Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)([OH:3])=[O:2].S(Cl)(Cl)=O.[CH3:19]O>>[CH3:19][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)CCc1ccc(C(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a suspension of 3-(4-carboxyphenyl)propionic acid (2.0 g, 10.1 mmol) in methanol (20 mL) was added thionyl chloride (38 μL, 0.50 mmol). The reaction mixture was stirred at room temperature for 16 h, and a clear solution was obtained. The solvent was removed under reduced pressure. The residue was taken up in ether (100 mL), washed with saturated aqueous NaHCO3 (2×50 mL) and water (50 mL). The combined NaHCO3 and water extract was acidified with concentrated HCl in an ice bath. The precipitated white solid was collected, washed with water and dried to yield 1.76 g (84%) of compound 166 as off-white solid. The material was used without further purification. mp 146-148° C. 1H NMR (400 MHz, CDCl3): δ 2.66 (t, J=7.7 Hz, 2H), 3.02 (t, J=7.7 Hz, 2H), 3.67 (s, 3H), 7.30 (d, J=8.3 Hz, 2H), 8.03 (d, J=8.1 Hz, 2H). LCMS (ES), m/z, 209 (M+H)+, 207 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:10]=3)[C@:5]3([CH2:25][O:24][C:23]([NH2:26])=[N:22]3)[C:4]=2[CH:3]=1.C(NC(C)C)(C)C.[C:34]([CH:36]1[CH2:38][CH2:37]1)#[CH:35]>CCOC(C)=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.[Cu]I>[CH:36]1([C:34]#[C:35][C:2]2[CH:15]=[CH:14][C:13]3[O:12][C:11]4[C:6](=[CH:7][C:8]([O:16][CH2:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:9][CH:10]=4)[C@:5]4([CH2:25][O:24][C:23]([NH2:26])=[N:22]4)[C:4]=3[CH:3]=2)[CH2:38][CH2:37]1
Reactant: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Reactant: C#CC1CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3CC3)ccc1O2
Temperature: 50 °C

Procedure:
A vial was charged with (4R)-2′-bromo-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine (52.5 mg, 126 μmol), tetrakis(triphenylphosphine)palladium(0) (14.5 mg, 12.6 μmol), copper(I) iodide (4.79 mg, 25.2 μmol), diisopropylamine (629 μl, 126 μmol), and ethynylcyclopropane (32.0 μl, 377 μmol). The vial was heated in a 50° C. oil bath for 15 h. The reaction mixture was diluted with EtOAc and filtered through celite. The filtrate was evaporated, and the crude residue was purified by chromatography on a 12-g Redi-Sep column, eluting with 0-5% MeOH/DCM to give (4S)-2′-(cyclopropylethynyl)-7′-(2,2-dimethylpropoxy)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=403.2 [M+H]+. Calc'd for C25H27N2O3: 403.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:23]C=2C=1.N>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:4]=1[C:5]([NH2:23])=[O:6]
Reactant: COc1cc(C)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cc(C)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of 2-methoxy-4-methylbenzoic acid (20 g, 120.4 mmol), EDC (23.1 g, 120.4 mmol) and HOBt (16.3 g, 120.4 mmol) in dichloromethane (1 L) was added NH3 (7N in MeOH, 52 mL, 3 eq) dropwise. The reaction mixture was stirred at room temperature overnight then washed successively with HCl (1N), saturated aq.NaHCO3, water and brine, dried over MgSO4, filtered and evaporated. The residue was recrystallized from ethyl acetate/hexane to give 16.5 gr of 2-methoxy-4-methylbenzamide (83% yield).
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH2:22]>>[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][NH:22][C:3]1[CH:2]=[C:1]([NH:17][C:14]2[CH:13]=[C:12]([CH3:11])[NH:16][N:15]=2)[N:10]=[C:1]([CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=1
Reactant: N#CC=Cc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Reactant: CN(C)CCN
Product: Cc1cc(Nc2cc(NCCN(C)C)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 66 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and N1,N1-dimethylethane-1,2-diamine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[N:7]([CH3:20])[C:8]([C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:11]([C:8]2[N:7]([CH3:20])[C:6]([CH2:5][C:4]([OH:21])=[O:3])=[CH:10][CH:9]=2)=[O:19])=[CH:13][CH:14]=1
Reactant: CCOC(=O)Cc1ccc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CC(=O)O)ccc1C(=O)c1ccc(Cl)cc1

