochloric acid (50 mL) was added dropwise into the solution. The organic layer was separated, and washed with 2N hydrochloric acid (4×25 mL), 2N aqueous NaOH (2×50 mL) and brine (50 mL). The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 10.0 g (90%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.07 (1H, s), 2.56 (3H, s), 2.35 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:26]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: NCc1ccc(F)c(Br)c1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Temperature: 15 °C
Yield: 198.2 %

Procedure:
To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[C:17]2[C:7]([NH:8][CH:9]=[C:10]2[CH2:11][C@@H:12]([C:14]([NH2:16])=[O:15])[NH2:13])=[CH:6][CH:5]=1)([O-])=O.[CH:19]1([N:25]2[C:29]3[CH:30]=[CH:31][C:32]([C:34](O)=[O:35])=[CH:33][C:28]=3[N:27]=[C:26]2[C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[NH2:1][C:4]1[CH:18]=[C:17]2[C:7](=[CH:6][CH:5]=1)[NH:8][CH:9]=[C:10]2[CH2:11][C@H:12]([NH:13][C:34]([C:32]1[CH:31]=[CH:30][C:29]2[N:25]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:26]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)=[N:27][C:28]=2[CH:33]=1)=[O:35])[C:14](=[O:15])[NH2:16]
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1
Reactant: NC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Product: NC(=O)[C@H](Cc1c[nH]c2ccc(N)cc12)NC(=O)c1ccc2c(c1)nc(-c1ccoc1)n2C1CCCCC1

Procedure:
The 5-nitrotryptophan amide derivative of example 53 was coupled to the carboxylic acid of example 2 in the usual manner. The nitro group was then reduced to the corresponding amine using SnCl2 dihydrate as described in example 48, to give the title compound of example 54 after purification by preparative C18 reversed-phase HPLC.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[C@@H:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27]>O>[CH2:29]([C@@H:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: CC[C@H](Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (5.90 g) in a mixed solvent of ethyl acetate (60 ml) and water (60 ml) were added sodium hydrogen carbonate (5.40 g) and (S)-2-chlorobutyryl chloride (7.00 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (70 ml), to the solution was added potassium carbonate (4.90 g) and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and the resulting crystals were taken by filtration to give (R)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (6.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].Br[CH:13]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].CCN(C(C)C)C(C)C>C(#N)C>[CH3:8][NH:7][C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CNC(=O)c1cccc(N)c1
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(Nc1cccc(C(=O)NC)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
3-Amino-N-methylbenzamide (371 mg, 2.47 mmol), ethyl 2-bromo-2-phenylacetate (0.29 ml, 1.64 mmol), and DIPEA (0.43 ml, 2.47 mmol) were dissolved in acetonitrile (5 ml) and stirred under microwave irradiation into a sealed vial at 100° C. for 60 minutes (UPLC-MS: complete conversion). Acetonitrile was evaporated, and the crude residue was purified by flash chromatography (DCM/EtOAc=8/2) to obtain ethyl 2-(3-(methylcarbamoyl)phenylamino)-2-phenylacetate (475 mg, 92% yield).
Reaction SMILES: [OH-:1].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7](F)=[N:8][CH:9]=1>O>[Cl:3][C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:1])=[N:8][CH:9]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: Oc1ncc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of NaOH (101 g, 2.5 mol) in water (500 mL) was added 5-chloro-2,3-difluoropyridine (101 g, 0.68 mol) as a liquid, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the mixture was filtered through a pad of celite and the pH was adjusted to 1 by the addition of concentrated HCl. The resulting solid was dissolved in ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The title compound was obtained as a white solid (78 g, 78%) and was used without additional purification. The product was characterized by 1H NMR.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([OH:13])[C:8]1=[O:14]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:13][CH:9]1[CH2:10][CH2:11][CH2:12][N:7]([CH3:6])[C:8]1=[O:14])(=[O:4])=[O:3]
Reactant: CN1CCCC(O)C1=O
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1CCCC(OS(C)(=O)=O)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
Methanesulfonyl chloride (0.8 ml., 0.01 mole) was added dropwise to a stirred solution of 1-methyl-2-oxo-3-piperidinol (1.29 g, 0.01 mole) and 4-dimethylaminopyridine (2.44 g., 0.02 mole), in 50 ml. methylene chloride at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 min. and at 25° C. for 2.5 hours. The reaction mixture was then washed with 50 ml. saturated aqueous sodium chloride solution containing 6.8 ml. of 6N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate and concentrated in vacuo to a thick oil of the title compound (1.8 g., 87% yield). NMR (CDCl3): 1.6-2.37 (c, 4H); 2.96 (s, 3H); 3.1-3.4 (c) and 3.24 (s) (total 5H); and 4.9 (m, 1H)ppm.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2].[OH-:26].[Na+].Cl>C(O)CO>[C:1]([C:3](=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:26])[NH2:2]
Reactant: COc1ccc(C(=C(C#N)CCC(=O)O)c2ccc(OC)cc2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: COc1ccc(C(=C(CCC(=O)O)C(N)=O)c2ccc(OC)cc2)cc1

