Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C@H:10]([CH3:14])[CH2:11][CH:12]=[O:13])=[CH:2]1.[CH2:15](O)[CH2:16][OH:17].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:13]1[CH2:15][CH2:16][O:17][CH:12]1[CH2:11][C@H:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:14]
Reactant: C[C@H](CC=O)c1c[nH]c2ccccc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C[C@H](CC1OCCO1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.2 %

Procedure:
(R)-3-(1H-Indol-3-yl)-butanal (89.5 mg, 0.479 mmol) was treated with ethylene glycol (130 μL, 2.4 mmol) and a catalytic amount of p-TSA in CH2Cl2 (2 mL). The reaction was stirred at room temperature for 12 h, at which time the organics were removed in vacuo. The solution was diluted with H2O (10 mL) and extracted with Et2O (3×20 mL). The collected organics where washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-(2-[1,3]-dioxolan-2-yl-1-methyl-ethyl)-1H-indole (15.7 mg 0.0680 mmol) after silica gel chromatography (20:80 EtOAc/hexanes). This residual material was then exposed to 1 mL of DMSO, finely crushed KOH (15.3 mg, 0.272 mmol), and benzyl bromide (12 μL, 0.13 mmol) at 0° C., then the solution was allowed to warm to room temperature and stirred for 12 h. The reaction was then treated with water (10 ml), and extracted with Et2O (2×20 ml). The aqueous layer was acidified to pH 4, extracted with Et2O 3×20 ml), dried over Na2SO4 and concentrated in vacuo to provide 14.7 mg of (R)-1-benzyl-3-(2-[1,3]dioxolan-2-yl-1-methyl)-1H-indole after preparative TLC (20:80 EtOAc/hexanes). The benzylated product was then refluxed with a catalytic amount of p-TSA in H2O (1 mL)/acetone (2 mL) overnight. The reaction mixture was diluted with H2O (5 mL), and extracted with Et2O (3×10 mL). The collected organics were washed with brine, dried over Na2SO4 and concentrated in vacuo to provide (R)-3-(1-benzyl-1H-indol-3-yl)-butanal (5.5 mg, 0.020 mmol) after preparative TLC. [α]D=+3.8 (c=1.0, CHCl3); reported rotation for (R)-3-(1-benzyl-1H-indol-3-yl)-butanal [α]D=+3.5 (c=1.0, CHCl3).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>CC(O)=O>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(C)(C)OC(=O)Cc1cccc2nccn12
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2nccn12
Temperature: 80 °C

Procedure:
To a stirring mixture of tert-butyl 2-(imidazo[1,2-a]pyridin-5-yl)acetate (200 mg) in HOAc (5 mL) was added 6N HCl (5 mL). The reaction mixture was warmed to 80° C. for 2 h. The crude product mixture was concentrated under reduced pressure and directly taken to the next reaction without further purification. Method[1], MS (ESI) 177.1 [M+H], Retention time=0.303 min.
Reaction SMILES: CS[C:3]([C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[F:32])=[N:4][C:5]([C:7]1[S:8][C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[C:10]([Br:13])[C:11]=1[CH3:12])=O.C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>C1(C)C=CC=CC=1.CCOCC>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[C:3]1[N:4]=[C:5]([C:7]2[S:8][C:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=3)=[C:10]([Br:13])[C:11]=2[CH3:12])[N:41]([CH2:39][CH3:40])[N:42]=1
Reactant: CCNN
Reactant: CSC(=NC(=O)c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C)c1c(F)cccc1Cl
Agent: O=C(O)C(=O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCn1nc(-c2c(F)cccc2Cl)nc1-c1sc(-c2ccc(OC(F)(F)F)cc2)c(Br)c1C
Temperature: 25 °C
Reaction time: 64 h
Yield: 0 %

