Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.[F-].[Cs+]>COCCOC.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>[Cl:14][C:6]1[CH:5]=[C:4]([CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of ethyl 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-4-methylpentanoate (1 g, 1 eq), 4-Trifluoromethyl phenylboronic acid (2.6 g, 1.4 eq), Pd(PPh3)4 (1.3 g, 0.1 eq) and Cesium Fluoride (13.1 g, 2 eq) in DME (30 ml) was stirred for overnight at 100° C. Upon completion, the precipitate was removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine, dried over Na2SO4 and concentrated under vacuo. The residue was purified by Flash Column Chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-4-methylpentanoate in 74% yield (1.08 g). 1H NMR (CDCl3, 400 MHz): 7.68 (m, 5H), 7.43 (s, 1H); 7.24 (s, 1H); 4.4 (q, 2H), 4.13 (q, 2H); 3.55 (t, 1H); 1.93 (m, 1H), 1.58 (m, 1H); 1.45 (m, 1H); 1.24 (t, 3H), 0.92 (d, 6H);
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].Cl[C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1>CO>[CH3:2][O:3][C:4]([CH:6]1[CH2:9][N:8]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7]1)=[O:5]
Reactant: Clc1ncccn1
Reactant: COC(=O)C1CNC1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CN(c2ncccn2)C1
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
To a stirred solution of 3-azetidine carboxylic acid methyl ester hydrochloride (150 mg, 0.99 mmol) and 2-chloropyrimidine (113.4 mg, 0.99 mmol) in methanol, was added TEA (200 mg, 1.98 mmol) at room temperature. The mixture was stirred at 50° C. for 5 hours and concentrated under reduced pressure. The residue was suspended in EtOAc (50 ml) and washed with water (15 ml), brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-azetidine-3-carboxylic acid methyl ester as a light yellow solid (137.3 mg, 72%): 1H NMR (CDCl3, 400 MHz) δ 8.37 (d, J=6.4 Hz, 2H), 6.58 (t, J=6.4 Hz, 1H), 4.30 (m, 4H), 3.77 (s, 3H), 3.56 (m, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7](S(C)(=O)=O)[N:6]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1.O>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]([C:7]2[N:6]=[C:5]([O:4][CH3:3])[CH:10]=[C:9]([O:11][CH3:12])[N:8]=2)[C:25]#[N:26])[CH:21]=[CH:22][CH:23]=1
Reactant: N#CCc1cccc(Cl)c1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(C(C#N)c2cccc(Cl)c2)n1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
Sodium hydride (6.0 g of 80% in oil) was added portionwise to a stirred solution of 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (21.8 g) and (3-chlorophenyl)acetonitrile (15.1 g) in dry dimethylformamide (150 ml) at 5° C. The mixture was stirred at 10° C. for 30 minutes, and then at room temperature for 3 hours. The resulting suspension was poured into water (1.2 l) and the oil was extracted into ether. The combined extracts were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to give an orange oil, which was purified by chromatography to give 26.3 g of the desired product as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O)([F:4])[F:3].[C@@H:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1>>[C@@H:14]1([NH:24][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[C:6]([S:5][C:2]([F:4])([F:3])[F:1])[CH:7]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=Cc1cccc(SC(F)(F)F)c1
Product: FC(F)(F)Sc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-[(Trifluoromethyl)sulfanyl]benzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: [CH3:1][C:2](=[N:9][NH:10]C(OC(C)(C)C)=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>C1COCC1.CO>[CH3:1][CH:2]([NH:9][NH2:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)=NNC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCC(C)NN
Temperature: 25 °C
Reaction time: 1 h

Procedure:
74.08 g (305.7 mmol) of tert-butyl N′-(1-methyl-heptylidene)-hydrazinecarboxylate are dissolved in a mixture of 235 ml of THF and 310 ml of methanol and, after 22.34 g (354.6 mmol) of sodium cyanoborohydride have been added, the mixture is stirred for 1 hour at room temperature. 213 ml of 6N HCl are added dropwise and, after the addition has ended, the mixture is refluxed for 1.5 hours. It is neutralized with 6N NaOH solution, then, after the non-aqueous solvents have been removed, extracted three times with dichloromethane, and, after the mixture has been dried over sodium sulphate, the solvent is removed in vacuo. This gives 37.5 g (85%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([NH:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6].[OH-].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([N:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[NH:7][C:5](=[O:6])[C:4]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
3,4-Dichlorobenzoyl-2-tert-butylhydrazine (5.63 g, 0.0215 mole) is added to a rapidly stirring mixture of 40 mL of methylene chloride and 20 mL of 10% aqueous sodium hydroxide (2 g, 0.05 mole). Benzoyl chloride (d=1.211, 2.5 mL, 3.03 g, 0.0215 mole) in methylene chloride is added and the reaction mixture stirred vigorously for approximately three hours at ambient temperature. The resulting solid is collected and washed with water and methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](OC2C=CC=CC=2)=[N:18][C:19]#[N:20])=[CH:12][CH:11]=1.C(N(CC)CC)C>ClCCl>[C:19]([NH:18][C:17](=[N:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)[O:16][C:13]1[CH:14]=[CH:15][CH:10]=[CH:11][CH:12]=1)#[N:20]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CNC(=Nc1cc(Cl)cc(Cl)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 66.6 %