Procedure:
Two grams of the acid obtained in Example 4 was heated with 10 ml of a 5N aqueous solution of NaOH in 50 ml of ethylene glycol at 150° C. for 12 hours. The product mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was treated with the chromatography of silicagel to obtain 0.5 g of the above intended compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[NH:14][C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1.[C:29](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:25])([F:26])[C:21]([F:24])([F:23])[F:22])[N:14]([CH3:29])[C:13]2=[O:27])=[C:4]([F:28])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CC(C)Oc1cc(-n2c(=O)c(F)c(C(F)(F)C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione in acetone with sodium bicarbonate and dimethyl sulphate there is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-1-methyl-6-pentafluoroethyl-2,4(1H,3H)-pyrimidinedione, m.p. 107°-109° C.;
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@@H:17](O)[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>ClCCl>[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@H:17]([F:7])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
Add (diethylamino)sulfur trifluoride (3.9 mL, 29.8 mmol) to a −78° C. cooled solution of 4-(R)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (3.81 g, 15.54 mmol) in dichloromethane (50 mL). Stir 2 h, then remove cold bath and stir 40 h at room temperature. Cool in ice bath and add saturated sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25° C.) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) to give the title compound as an oil (4.01 g, 97%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[S:37]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3cnccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrazin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester of Step A and pyridine-3-sulfonyl hydrochloride, of Preparation 2, following the method described in Example 3, Step B 1H NMR (400 MHz, CDCl3) δ 9.05 (s, 1H), 8.97 (m, 1H), 8.78 (m, 1H), 8.60 (m, 1H), 8.50 (d, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.42 (m, 1H), 7.23 (m, 2H), 7.13 (m, 1H), 6.66 (m, 1H), 6.65 (m, 2H), 4.43 (s, 2H), 4.39 (s, 2H), 4.35 (s, 2H), 1.47 (s, 9H); MS 547 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:13]/[OH:14])/[CH3:9])[CH:7]=1
Reactant: NO
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: C/C(=N\O)c1cc(Br)ccc1O
Yield: 98.2 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (2.0 g, 9.30 mmol) in ethanol (20 mL) were added hydroxylamine hydrochloride (0.7 g, 10.2 mmol) and potassium acetate (1.0 g, 10.2 mmol). The mixture was stirred at reflux temperature for 16 h. After this time, the mixture was cooled, concentrated and the residue was diluted with CH2Cl2 (25 mL) and washed with H2O (25 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford title compound (11) (2.1 g, 95%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.20 (dd, J=8.8, 2.0 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 2.50 (bs, 1H), 2.20 (s, 3H); MS (ESI, M+H+) C8H9BrNO2, calcd. 230.0. found 230.0, 232.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[OH-].[Na+].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Yield: 51.9 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C(N(CC)CC)C.F[C:15]1[C:22]([F:23])=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[C:16]=1[CH:17]=O>CN(C)C=O>[F:23][C:22]1[C:15]2[S:3][C:2]([C:1]([O:5][CH3:6])=[O:4])=[CH:17][C:16]=2[C:19]([O:24][CH3:25])=[CH:20][CH:21]=1
Reactant: COC(=O)CS
Reactant: COc1ccc(F)c(F)c1C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(OC)ccc(F)c2s1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 87.4 %

Procedure:
Methyl thioglycolate (28.8 mL, 320 mmol) was added under nitrogen to a solution of triethylamine (86.6 mL) in dry N,N-dimethylformamide (220 mL) at 80° C. Stirred at 100° C. for 15 mins. A solution of 2,3-difluoro-6-methoxybenzaldehyde (55.1 g, 320 mmol) in N,N-dimethylformamide (80 mL) was added and the mixture heated at 130° C. for 3 h. Allowed to cool then poured onto ice-water (2 L). The resulting yellow solid was filtered, washing with water (2×200 mL). Dried under vacuum over phosphorus pentoxide at room temperature overnight to give the title compound (67.2 g, 87%); δH (300 MHz, CDCl3) 8.20 (1H, d, ArH), 7.06 (1H, t, ArH), 6.68 (1H, m, ArH) and 3.99 (6H, s, OCH3 and CO2CH3).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14]>O1CCCC1>[NH:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:15]([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)CN(C(=O)CN)c1ccccc1Nc1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2Nc2ccccc2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
3-Methylphenyl isocyanate (1.07 g) is added at a temperature in the region of 20° C. to a solution of tert-butyl 2-[2-amino-N-(2-anilinophenyl)acetamido]acetate (2.6 g) in anhydrous tetrahydrofuran (20 cc). The solution obtained is stirred for 2 hours at a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The residual oil is purified by chromatography on silica (0.063-0.2 mm) (150 g) contained in a column 2 cm in diameter [eluent: cyclohexane/ethyl acetate (50:50 by volume)], collecting 20-cc fractions. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-anilinophenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (1.15 g), m.p. 180° C., is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3F)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1>Cl.C(OCC)C>[ClH:16].[ClH:16].[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Fc1cccc2ncnc(Nc3c(Cl)ccc4c3OCO4)c12
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1Nc1ncnc3cccc(OCC4CCNCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Using an analogous procedure to that described in Example 37, N-(tert-butoxycarbonyl)piperidin-4-ylmethanol was reacted with 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.1 g). The product so obtained was dissolved in a 2M solution of hydrogen chloride in diethyl ether (20 ml) and stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was washed with diethyl ether and dried under vacuum. There was thus obtained the tilte compound (0.121 g); NMR Spectrum: (DMSOd6) 1.5-1.6 (m, 2H), 1.9-2.0 (m, 2H), 2.3-2.4 (m, 1H), 2.8-2.9 (m, 2H), 3.3 (d, 2H), 4.42 (d, 2H), 6.15 (s, 2H), 7.07 (d, 1H), 7.15 (d, 1H), 7.53 (m, 2H), 8.06 (m, 1H), 8.87 (s, 1H), 10.57 (br s, 1H); Mass Spectrum: M+H+ 413 and 415.