Procedure:
Methyl-N-{[3-methyl-4-bromo-5-(4-trifluoromethoxyphenyl)-2-thienyl]-carbonyl}-2-fluoro-6-chlorobenzenecarbimidothioate (0.85 g, 1.5 mmol) and ethylhydrazine oxalate (0.90 g, 6 mmol) were combined in toluene (5 mL) and stirred 64 h at 25° C. and heated to reflux for 18 h. The reaction mixture was diluted with ether and washed with 0.1 M hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated to a crude pale yellow oil. Chromatography (silica gel, 10% ethylacetatelhexane) afforded the product as a clear oil (0.250 mg, 30%): 1H NMR (CDCl3) δ 7.73 (2H, d), 7.0-7.5 (5H, m), 4.3 (2H, q), 2.40 (3H, s), 1.55 (3H, t); EI/MS 546 m/e (M+).
Reaction SMILES: [ClH:1].[O:2]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[S:20][C:19]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27]C(=O)OC(C)(C)C)[CH2:24][CH2:25][CH3:26])=[N:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C>[ClH:1].[NH2:27][C@@H:23]([CH2:24][CH2:25][CH3:26])[C:22]([NH:21][C:19]1[S:20][C:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:17][N:18]=1)=[O:35]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ncc(-c2ccccc2COc2ccccc2)s1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCC[C@H](N)C(=O)Nc1ncc(-c2ccccc2COc2ccccc2)s1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
25 ml of a solution of gaseous hydrochloric acid (4.5 M) in ethyl acetate are added dropwise at 0° C. to 5 g of tert-butyl(1S)-2-[(5-{2-[(phenoxy)-methyl]phenyl}-1,3-thiazol-2-yl)amino]-1-propyl-2-oxoethylcarbamate, obtained in step 1.6, in solution in 60 ml of ethyl acetate. The mixture is stirred for 18 hours at 20° C. The precipitate formed is filtered, rinsed twice with diethyl ether and dried to give 3 g of a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[S:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([CH3:22])[C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:22][C:17]1[C:15]2[N:16]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[S:13][C:14]=2[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: C#CCCc1nc2c(C)ccc(C)c2s1
Reactant: Brc1ccccn1
Product: Cc1ccc(C)c2sc(CCC#Cc3ccccn3)nc12
Yield: 17931 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (46 mg, 0.29 mmol) and 2-but-3-ynyl-4,7-dimethyl-benzo[d]thiazole (63 mg, 0.29 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1 to 98:2) to yield 15 mg (52 mmol, 18%) of 4,7-dimethyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]thiazole as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:7]=1.[C:14]([NH:18][NH2:19])(=O)[CH2:15][CH3:16]>C(O)CCC>[CH2:15]([C:14]1[N:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:6]=[CH:7][C:2]2=[N:19][N:18]=1)[CH3:16]
Reactant: Clc1ccc(-c2ccccn2)nn1
Reactant: CCC(=O)NN
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3ccccn3)nn12

Procedure:
As for Example 4, a mixture of 1.0 g. of 3-chloro-6-(2-pyridyl)pyridazine, propionic acid hydrazide and 50 ml. of n-butyl alcohol is refluxed for 48 hours to give the product of the Example.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[N:23][C:24](Cl)=[C:19]4[CH:18]=[N:17]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:27][CH3:28].[C:29](=O)([O-])[O-:30].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:26])[CH2:15][N:16]3[C:20]4=[N:21][CH:22]=[N:23][C:24]([O:30][CH3:29])=[C:19]4[CH:18]=[N:17]3)[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:27][CH3:28]
Reactant: COc1cc(N2CCN(C(=O)Cn3ncc4c(Cl)ncnc43)CC2)ccc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(N2CCN(C(=O)Cn3ncc4c(OC)ncnc43)CC2)ccc1Cl

Procedure:
To a solution of 1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-(4-chloro-pyrazolo[3,4-d]pyrimidine-1-yl)-ethanone (0.024 Mmol, 1 eq.) in 1 mL of MeOH was added solid potassium carbonate (excess), the resultant mixture was heated at 70° C. for 30 minutes, then filtered and dried under vacuum. The crude product was purified by HPLC to provide the desired product as a white powder: 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 8.07 (s, 1H), 7.22 (d, 1H), 6.50 (d, 1H), 6.44 (dd, 1H), 5.29 (s, 2H), 3.90 (s, 3H), 3.81 (m, 4H), 3.19 (m, 4H), 2.25 (s, 3H). LCMS observed for (M+H)+: 418.9.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1>COCCOC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)o1
Reactant: Ic1nn(Cc2ccccc2)c2ccccc12
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of methyl 5-bromofuranoate (0.75 g, 3.66 mmol), hexamethylditin (1.0 g, 3.05 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) in DME (50 mL) was heated to reflux overnight. The initial amber coloured solution became black The solution was allowed to cool and then filtered and concentrated under reduced pressure. The crude stannane was purified by passage through a plug of silica (1:9 EtOAc:cyclohexane) to give methyl 2-trimethylstannyl-5-furanoate (0.17 g, 19%): 1H-NMR (CDCl3); The low yield of the product may be due to its suspected volatility. Pd(PPh3), (9 mg, 0.008 mmol) was added to a solution of 1-benzyl-3-iodo-1H-indazole (0.13 g, 0.39 mmol) and methyl 2-trimethylstannyl-5-furanoate (0.17 g, 0.588 mmol) in DME (20 mL) and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool to rt, filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica (3:7 EtOAc:cyclohexane) gave the product as a slightly contaminated yellow solid (88.6 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16](CO)=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:21]N1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(#N)C>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:18]=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(CO)cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CC(=O)O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.6 %