Procedure:
To a solution of 3,5-dichloroaniline (11 mmol, 1.79 g) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g) and triethylamine (11 mmol, 1.53 ml) were added. The reaction mixture was stirred under nitrogen for 65 h at room temperature. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 2.04 g of the title compound (67%); 1H-NMR (CDCl3): δ 7.12 (d, 2H), 7.22 (s, 1H), 7,35 (m, 3H), 7.45 (d, 2H), 9.4 ppm (br s,1H). EI SP/MS: 305 (M+), 307 (M+2), 309 (M+4).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[CH:17][CH:16]=1)=[C:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc2c(Oc3ccc(N)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask containing a solution of 29 (0.21 g, 0.59 mmol), Et3N (0.18 g, 1.78 mmol) and DMAP (0.034 g, 0.28 mmol) in CH2Cl2 (5 mL) was added ethanesulfonyl chloride (0.19 g, 1.48 mmol), dropwise, at RT and the reaction allowed to stir overnight at RT.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.[CH2:24]([N:26]([CH2:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1)[C:27]([NH:29][CH3:30])=[O:28])[CH3:25].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[CH:6]=[C:7]([C:33]2[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:32]=2[CH2:31][N:26]([CH2:24][CH3:25])[C:27]([NH:29][CH3:30])=[O:28])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NC
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: COCCOC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)NC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(3-Trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester (0.063 g, 0.18 mmol), 1-ethyl-3-methyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea (0.070 g, 0.18 mmol, potassium carbonate (0.062 g, 0.45 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.02 mmol) were combined in 2:1 DME:H2O (3 mL) and degassed with N2 for 10 minutes. The reaction was then stirred at 90° C. for 2 hours, until no starting material was seen by analytical LCMS. The mixture was cooled to room temperature and used directly in the hydrolysis step.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=O)[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:9](=[S:24])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCn1[nH]c(C(F)(F)F)cc1=O
Solvent: Cc1ccccc1
Product: CCCCn1[nH]c(C(F)(F)F)cc1=S
Reaction time: 6 h
Yield: 99.6 %

Procedure:
5.00 g of 1-butyl-3-(trifluoromethyl)pyrazol-5-one (8-3), and 7.88 g of Lawesson's reagent were suspended in 300 ml of anhydrous toluene. The suspension was heated under reflux with stirring for 6 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to produce 4.35 g of 1-butyl-3-(trifluoromethyl)pyrazol-5-thione (8-6).
Reaction SMILES: [CH:1]#[C:2][CH3:3].C([Li])CCC.[Cl-].C([Al+]CC)C.[CH2:15]([O:22][CH2:23][C@H:24]1[CH2:26][O:25]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:22][CH2:23][C@H:24]([OH:25])[CH2:26][C:1]#[C:2][CH3:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CC
Reactant: c1ccc(COC[C@H]2CO2)cc1
Agent: CC[Al+]CC
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC#CC[C@@H](O)COCc1ccccc1
Reaction time: 0.17 h

Procedure:
Prop-1-yne was bubbled through a solution of n-butyllithium (2.5 M in hexanes, 1.06 L, 2.65 mol) in toluene (5 L) at 0° C. for 1.5 hours, until a thin suspension was obtained. Diethylaluminum chloride (1 M in hexanes, 2.44 L, 2.44 mol) was added, and the reaction mixture was stirred at 0° C. for 2 hours, whereupon (2R)-2-[(benzyloxy)methyl]oxirane (200 g, 1.22 mol) was added. After 10 minutes, the reaction was quenched with water (100 mL) and then with aqueous hydrochloric acid (2 M, 2 L). The mixture was extracted with ethyl acetate (2 L), and the combined organic layers were dried over sodium sulfate, concentrated, and purified by chromatography on silica gel (Gradient: 2% to 17% ethyl acetate in petroleum ether) to afford the product as a pale brown oil. Yield: 250 g, 1.22 mol, 100%. 1H NMR (400 MHz, CDCl3) δ 7.28-7.41 (m, 5H), 4.58 (s, 2H), 3.89-3.97 (s, 1H), 3.60 (dd, half of ABX pattern, J=9.5, 3.9 Hz, 1H), 3.50 (dd, half of ABX pattern, J=9.5, 6.7 Hz, 1H), 2.50 (br s, 1H), 2.38-2.43 (m, 2H), 1.79 (t, J=2.6 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH:25]=[O:26])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: CN(C)C=O
Reactant: c1cncc(-c2ccnc3ccnn23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(-c3cccnc3)ccnc12
Temperature: 0 °C