Procedure:
A suspension of 3.06 g. (0.01 mole) of ethyl-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate in 25 ml. of 0.5 N sodium hydroxide is refluxed for 30 minutes. About two-thirds of this solution is cooled, washed with ether, and then acidified with dilute hydrochloric acid. The resulting solid precipitate is collected by filtration, dried and recrystallized from ethanol-water to give the product, 5-(p-chlorobenzoyl)-1-metylpyrrole-2-acetic acid; m.p. 189-191° C. Upon recrystallization from ethanol-water, the melting point is 188-190° C. Analysis: Calcd. for C14H12ClNO3 : C, 60.54; H, 4.36; N, 5.05%. Found: C, 60.54; H, 4.37; N, 5.14%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1([CH3:35])[CH:18]=[C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)[C:16]2[CH:29]=[C:30]([C:33]#[N:34])[CH:31]=[CH:32][C:15]=2[O:14]1>ClCCl>[C:33]([C:30]1[CH:31]=[CH:32][C:15]2[O:14][C:13]([CH3:35])([CH3:12])[CH:18]=[C:17]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]=3[O-:9])[C:16]=2[CH:29]=1)#[N:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=C(c2ccc3ccccc3n2)c2cc(C#N)ccc2O1
Solvent: ClCCl
Product: CC1(C)C=C(c2ccc3ccccc3[n+]2[O-])c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 6.9 %

Procedure:
450 mg of m-chloroperbenzoic acid were added at room temperature to a solution of 624 mg of 2,2-dimethyl-4-(2-quinolyl)-2H-1-benzopyran-6-carbonitrile in 20 ml of dichloromethane. After stirring at room temperature for 6 hours the mixture was washed with sodium bicarbonate solution and the organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (4:1) for the elution and then chromatographed on silica gel a second time using methanol/ethyl acetate (1:9) for the elution. The product was recrystallized from toluene to give 45 mg of 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)quinoline 1-oxide of melting point 177° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[CH3:8])=[O:5])[CH3:3].[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C1COCC1>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:4]([NH:6][C@H:7]([C:9]([NH:11][C@H:12]([C:14]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[O:16])[CH3:13])=[O:10])[CH3:8])=[O:5])[CH3:3]
Reactant: NCCCO
Reactant: C[C@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCO

Procedure:
The desired compound was synthesized by the procedure of Example 4 using Boc-Ala-Ala-Ala-OH and H2N—(CH2)3—OH except that the solvent was a mixture of THF and DMF (8 h). In a typical reaction of 4.59 mmol scale, the desired product was obtained in good yields, (1.401 gm, 79%) as a solid (m.p.—201° C.) after purification by silica gel flash column chromatography (MeOH:EtOAc—1:25). TLC (MeOH:DCM—1: 3; Rf—0.53).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:32])[C:20]3[CH:25]=[CH:24][C:23]([CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[NH4+:36]>C(O)C>[CH:26]1([C:23]2[CH:22]=[CH:21][C:20]([C:19]([N:10]3[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13][N:14]4[C:5]([C:3]([NH2:36])=[O:4])=[CH:6][CH:7]=[C:8]4[CH2:9]3)=[O:32])=[CH:25][CH:24]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reaction time: 4 h

Procedure:
2,2,2-Trichloro-1-[10-cyclohexyl-benzoyl)-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-1-ethanone of Example 7 (0.60 g) was added to a pressure flask containing concentrated ammonium hydroxide (25 mL) and absolute ethanol (25 mL). The mixture was heated in an oil bath held at 110° C. for four hours. On cooling the title compound crystallized out and was filtered off to provide colorless crystals (0.66 g), m.p. 122–123° C.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][CH3:3].N1CC[CH2:9][CH2:8][CH2:7]1.[CH:12](O)(C)C>>[CH:8]([O:4][C:1](=[O:5])[CH2:2][CH2:3][CH3:12])([CH3:9])[CH3:7]
Reactant: CC(C)O
Reactant: CCC(=O)O
Reactant: C1CCNCC1
Product: CCCC(=O)OC(C)C

Procedure:
In Scheme 2,3-nitrobenzaldehyde was added to cooled isopropanol. The mixture was heated to yield a completely dissolved solution, to which, was added isopropyl acetatoacetate, propionic acid and piperidine. The resultant solution was held until completion of reaction to yield crude Intermediate II, 3-oxo-2-)3-nitrophenylmethylene)butanoic acid isopropyl ester. The resultant mixture was then cooled and held for crystal formation. The crude Intermediate II crystals were isolated by centrifugation, rinsed with additional isopropanol, subsequently charged into cooled isopropanol, heated and agitated, then isolated again by centrifugation and finally dried using vacuum and heating to yield pure Intermediate II.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[CH3:19][N:20]([CH3:38])[C:21]1[CH:37]=[CH:36][C:24]([CH:25](O)[C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:34][N:32]([CH3:33])[C:29]1[CH:28]=[CH:27][C:26]([CH:25]([C:24]2[CH:36]=[CH:37][C:21]([N:20]([CH3:38])[CH3:19])=[CH:22][CH:23]=2)[S:15][CH2:14][C:13]([O:17][CH3:18])=[O:16])=[CH:31][CH:30]=1
Reactant: CN(C)c1ccc(C(O)c2ccc(N(C)C)cc2)cc1
Reactant: COC(=O)CS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CSC(c1ccc(N(C)C)cc1)c1ccc(N(C)C)cc1
Reaction time: 1 h
Yield: 53 %

