Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1([CH3:30])[N:22]([CH2:23][CH2:24][OH:25])[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[C:38]([O:25][CH2:24][CH2:23][N:22]1[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]([CH3:29])[C:3]1([CH2:1][CH3:2])[CH3:30])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCO)C(C)(CC)C2C)C1=O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCOC(=O)c3ccccc3)C(C)(CC)C2C)C1=O
Yield: 49.9 %

Procedure:
To a solution of 2.5 g of the oily product obtained in Example 6 in 30 ml of benzene were added 1.2 g of triethylamine; 0.8 g of benzoyl chloride was then added dropwise with ice-cooling. The mixture was refluxed by heating for 2 hours and, after cooling, an aqueous solution of potassium carbonate was added. The mixture was extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulphate and then concentrated by evaporation under reduced pressure. The resulting oily product was first purified by column chromatography on silica gel (eluent: a 10 : 0.5 by volume mixture of hexane and triethylamine) and then by recrystallization from diethyl ether, giving 1.5 g of Compound 130 as crystals melting at 123° - 124.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13](N(OC)C)=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:4][CH:3]=1.FC1C=CC(N2[C:41]([C:42](O)=[O:43])=CN=C2SC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.FC1C(F)=CC=C(F)C=1CBr.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:43][CH2:42][CH3:41])=[O:14])=[CH:11][N:10]=[C:9]2[S:19][CH2:20][C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1-c1ccc(F)cc1
Reactant: CON(C)C(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: Fc1ccc(F)c(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1

Procedure:
Ethyl 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (10) was prepared in a similar manner as that described for the synthesis of compound 9 using ethyl 1-(4-fluorophenyl)-2-mercapto-1H-imidazole-5-carboxylate (6) (202 mg, 0.76 mmol), 2,3,6-trifluorobenzyl bromide (0.1 mL, 0.76 mmol), and potassium carbonate (125.9 mg, 0.91 mmol) in acetone (3 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[C:34](=O)(OC)OC.C1N2CCN(CC2)C1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:34])[CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reactant: COC(=O)OC
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12

Procedure:
To a solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]butanoate (D53) (150 mg) and dimethyl carbonate (5.0 mL) in N,N-dimethylformamide (DMF) (0.5 mL) was added DABCO (18 mg). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 150° C. for 1.5 h. After cooling the reaction, the mixture was concentrated to afford the crude product ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]butanoate (D57) (180 mg), which was used for the next hydrolysis step without further purification. MS (ES): C26H28ClN3O4 requires 481. found 482.2 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH3:27])[C:24](O)=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].C1C=CC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CCN(CC)CC>C(Cl)Cl>[C:15]([O:19][C:20](=[O:21])[NH:22][C@H:23]([C:24](=[O:25])[NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:27])([CH3:16])([CH3:17])[CH3:18]
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.5 %

Procedure:
To a mixture of N2-phenylpyridine-2,3-diamine (2.00 g, 0.011 mol), (S)-2-tertbutoxycarbonylaminopropionic acid (3.06 g, 0.0162 mol), HOBt (2.19 g, 0.0162 mol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.10 g, 0.0162 mol) in DCM (80 mL) cooled to 0° C. under a nitrogen atmosphere was added Et3N (4.5 mL, 0.0324 mol). The reaction mixture was stirred at 0° C. for 5 min, then slowly warmed to RT and stirring was continued for 20 h. The resulting mixture was partitioned between EtOAc and a saturated solution of NaHCO3. The aqueous phase was further extracted with EtOAc and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The residue thus obtained was purified column chromatography (Si—PCC, gradient 0-5% 2M NH3/MeOH in DCM) affording [(S)-1-(2-phenylaminopyridin-3-ylcarbamoyl)ethyl]carbamic acid tertbutyl ester as a pale pink solid (2.05 g, 4.56 mmol). LCMS: RT 3.75 min [M+H]+ 390.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:25][CH2:24][C:20]2[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1cccnc1
Solvent: COCCOC
Product: N#Cc1c(NCc2cccnc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-picolylamine in DME. ES-MS m/e (%): 293 (M+H+, 100).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[N:5]1([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3([C:26]#[N:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[CH2:9][CH2:8][CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:23]1[CH2:22][CH2:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][CH2:10][N:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)=[CH:15][CH:16]=2)([C:26]#[N:27])[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C#N)(c2ccc(OCCCN3CCCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Acetyl chloride (27 μl, 0.37 mmol) was added dropwise to a solution of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]piperidine-4-carbonitrile (90 mg, 0.28 mmol) and triethylamine (78 μl, 0.56 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (15 ml) and washed with water (15 ml). The layers were separated and the aqueous layer was further extracted with dichloromethane (2×10 ml). The organics were combined, washed with brine, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:methanol:ammonia (95:5:0.5 by volume) to provide the title compound (28 mg, 28%). 1H NMR (400 MHz, CD3OD) δ 1.82-1.85 (m, 4H), 1.89-2.18 (m, 9H), 2.60-2.63 (m, 4H), 2.69 (t, 2H), 3.00 (t, 1H), 3.50 (t, 1H), 4.03-4.12 (m, 3H), 4.70 (d, 1H), 6.97 (d, 2H), 7.44 (d, 2H). HRMS ESI+ m/z 356.2329 [MH]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17]I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([NH:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][N:22]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNCCC
Reactant: ICCCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CCC)CCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 29 h