Procedure:
A 1.0 g. sample of 7-(3-pyridyl)pyrazolo[1,5-a]-pyrimidine is added to an ice cold solution of 1.0 ml. of phosphorus oxychloride in 3 ml. of N,N-dimethylformamide. The reaction mixture is heated on a steam bath for 3 hours and poured into ice. The mixture is made basic with a solution of sodium hydroxide and extracted into dichloromethane. The dichloromethane solution is washed with water and passed through a column of hydrous magnesium silicate. The eluent is concentrated and diluted with hexane to give the product of the example as crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]1[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[N:24]=[CH:23]1.Cl>O>[CH3:21][N:22]1[CH:26]=[C:25]([S:27]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:13][CH:14]=2)(=[O:29])=[O:28])[N:24]=[CH:23]1
Reactant: NCCc1ccc(OCC(=O)O)cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cn1cnc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)c1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
6.3 g (32 mmol) of 4-(2-aminoethyl)phenoxyacetic acid are added to a solution of 9.7 g (79 mmol) of potassium carbonate in 50 ml of water and the mixture is stirred for 5 minutes. A suspension of 5.8 g (32 mmol) of 1-methyl-4-imidazolesulfonyl chloride from Example C-1 in 20 ml of water is slowly added to this suspension. The mixture is heated to 80° C. and stirred at this temperature for 2 hours. After cooling to room temperature, the reaction solution is acidified to pH 4 using 2N hydrochloric acid. The precipitate deposited is separated off, washed several times with water and recrystallized from dilute acetic acid in order to give the title compound of melting point 203°-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:20])[N:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][OH:19])[CH2:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([N:10]([CH3:11])[C@H:12]2[CH2:17][CH2:16][C@H:15]([CH2:18][O:19][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:14][CH2:13]2)=[O:20])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](CO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 0.6 g (2.03 mmol) of trans-(4-Hydroxymethyl-cyclohexyl)-methyl-carbamic acid 4-chloro-phenyl ester in 15 ml CH2Cl2 was treated with 0.17 ml (2.24 mmol) methanesulfonylchloride, 0.5 ml (6.1 mmol) pyridine and 0.25 g (2.03 mmol) DMAP at 0° C. The reaction mixture was warmed up over night to room temperature, water (2 ml) was added and the reaction mixture was stirred for 5 min. After extraction with aqueous 10% KHSO4/Et2O (3×), the organic phases were washed with aqueous saturated NaHCO3 (2×), aqueous 10% NaCl, dried over Na2SO4 and evaporated to yield 0.74 g (96%) of trans-Methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl ester, mp: 134-135° C.; MS: 376 (MH+, 1 Cl).
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.F[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(Cl)Cl>C(O)C.[OH-].[Na+]>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])[C:14]([OH:16])=[O:15]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1ccccc1NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.4 %

Procedure:
A solution of 928 mg (4 mmoles) of Nα -Boc-L-ornithine and 968 mg (8 mmoles) of 2-fluorobenzonitrile in 4 mL of ethanol and 4 mL of 1N NaOH were heated at reflux for 24 hours. Another 8 mmoles each of 1N NaOH and 2-fluorobenzonitrile were then added and reflux was continued for another 24 hours. The clear solution was cooled to room temperature, and the white paste dumped into 125 mL of CH2Cl2 and extracted with 100 mL of water made basic (pH 12) with NaOH. The aqueous extract was acidified with 5N HCl, and extracted with 125 mL of CH2Cl2. The organic phase was washed with 1M HCl, dried (Na2SO4) and concentrated in vacuo to give an oil. The oil was purified by flash chromatography on silica gel, eluting with 2:1 ethyl acetate:ethanol containing 1% triethylamine. The sole fluorescent product was an oil, 132 mg (10%), with rf of 0.49 in the elution solvent. 125 mg of the oil was dissolved in 22 mL of 5:1:1 acetic acid/water/12M HCl, and stirred for 3 hours at room temperature. The sample was concentrated in vacuo, then ethanol was added and the sample again concentrated in vacuo to give a waxy solid. This was recrystallized from water to give 22.5 mg of white needles. The mother liquor yielded 67 mg of white foam on concentration. Yield (100%).: mp >265°; MS (FAB) m/e calc'd for C12H10N3O2 : 234.1243, found 234.1231; M/Z 223 (M+), 224 (M+H)+. 1H NMR (300 MHz, D2O) δ: 1.74 (m, 2H), 1.96 (m, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.79 (t, J=5.8 Hz, 1H), 6.71 (t, J=7 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 7.55 (m, 1H).
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C@@H:11]([NH:26]C(OC(C)C3C=CC=CC=3)=O)[C:10]2=[O:38])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:39]>C(Cl)Cl>[BrH:39].[N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C@@H:11]([NH2:26])[C:10]2=[O:38])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(OC(=O)N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(=O)N2CCCC2)C1=O