Procedure:
A slurry of ρ-toluenesulfonic acid monohydrate (1.50 g, 7.89 mmol) and activated 3 Å molecular sieves (300-500 mg) in 7 mL of toluene is stirred for 15 minutes. Methyl thioglycolate (410 mg, 3.86 mmol) is then added followed by 4,4'-bis(dimethyamino)benzhydrol (Aldrich) (950 mg, 3.51 mmol) and stirred for 1 hour. The reaction is diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine and dried over magnesium sulfate. Chromatography on silica gel, eluting with a 1:4 mixture of ethyl acetate: hexane, provides methyl [[bis-(4-dimethylaminophenyl)methyl]thio]acetate as a greenish yellow solid in 53% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([O:13]CC)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([S:22][C@H:23]1[NH:26][C:25](=[O:27])[C@@H:24]1OC)(=[O:21])[CH3:20].C(OCC)(=O)C>C1(C)C=CC=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10](=[O:16])[CH:11]([N:26]2[C@H:23]([S:22][C:19](=[O:21])[CH3:20])[CH2:24][C:25]2=[O:27])[OH:13])=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Reactant: CCOC(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)S[C@@H]1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
200 mg of 2-ethoxy-2-hydroxyacetic acid p-nitrobenzyl ester and 2 g of molecular sieves A4 are added to a solution of 54.5 mg of (3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidine in a mixture of 4 ml of toluene and 1 ml of dimethylformamide, and the mixture is stirred for 2 hours at 50°. The molecular sieves are filtered off and the filtrate is concentrated in vacuo. The residue is chromatographed over silica gel, and by elution with toluene/ethyl acetate (9:1) the title compound, contaminated with some glyoxylate, is obtained. TLC: Rf =0.48 (ethyl acetate); IR spectrum (in CH2Cl2): absorption bands at 2.89 (broad), 5.64, 5.73, 5.91, 6.24, 6.56, 7.44, 7.62, 7.83-8.15 (broad, sh), 8.26, 8.39 and 8.80-9.30 (broad) μ.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][C:14](OCC)=[O:15].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:8]([C:7]1[C:2]2[NH:1][C:14](=[O:15])[CH2:13][O:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2cccc([N+](=O)[O-])c2N1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2-amino-3-nitrophenol (1.54 g, 10 mmol), ethyl bromoacetate (1.67 g, 10 mmol), potassium carbonate (1.54 g, 11 mmol) and DMF (5.0 mL) was stirred at room temperature for 20 h. Reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). Combined ethyl acetate layers were washed with water (50 mL×2), dried (brine, sodium sulphate), concentrated and dried on high vacuum to give 5-Nitro-4H-benzo[1,4]oxazin-3-one, K-64 (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)CC#N)CC4)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (54.0 mg, 0.14 mmol) in a mixture of dichloromethane and DMF (8 mL/2 mL) were added 2-cyanoacetic acid (30.7 mg, 0.36 mmol), Et3N (52.1 mg, 0.52 mmol) and HATU (164.2 mg, 0.43 mmol). The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM (V/V)=1/10) to give the title compound as a light yellow solid (53.0 mg, 83.3%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:17][C:18]1[C:27]([CH2:28][C:29](Cl)=[O:30])=[C:26]([F:32])[CH:25]=[C:24]2[C:19]=1[CH:20]=[CH:21][CH:22]=[N:23]2>CN(C)C=O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:29](=[O:30])[CH2:28][C:27]2[C:18]([F:17])=[C:19]3[C:24](=[CH:25][C:26]=2[F:32])[N:23]=[CH:22][CH:21]=[CH:20]3)=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1c(F)cc2ncccc2c1F
Reactant: NNc1ccc(Cl)nn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1c(F)cc2ncccc2c1F)NNc1ccc(Cl)nn1