Procedure:
To a solution of 3-(4-benzyloxyphenyl)propyl iodide (1.790 g) in DMF (20 ml) were added N,N-dipropylamine (1.3 ml) and potassium carbonate (1.391 g). The reaction mixture was stirred at room temperature for 29 hr, diluted with water, and extracted with ethyl acetate. The residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1/1) to obtain 3-(4-benzyloxyphenyl)propyl-N,N-dipropylamine (1.589 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1>C(Cl)Cl>[CH3:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[N:19]=2)[S:11][N:10]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)sn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)sn1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68.5 %

Procedure:
Trifluoroacetic acid (2889 μl, 37505 μmol) was added to a stirred suspension of tert-butyl (6-(3-methylisothiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (464 mg, 1339 μmol) in DCM (10 mL) at RT. The reaction mixture was stirred at RT for 45 min. and then concentrated in vacuo. 2M NH3 in MeOH was added. Purification by MPLC (DCM/MeOH+1% NH4OH) afforded the title compound (226 mg, 69% yield). MS m/z=247.1 [M+H]+. Calc'd for C, 10; H, 10; N, 6; S: 246.30.
Reaction SMILES: CN(C)C=O.[H-].[Na+].[C:8]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][C:22]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[N:23]=3)[CH2:17][CH2:16]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:32][C:33]1[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=1>O>[C:8]1([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([CH2:21][C:22]3[N:23]([CH2:32][C:33]4[O:37][C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:35][CH:34]=4)[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[CH2:19][CH2:20]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)o1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To 470 parts of N,N-dimethylformamide were added portionwise 17.3 parts of a dispersion of sodium hydride in mineral oil (50%) and 91.6 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole (as prepared in Example 16 of U.S. Pat. No. 4,695,575) while stirring under a nitrogen atmosphere. After stirring for 1 hour, 67.9 parts of ethyl 5-chloromethyl-2-furancarboxylate were added dropwise while cooling. Stirring was continued for 1 hour and then water was added to the reaction mixture. The product was extracted with methylbenzene and the extract was washed with water, dried, filtered and evaporated. The residue was dried azeotropically with methylbenzene (2x), yielding 119 parts (86.7%) of ethyl 5-[[2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazol-1-yl]methyl]-2-furancarboxylate (interm. 4). Following the same procedure and starting from the appropriate starting materials, there were also prepared:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][CH:12]1[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(C2C=CC=CC=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C@H:12]2[CH2:17][CH2:16][Si@H:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][CH2:13]2)=[CH:4][C:3]=1[CH3:9]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(CBr)CC1
Reactant: Cc1cc(O)ccc1Cl
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)c(C)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 4-chloro-3-methylphenol and 4-bromomethyl-1-n-heptyl-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][NH:9][C:8](=[O:12])[C:7]1=[O:13].N12CCCN=C1CCCCC2.[C:31]([O:35][CH3:36])(=[O:34])[CH:32]=[CH2:33]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:33][CH2:32][C:31]([O:35][CH3:36])=[O:34])[C:8](=[O:12])[C:7]1=[O:13]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CN2CCNC(=O)C2=O)c(OC)c1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCN1CCN(Cc2ccc(OC)cc2OC)C(=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 1.0 g of 1-(2,4-dimethoxybenzyl)-2,3-dioxopiperazine, 0.28 ml of 1,8-diazabicyclo[5.4.0]-undec-7-ene, 0.34 ml of methyl acrylate and 10 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours. Then, the solvent was distilled off under reduced pressure, after which the resulting residue was added to a mixed solvent of 30 ml of ethyl acetate and 30 ml of water, and the pH was adjusted to 3 with 2N hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with three 30-ml portions of ethyl acetate. The combined organic layer was washed with water and then a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent; chloroform : methanol=20:1) to obtain 0.68 g of methyl 3-[4-(2,4-dimethoxybenzyl)-2,3-dioxopiperazin-1-yl]propionate as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.Br[C:24]1C=CC([N+]([O-])=O)=CC=1C(OC)=O.COC1C=CC(C)=CC=1B(O)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>[CH3:22][O:21][C:5]1[CH:4]=[CH:3][C:2]([CH3:24])=[CH:7][C:6]=1[C:8]1[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(C)cc1B(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(C)ccc1OC
Yield: 98 %