Procedure:
1,3-Dihydro-1-(pyrrolidinylcarbonyl)methyl-3(R){[(α-methyl)benzyloxy-carbonyl]-amino}-5-phenyl-2H-1,4-benzodiazepin-2-one (109 mg) was dissolved in 10 ml of dry methylene chloride. The solution was cooled to 0° C. and saturated with hydrogen bromide gas. After 30 minutes the solvent and excess hydrogen bromide were removed under reduced pressure to give 147 mg of the title compound as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[CH:8][C:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:11][CH2:10]1)[C:5]([OH:7])=[O:6])C.C(O)(=O)C.O>S(=O)(=O)(O)O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1([CH2:8][C:4](=[O:3])[C:5]([OH:7])=[O:6])[CH2:11][CH2:10]1
Reactant: CCOC(=CC1(c2ccccc2Cl)CC1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C(=O)CC1(c2ccccc2Cl)CC1
Yield: 106.8 %

Procedure:
11.2 g of 2-ethoxy-3-[1-(2-chlorophenyl)-1-cyclopropyl]-acrylic acid is stirred in 230 ml of 1 M sulfuric acid and 42 ml of concentrated acetic acid for 24 hours at 110° C. Water is added, it is extracted with ethyl acetate, and ethyl acetate solution is washed with water. After drying (Na2SO4) and concentration by evaporation, 10.7 g of the product is obtained.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]2=[O:15])=[CH:6][CH:5]=1)#[N:3].[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>>[Br:18][CH2:19][C:20]1[CH:21]=[C:22]([S:26]([N:12]2[CH2:13][CH2:14][N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:17][CH:16]=3)[C:10](=[O:15])[CH2:11]2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(CBr)c1
Reactant: N#Cc1ccc(CN2CCNCC2=O)cc1
Agent: Cl
Product: N#Cc1ccc(CN2CCN(S(=O)(=O)c3cccc(CBr)c3)CC2=O)cc1

Procedure:
A solution of 4-[3-(bromomethyl)benzenesulfonyl]-1-(4-cyanobenzyl)-2-piperazinone (1.21 g) obtained from 1-(4-cyanobenzyl)-2-piperazinone hydrochloride and 3-(bromomethyl)benzenesulfonyl chloride according to a method described in Reference Example 6 and imidazole (613 mg) in DMF (20 ml) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added ethyl acetate. The mixture was washed with sodium bicarbonate solution and saturated brine, dried (MgSO4) and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate:methanol containing 10% ammonia solution=85:15) to give pale yellow amorphous of 1-(4-cyanobenzyl)-4-[3-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-2-piperazinone (734 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH2:5].Cl.O1CCOCC1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[F:35])[N:28]=[CH:27][N:26]=1>C(#N)C>[F:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:34]=1[C:25]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:2]([CH3:1])[CH:3]=1)=[N:26][CH:27]=[N:28]2
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: Fc1cccc2ncnc(Cl)c12
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(F)c34)cc2C)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
3-Methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (6.42 g, 30 mmol) and 4N hydrogen chloride in dioxane (7.55 ml, 30 mmol) were added to a suspension of 4-chloro-5-fluoroquinazoline (5 g, 27.5 mmol; obtained as described in PCT Int. Appl. WO2001094341, AstraZeneca) in acetonitrile (100 ml). The mixture was stirred at 80° C. for 2 hours. After cooling, the precipitate washed with acetonitrile. This precipitate was partitioned between DCM and 5% aqueous sodium bicarbonate and the pH was adjusted to 8. The organic layer washed with brine and dried over MgSO4. Evaporation of the solvents gave 5-fluoro-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (9.3 g, 94%) as a dark gum which crystallised on standing; NMR spectrum (CDCl3); 2.30 (s, 3H), 2.54 (s, 3H), 6.93 (d, 1H), 7.15-7.08 (m, 2H), 7.22 (m, 1H), 7.56 (d, 1H), 7.63 (s, 1H), 7.71 (m, 2H), 8.27 (s, 1H), 8.37 (d, 1H), 8.71 (s, 1H).