Procedure:
To a solution of dl-N-t-butoxycarbonyl-p-hydroxymethylphenylglycine (3.0 g, 0.011 mole) and N-hydroxysuccinimide (1.25 g., 0.011 mole) in 10 ml dry tetrahydrofuran and 50 ml dry acetonitrile was added N,N'-dicyclohexylcarbodiimide (2.238 g., 0.011 mole). The mixture was stirred at room temperature overnight. The dicyclohexylurea was filtered off and the filtrate taken to dryness under reduced pressure. The resulting solid was triturated with ether and filtered to give the N-hydroxysuccinimide ester of N-t-butoxycarbonyl-p-hydroxyphenylglycine (3.4 g., 83 percent yield) m.p. 141°-148° dec.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(F)cc1F
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2F)c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(F)c1

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-4-chlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[Cl:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[Cl:16]
Reactant: O=C(c1ccccc1)c1ccc(Br)c(Cl)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-chlorophenyl)-phenylmethanone (200 mg, 0.677 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:15])[CH3:14])[C:9](=[O:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].I[C:18]1[CH:19]=[C:20]([O:24][CH3:25])[CH:21]=[CH:22][CH:23]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]([CH:13]([CH3:14])[CH3:15])[C:9](=[O:12])/[CH:10]=[CH:11]/[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Reactant: COc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 88.6 %

Procedure:
To a solution of ((R)-1-Isopropyl-2-oxo-but-3-enyl)-carbamic acid tert-butyl ester (13.54 g, 59.6 mmol) in dry acetonitrile (150 mL) under argon, was added 3-iodoanisole (13.96 g, 59.6 mmol), triethylamine (9.1 mL, 65.6 mmol) followed by palladium (II) acetate (335 mg, 1.49 mmol). The resulting clear yellow solution was heated to 80° C. Upon heating, the reaction darkened and the precipitation of palladium black occurred. After 15 h, the reaction mixture was allowed to cool to room temperature, quenched with water (150 mL) and diluted with ether (150 mL). The ether layer was washed with brine (100 mL) and the combined aqueous layers were extracted with ether (two 50 mL portions). The extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was immediately purified by silica gel chromatography (9:1 hexanes/EtOAc) to provide 17.6 g (88%) of [(R)-(E)-1-Isopropyl-4-(3-methoxy-phenyl)-2-oxo-but-3-enyl]-carbamic acid tert-butyl ester as a yellow oil. MS (ES+) m/e 334.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28]O)[CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:22][C:23]1[S:27][CH:26]=[C:25]([CH2:28][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)[CH:24]=1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg), (5-chlorothiophen-3-yl)methanol (158 mg) and tributylphosphine (322 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (401 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with DCM (100 ml), washed with water and brine successively, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to afford the title compound (90 mg) as a white solid.
Reaction SMILES: NCC1C=NC=CC=1.[S:9]1[C:13]([CH2:14][NH2:15])=[CH:12][N:11]=[CH:10]1.[F:16][C:17]1([F:36])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([OH:34])=O)=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]>>[F:36][C:17]1([F:16])[CH2:19][CH:18]1[CH2:20][N:21]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:32]([NH:15][CH2:14][C:13]3[S:9][CH:10]=[N:11][CH:12]=3)=[O:34])=[C:29]([CH3:31])[N:30]=2)[C:22]1=[O:35]
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Reactant: NCc1cncs1
Agent: NCc1cccnc1
Product: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)NCc1cncs1
Yield: 68 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 3-(aminomethyl)pyridine with (thiazole-5-yl)methylamine to react with 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colourless solid in 68% yield: mp 182-184° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.61 (t, J=6.0 Hz, 1H), 7.74 (s, 1H), 4.53 (d, J=6.0 Hz, 1H), 4.01-3.95 (m, 2H), 3.64-3.47 (m, 3H), 3.19-3.12 (m, 1H), 2.44 (s, 3H), 2.04-1.88 (m, 1H), 1.67-1.55 (m, 1H), 1.37-1.26 (m, 1H); MS (ES+) m/z 414.9 (M+1).
Reaction SMILES: C(OC(C1C(O)=C2C=C(C3C=CC(OC)=CC=3)SC2=C(Cl)N=1)=O)CCC.[CH2:27]([O:31][C:32]([C:34]1[N:39]=[C:38](Cl)[C:37]2[CH:41]=[C:42]([C:44]3[CH:49]=[CH:48][C:47]([O:50][CH3:51])=[CH:46][CH:45]=3)[S:43][C:36]=2[C:35]=1[OH:52])=[O:33])[CH2:28][CH2:29][CH3:30]>>[CH2:27]([O:31][C:32]([C:34]1[N:39]=[CH:38][C:37]2[CH:41]=[C:42]([C:44]3[CH:45]=[CH:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=3)[S:43][C:36]=2[C:35]=1[OH:52])=[O:33])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCOC(=O)c1nc(Cl)c2cc(-c3ccc(OC)cc3)sc2c1O
Agent: CCCCOC(=O)c1nc(Cl)c2sc(-c3ccc(OC)cc3)cc2c1O
Product: CCCCOC(=O)c1ncc2cc(-c3ccc(OC)cc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 7-chloro-4-hydroxy-2-(4-methoxy-phenyl)-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester and 4-chloro-7-hydroxy-2-(4-methoxy-phenyl)-thieno[3,2-c]pyridine-6-carboxylic acid butyl ester, example 3-c, analogously to experimental conditions for example 1-g; with isolation of the higher Rf isomer. MS: (+) m/z 358.05 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][NH:20]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.C([O:33][CH2:34][C:35](Cl)=[O:36])(=O)C>C(Cl)Cl.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:29])=[C:5]([CH:26]=[CH:27][CH:28]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:24][CH3:25])=[C:14]([O:17][CH2:18][C@@H:19]3[CH2:23][CH2:22][CH2:21][N:20]3[C:34](=[O:33])[CH2:35][OH:36])[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC[C@@H]1CCCN1C(=O)CO
Temperature: 4 °C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline hydrochloride (0.25 g, 0.57 mmole; prepared as described in Example 31-starting materials) was dissolved in a mixture of methylene chloride (5 ml) and diisopropylethylamine (0.3 ml). The solution was cooled in an ice/water bath to 4° C. and acetoxyacetyl chloride (0.064 ml, 0.6 mmol) added. The reaction mixture was stirred cold for two hours and then partitioned between methylene chloride and saturated aqueous NaHCO3. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was dissolved in methanol (5 ml) containing anhydrous powdered potassium carbonate (0.2 g). After stirring overnight the solvent was evaporated and the residue purified by column chromatography eluting with methylene chloride/isopropanol (96/4)(containing 0.5% triethylamine). The fractions containing the expected product were evaporated and the residue was triturated with diethylether to give the title product as a white solid (0.1 g, 38%); 1H NMR Spectrum: (CDCl3) 1.95-2.29 (m, 4H); 3.29 (m, 1H); 3.46 (m, 2H); 4.03 (s, 3H); 4.07-4.18 (m, 3H); 4.55 (d, 1H); 4.69 (t, 1H); 7.13-7.16 (m, 2H); 7.26 (s, 1H); 8.26 (m, 1H); 8.35 (s, 1H); 8.48 (s, 1H); 8.66 (s, 1H); Mass Spectrum: (M+H)+ 461.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=4)=[CH:36][CH:35]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (90 mg), 4-(4-pyridyl)benzoic acid (52 mg), triethylamine (35 mg) and HOBt (39 mg) in DMF (10 ml) was added WSC hydrochloride (55 mg) under ice-cooling and the solution was stirred at room temperature 4 hours and concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated, and the residue was crystallized with ether to give colorless crystals of the title compound (122 mg).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:16][C:17](=[O:30])[C@H:18]([CH2:27][CH2:28]O)[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH2:15].[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH2:13]([O:16][C:17](=[O:30])[CH:18]([CH2:27][CH2:28][N:35]1[C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]2[C:31]1=[O:41])[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)[C@H](CCO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=CCOC(=O)C(CCN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Yield: 72.6 %

