Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11](Cl)=[O:12])=[CH:6][C:5]=1[F:18])[CH3:2].[F:19][C:20]([F:24])([F:23])[CH2:21][OH:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([O:22][CH2:21][C:20]([F:24])([F:23])[F:19])=[O:12])=[CH:6][C:5]=1[F:18])[CH3:2]
Reactant: OCC(F)(F)F
Reactant: CCOc1ccc(C(C(=O)Cl)C(C)(C)C)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOc1ccc(C(C(=O)OCC(F)(F)F)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g (0.011 mol) 2-(4-Ethoxy-3-fluorophenyl)-3,3-dimethylbutyryl chloride was added dropwise to a solution of 1.12 g (0.0121 mol) 2,2,2-trifluoroethanol and 100 mg 4-dimethylaminopyridine in 15 ml pyridine at 0° C. After stirring for two hours at room temperature, tlc showed complete reaction. The mixture was added to ice/water, made weakly acidic, extracted with ether, the extract dried over magnesium sulphate and evaporated under reduced pressure. After silica gel chromatography, 2.80 g (=75.6% of theory) of a pale yellow oil was obtained. nD20 : 1.4783
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(C)=O>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])=[CH:7][CH:6]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of 200 g of methyl 4-hydroxyphenylacetate, 350.4 g of 1-bromotetradecane, 207.9 g of potassium carbonate, 10 g of potassium iodide and 1.5 L of acetone is heated at reflux temperature for 24 hours. The reaction is cooled to room temperature, concentrated in vacuo and the residue is recrystallized from cold hexane to give 276.0 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][SH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:18](OCC)[CH2:19][Br:20])C.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:18]([CH2:19][Br:20])[S:14][CH2:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(CCCS)cc1OC
Reactant: CCOC(CBr)OCC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(CBr)SCCC2
Reaction time: 8 h

Procedure:
A mixture of 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol, 1.0 g of bromoacetaldehyde diethylacetal, 0.16 ml of trifluoroacetic acid, and 25 ml. of nitromethane as solvent is stirred at room temperature for 1 hour, stored overnight in the freezer, and then heated at 70° for 2 hours after an additional 0.05 ml trifluoroacetic acid is added. After cooling, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is taken to dryness, and the residue is chromatographed one time on silica gel with methylene chloride as eluent and a second time with 10% ethyl acetate/Skellysolve B as eluent to yield 7,8-di-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C[O-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][C:3](=[O:16])[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COC(=O)CCc1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CCN)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC

Procedure:
3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester is dissolved in toluene, 1.05 equivalents 2-(3,4-dimethoxy-phenyl)-ethylamine (commercially available) and 1.1 equivalents sodium methoxide (30% in methanol) are added. At normal pressure the reaction mixture is heated to a maximum of 110° C. and methanol distilled until full conversion is reached. The reaction mixture is washed with water and sulfuric acid. During cooling of the organic phase, the compound 3 crystallises and is filtered, washed with cold toluene and dried in vacuo at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][OH:16]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:16][CH2:15][CH2:14][CH2:13][O:12][CH3:11])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: COCCCO
Product: COCCCOc1cc(Cl)ccc1CN

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 3-methoxy-propanol analogously to the preparation of Intermediate 98.1 as a colorless solid; ES-MS: M+=230.1; HPLC: AtRet=2.81 min.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[N:14](C(OC(C)(C)C)=O)[C:13]1=[O:26].C([N-]C(C)C)(C)C.[Li+].Cl([F:39])(=O)(=O)=O>O1CCCC1>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1([F:39])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:26]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC(N2C(=O)c3ccccc3C2=O)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CCC(F)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dioxo-2-(1-tert.-butoxycarbonyl-2,6-dioxopiperidin-3-yl)isoindoline (1.0 g. 2.8 mmol) in tetrahydrofuran (10 mL) is added lithium diisopropylamide (1.5 mL, 3.0 mmol, 2M) at . After 30 minutes, perchloryl fluoride (5 mmol) is bubbled into the mixture. The mixture is allowed to reach room temperature and the solvent then removed in vacuo. The residue is stirred with ethyl acetate (10 mL) and IN hydrochloric acid (10 mL) for one hour. The organic layer is separated and the solvent removed in vacuo to yield 1,3-dioxo-2-(2,6-dioxo-3-fluoropiperidin-3-yl)isoindoline which can be further purified through chromatography.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH:19]([NH2:23])([CH2:21][CH3:22])[CH3:20]>C(O)C>[CH:19]([NH:23][C:2]1[C:3]([C:15]([F:18])([F:17])[F:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([Cl:11])[C:7]=1[N+:8]([O-:10])=[O:9])([CH2:21][CH3:22])[CH3:20]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCO
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c(Cl)c1[N+](=O)[O-]