Procedure:
(6-Chloro-pyridazin-3-yl)-hydrazine (531 mg, 3.67 mmol) was added to an oven-dried round-bottom flask and dissolved in dimethylformamide (7 mL) and triethylamine (1.54 ml, 11.01 mmol). The solution was cooled to 0° C. (5,7-Difluoro-quinolin-6-yl)-acetyl chloride (887 mg, 3.67 mmol) was dissolved in dimethylformamide (8 mL) and added to the reaction mixture dropwise. The reaction was complete upon addition of the acid chloride. The solution was concentrated down under vacuo to dryness to afford (5,7-difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide. LCMS [M+H+]=350.0. (5,7-Difluoro-quinolin-6-yl)-acetic acid N′-(6-chloro-pyridazin-3-yl)-hydrazide (1.28 g, 3.67 mmol) was suspended in acetic acid (30 mL) and the solution heated to 60° C. for 16 hours. The mixture was then concentrated in vacuo and the residue dissolved in dichloromethane (125 ml) and washed with saturated NaHCO3 (100 ml) and brine (100 ml). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting solid was triturated with methanol and the title compound was collected in quantitative via filtration and dried. Analytical data presented in Table 1.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=O>>[Cl:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1/[CH:20]=[CH:21]/[C:22]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=C(O)C=Cc1ccccc1Cl
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3Cl)nc2n(CCC)c1=O
Yield: 75 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.00 g (13.3 mmol) of 5,6-diamino-1,3-dipropyluracil and 2.67 g (14.6 mmol) of 2-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from toluene to give 3.72 g (yield 82%) of Compound 40 as white needles.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CCO
Reactant: O=C(O)C=Cc1nccs1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1nccs1

Procedure:
A solution of 2-thiazoleacrylic acid (26.76 g) and concentrated sulphuric acid (10 ml) in ethanol (150 ml) was refluxed for 18 hours. The solution was partially evaporated and dissolved in water. This solution was extracted with ether and the etheral extracts were evaporated to give ethyl 2-thiazoleacrylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH2:12][N:13](CC)[CH2:14][CH3:15].N1CCCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][CH2:11][CH2:12]2)=[CH:4][C:3]=1[Cl:10]
Reactant: CCN(CC)CC
Reactant: ClCc1ccc(Br)c(Cl)c1
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Clc1cc(CN2CCCC2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene (25.2 g, 105.03 mmol) and Et3N (16.1 ml, 115.53 mmol) in THF (150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was added dropwise. The r.m. was stirred overnight at r.t. and was then concentrated in vacuo. The residue was taken up into water and extracted with CH2Cl2 (3×100 ml). The combined organic layer was washed with saturated NaHCO3 and brine, and was then dried (MgSO4), filtered and the solvent was evaporated in vacuo. Yield: 25.8 g of 1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude product; used in next reaction step, without further purification).
Reaction SMILES: [Cl-].[Li+].[C:3]([Si:7]([CH3:44])([CH3:43])[O:8][CH:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:28]=[CH:27][C:26](OS(C(F)(F)F)(=O)=O)=[C:25]([CH3:37])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:38])([CH3:6])([CH3:5])[CH3:4].O.[C:46](OCC)(=O)[CH3:47].[CH2:52]([CH2:55][O:56][CH3:57])[O:53]C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]([Si:7]([CH3:44])([CH3:43])[O:8][CH:9]([C:39]([CH3:41])([CH3:42])[CH3:40])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:28]=[CH:27][C:26]([C:57]3[O:56][C:55]([CH:52]=[O:53])=[CH:47][CH:46]=3)=[C:25]([CH3:37])[CH:24]=2)([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:14][C:13]=1[CH3:38])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCOC(C)=O
Reactant: COCCOC
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C=O)o2)c(C)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 24 %

Procedure:
Lithium chloride (593 mg, 14 mmol), bis(triphenylphosphine)palladium (II) dichloride (123 mg, 0.175 mmol) and 5-tributylstannyl-1-furan-2-carbaldehyde (2.02 mg, 5.25 mmol) were added to a suspension of trifluoromethanesulfonic acid 4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl ester (Example 3-(5); 1.10 g, 1.75 mmol) in dimethoxyethane (5.3 mL), and the mixture was stirred at 60° C. for 15 hours. Water and ethyl acetate were added to the mixture. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane only to hexane/ethyl acetate=90/1) to give the title compound (2404 mg, 24%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([C:18]4[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[N:22][C:23]=4[F:24])=[C:13]([C:14]([F:17])([F:16])[F:15])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl.C(OCC)(=O)C>[CH3:34][S:35]([O:26][CH2:25][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[CH:11]=[CH:10][C:9]3[N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[N:6]=[N:7][C:8]=3[C:13]=2[C:14]([F:15])([F:17])[F:16])=[C:23]([F:24])[N:22]=1)(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2C(F)(F)F)c(F)n1
Temperature: 0 °C

Procedure:
{5-[1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl]-6-fluoropyridin-2-yl}methanol (20 mg, 0.055 mmol) was dissolved in dichloromethane (0.36 mL), cooled to 0° C. and treated with triethylamine (0.023 mL, 0.16 mmol) followed by methanesulfonyl chloride (4.7 uL, 0.060 mmol). The mixture was warmed to room temperature and stirred until complete, at which time the mixture was diluted with ethyl acetate and washed with sodium bicarbonate (2×5 mL, aqueous saturated). The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.