Procedure:
Diethyl azodicarboxylate (5.7 ml, 36.2 mmol, abbreviated as DEAD hereinafter) was added dropwise to a mixture of (±)-N-(tert-butoxycarbonyl)homoserine allyl ester (7.79 g, 30.0 mmol), phthalimide (4.41 g, 30 mmol), triphenylphosphine (9.45 g, 36.0 mmol) and tetrahydrofuiran (75 ml) at room temperature with stirring. This mixture was stirred for 1 hour. The solvent of the reaction mixture was evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1 as the eluent to afford the desired compound (8.46 g, yield 73%) as a white powder.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH3:19])=[CH:16][CH:17]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:1][C:16]1[CH:17]=[C:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)=[O:11])[CH:13]=[N:14][C:15]=1[NH:18][CH3:19]
Reactant: BrBr
Reactant: CNc1ccc(C(=O)c2ccc(Cl)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1ncc(C(=O)c2ccc(Cl)cc2)cc1Br
Reaction time: 1 h
Yield: 193.2 %

Procedure:
A solution of bromine (2.29 mL, 14.31 mmol) in acetic acid (30 mL) was added to a solution of compound C (11.0 g, 44.7 mmol) in acetic acid (80 mL) at RT. The mixture was stirred for 1 h, neutralized by the addition of saturated NaHCO3 solution and extracted with ethyl acetate (200 mL). The organic layer was washed with 10% sodium thiosulfate solution, water and brine. The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified using column chromatography to obtain 9.0 g (62%) of compound D viscous light yellow colored oil.