Procedure:
To a stirred mixture of 20 g. (0.0655 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 150 ml. of absolute ethanol was added 9.58 g. (0.131 mole) of sec-butylamine, dropwise, over a period of about 15 minutes. The resultant solution was refluxed for 2 hours and the ethanol then removed by distillation under reduced pressure. The solid yellow residue was triturated with 300 ml. water to dissolve the sec-butylamine hydrochloride. The water insoluble product was isolated by filtration, washed with water, and then dissolved in 600 ml. of refluxing 95% ethanol. Upon cooling, the product crystallized. Filtration gave 20.4 g. of a yellow crystalline solid, melting at 90.5°-91.5° C.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH2:21][O:20][CH3:19])[O:23][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: COCc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Product: COCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)n2)c(-c2ccccc2)o1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methoxymethyl-5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:8][C:7]1[C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][OH:9])=[CH:12][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: OCc1ccc(B(O)O)cc1
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: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1ccc(CO)cc1
Yield: 45.9 %

Procedure:
A mixture of 2-bromo-3-methylpyridine (22.5 g, 0.1312 mol), 4-(hydroxymethyl)phenylboronic acid (25 g, 0.164 mol), Pd(PPh3)4 (9.5 g, 0.0082 mol), and sodium carbonate (200 g in 500 ml of water) in toluene (750 ml) were refluxed under nitrogen atmosphere for 15 h. Separated the toluene layer and distilled under reduced pressure to give a residue. The residue was then purified by column chromatography to yield [4-(3-methyl-2-pyridinyl)phenyl]methanol (12 g, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:24])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C1COCCN1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](C(=O)N1CCOCC1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 17] (0.105 g) in DCM (10 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.152 g), HOBT (0.107 g) and triethylamine (0.222 ml) and the mixture was stirred at room temperature for 30 min. Morpholine (0.07 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, and ethyl acetate) to give the title compound (0.1 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCCBr
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(O)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(OCCCCBr)cc1

Procedure:
In analogy to example 1.4, reaction of (4-Hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester with 1,4-dibromobutane yielded [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid tert-butyl ester, MS: 360 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](OC)(OC)[CH2:16][CH3:17].C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[C:15]([O:14][CH3:13])[CH2:16][CH3:17])[C:9]#[N:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCC(OC)(OC)OC
Reactant: N#CCC(=O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: CCC(OC)=C(C#N)C(=O)c1ccc(F)cc1

Procedure:
A solution containing 30 g. of (p-fluorobenzoyl)acetonitrile, 36.4 g. of trimethylorthopropionate and 57 g. of acetic anhydride is heated in an oil bath at 130° for 3 hours. The ethanol and excess acetic anhydride is distilled off and the residue is diluted with chloroform. The chloroform solution is passed quickly through Magnesol® and concentrated, then cooled to produce the title product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4].I[CH2:17][CH3:18].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:17]([O:1][CH2:2][C@@H:3]([N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH3:4])[CH3:18]
Reactant: CCI
Reactant: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](C)N1C(=O)c2ccccc2C1=O
Reaction time: 15 h
Yield: 73.8 %

Procedure:
To a solution of 2-[(1S)-2-hydroxy-1-methyl-ethyl]isoindoline-1,3-dione (47 g, 229 mmol) and iodoethane (89.3 g, 572.5 mmol) in THF (376 mL) is added potassium tert-butoxide (64.25 g, 572.5 mmol) in one portion. The mixture is stirred under a nitrogen atmosphere for 15 h. The mixture is diluted with ethyl acetate (200 mL) and washed with brine (200 mL). The aqueous phase is extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over MgSO4, filtered, concentrated under reduced pressure, and then dried under high vacuum to afford the title compound (39.4 g, 74%) as an orange solid that is used without further purification. LC-ES/MS m/z 234 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[N:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:11][C:8]2[N:9]=[C:10]3[C:2]([CH3:1])=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:17])[CH3:19])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cn(COCC[Si](C)(C)C)c2ncc(N)nc12
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Product: Cc1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Temperature: 25 °C
Yield: 64.1 %

Procedure:
7-Methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (41 mg, 0.147 mmol) was dissolved in 1,2-dichloroethane (1.5 mL). Cyclohexylisocyanate (0.19 mL, 1.47 mmol) was added and the reaction mixture was heated to reflux for 64 hr, cooled to RT, concentrated, purified by SiO2 chromatography (8 g SiO2, hexanes/EtOAc 0-50% EtOAc) to give 38 mg of 1-cyclohexyl-3-[7-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid (64% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15](Cl)=[S:16])=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]([CH:18]([CH2:20][CH3:21])[CH3:19])[C:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:16])=[CH:22][CH:23]=1
Reactant: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Cl
Reactant: Nc1ccccc1
Solvent: Cc1ccccc1
Product: CCC(C)N(Cc1ccc(Cl)cc1)C(=S)Nc1ccccc1
Yield: 68.2 %

Procedure:
19 g of aniline were dissolved in 300 ml of toluene. To the resulting solution, a solution of 28 g of N-(4-chlorobenzyl)-N-sec.-butyl-thiocarbamoyl chloride in 70 ml of toluene was added dropwise, under cooling and stirring. After the dropwise addition, the temperature of the solution was gradually raised, and then the solution was stirred at a temperature of 70°-80° C. for about 5 hours. The solution was cooled to precipitate aniline hydrochloride, which was then separated by filtration. The toluene layer was washed with 100 ml of cold water and dried with anhydrous sodium sulfate. Then, the toluene was distilled off. The residue was subjected to recrystallization from a mixture of hexane and ethyl alcohol, whereby 23 g of N-(4-chlorobenzyl)-N-sec.-butyl-N'-phenylthiourea were obtained. Yield: 70%. Melting point: 134°-134.5° C.
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5].[N-:15]=[N+:16]=[N-:17].[Na+].CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[N:15]([CH2:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]([NH2:14])=[NH:13])[S:9][CH:10]=1)=[O:5])=[N+:16]=[N-:17]
Reactant: N=C(N)Nc1nc(C(=O)CBr)cs1
Reactant: [N-]=[N+]=[N-]
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC(=O)c1csc(NC(=N)N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 50 g (0.14 mol) of 2-bromo-1-(2-guanidino-4-thiazolyl)ethanone hydrobromide, 23.6 g (0.36 mol) of sodium azide, and 250 ml of dimethylformamide was stirred at room temperature for 1.5 hours. The mixture was poured into 1.5 liters of water, and the aqueous solution was made basic with solid sodium carbonate. The resulting precipitate was filtered, washed well with water, and dried, thereby affording 30.6 g (93%) of 2-azido-1-(2-guanidino-4-thiazolyl)-ethanone as a light brown crystalline solid, mp 177° (dec). Analytically pure material can be prepared by recrystallization from absolute ethanol: Calcd. for C6H7N7OS: C, 32.00; H, 3.13; N, 43.53; S. 14.24; found: C, 32.22; H, 3.43; N, 41.93; S, 13.97.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:19][CH3:20])[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[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.O>[CH2:19]([N:8]([C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=2)[CH:7]=[CH:6][CH:5]=1)[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:10])[CH3:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(C=O)cc2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
135 mg (5 mol %) of tetrakis(triphenylphosphine)palladium are added to a solution of 800 mg (2.34 mmol, 1 eq) of 1-(3-bromophenyl)-1-ethyl-3-heptylurea and 460 mg (3.0 mmol, 1.3 eq) of 4-formylphenylboronic acid in 10 mL of a mixture of dimethylformamide and of 2M potassium phosphate solution (8/2). The reaction mixture is stirred for 3 hours at 90° C. The reaction is stopped by addition of 50 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 740 mg of 1-ethyl-1-(4′-formylbiphenyl-3-yl)-3-heptylurea are obtained in oil form. Yield=86%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:15]=[C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:3][CH:4]=2)=[O:9])[S:12][C:13]=1[N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(N2CCOCC2)nc1
Yield: 84.3 %

Procedure:
Compound 32 (391 mg, 1.00 mmol) was dissolved in 1,4-dioxane (10 mL), and morpholine (0.44 mL, 5.00 mmol) was added thereto, followed by stirring under heating and reflux for 10 hours. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous solution of sodium chloride was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=19:1) to afford the entitled Compound 34 (372 mg, 84%).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1)=[O:2].[C:20](OC(=O)C)(=[O:22])[CH3:21]>N1C=CC=CC=1.C(Cl)Cl>[C:20]([O:19][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[N:8]=[CH:7][C:6]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:22])[CH3:21]
Reactant: COc1ccc(COC2C=NC(C=O)=CC2=O)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(COc2cnc(C=O)cc2OC(C)=O)cc1
Reaction time: 2 h
Yield: 547.3 %

Procedure:
To a solution of 0.05 g of 6-formyl-3-(p-methoxybenzyl)oxy-4-pyridone in 5 ml of pyridine is added 0.133 g of acetic anhydride, and the mixture is stirred for 2 hours. The reaction mixture is condensed under reduced pressure, and the residue is dissolved in 20 ml of methylene chloride, washed with water, 5% aqueous potassium hydrogen sulfatge solution and 7% aqueous sodium hydrogen carbonatge solution in this sequence, dried over magnesium sulfate, and condensed to dryness under reduced pressure to give 0.318 g of the title compound as colorless crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10](I)=[CH:9]2)[CH2:4][O:3]1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[CH3:1][C:2]1([CH3:20])[O:6][CH:5]([CH2:7][N:8]2[C:16]3[CH:15]=[CH:14][N:13]=[C:12]([O:17][CH3:18])[C:11]=3[C:10]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=3)=[CH:9]2)[CH2:4][O:3]1
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2CC1COC(C)(C)O1
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: CN(C)C=O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2CC1COC(C)(C)O1
Temperature: 130 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (120 mg) in DMF (3 mL)/water (0.30 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (131 mg), tetrakis(triphenylphosphine)palladium(0) (35.7 mg) and potassium carbonate (85.4 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (32.0 mg).