Procedure:
This compound was prepared in a manner similar to that of methyl 5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (1.80 g, 6.92 mmol), (PPh3)4Pd (0.33 g, 0.28 mmol), and 2-methoxy-5-methylphenylboronic acid (1.58 g, 9.51 mmol) to afford 2.03 g (98%) of methyl 2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate as a white solid. Data for methyl (2'-methoxy-5'-methyl-4-nitro-2-biphenylcarboxylate): 1H NMR (400 MHz, CDCl3) 8.69 (d, J=2.5, 1H ), 8.36 (dd, J=8.4, 2.5, 1H), 7.51 (d, J=8.5, 1H), 7.20 (m, 1H), 7.07 (d, J=2.1, 1H), 6.81 (d, J=8.4, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][N:5]2[C:6](=[O:8])[CH:7]=1.S(Cl)([Cl:19])(=O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:19][C:7]1[C:6](=[O:8])[N:5]2[CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:11][C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: COC(=O)c1cn2c(=O)cc(C)nc2s1
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COC(=O)c1cn2c(=O)c(Cl)c(C)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (5.5 g; m.p. 146°-148° C.), prepared according to Example 1, was reacted with sulfuryl chloride (3.6 g) in dichloroethane (150 ml) under stirring at room temperature for 30 minutes. The reaction mixture was poured into ice water containing NaHCO3 : the organic phase was separated and evaporated in vacuo to dryness: crystallization from methanol gave 6-chloro-7-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, methyl ester (4.28 g), m.p. 218°-220° C., which was reacted with benzaldehyde (3.5 g) in methanol (150 ml) in the presence of sodium methoxide (2.68 g) under stirring at reflux temperature for 24 hours. The precipitate was filtered and dissolved in a mixture of dimethylformamide and formic acid; the solution was diluted with ice water and the precipitate was filtered and washed with water until neutral. Crystallization from CH2Cl2 -methanol gave 3.1 g of 6 -chloro-7-trans-(2-phenyl-ethenyl)-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, m.p. 265°-270° C. dec., N.M.R. (CF3COOD-CDCl3) δp.p.m.: 7.59 (d) (1H,β-ethenyl proton), 7.40-7.80 (m) (5H, phenyl protons), 8.01 (d) (1H,α-ethenyl proton), 8.88 (s) (1H, C-3 proton); JHαHβ =16 Hz.
Reaction SMILES: Cl.[C:2]([NH2:5])(=[NH:4])[CH3:3].C[O-].[Na+].[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[C:21]([F:23])[C:20]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[C:19]([F:36])[CH:18]=1)#[N:10].O>CO>[CH2:31]([C:30]1[N:4]=[C:2]([CH3:3])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:20]1[C:21]([F:23])=[CH:22][C:17]([C:12]2[C:11]([C:9]#[N:10])=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:18][C:19]=1[F:36])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCC(=O)C(Cc1c(F)cc(-c2ccccc2C#N)cc1F)C(=O)OC
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCc1nc(C)[nH]c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Yield: 63.1 %

Procedure:
To a suspension of acetamidine hydrochloride (3.9 g) in methanol (30 mL) were added sodium methoxide (28% methanol solution, 12 mL) and then methyl 2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (7.93 g), and the mixture was stirred for 15 hr. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was triturated with diisopropyl ether to give the title compound (5.11 g, 63%) as pale-yellow crystals.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[CH:4][CH:3]=1.[OH-].[K+].CO.[C:15](=S)=[S:16]>O>[Br:1][C:2]1[O:6][C:5]([C:7]2[O:8][C:15]([SH:16])=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Br)o1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Sc1nnc(-c2ccc(Br)o2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-Bromo-furan-2-carboxylic acid hydrazide (20.5 g, 100 mmol) was added to a mixture of potassium hydroxide (6.2 g, 110 mmol) and methanol (125 ml). The mixture was stirred for 30 minutes at room temperature. Carbon disulfide (15.2 g, 200 mmol) was added. The mixture was stirred at reflux for 30 hours. Water (60 ml) was added and the excess of carbon disulfide and methanol was evaporated. The aqueous suspension was acidified by adding concentrated hydrochloric acid (14 ml). The product precipitated and was washed with water (20 ml), dried and evaporated. Yield 8.58 g (35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Cl-].[Al+3].[Cl-].[Cl-].[F:15][C:16]([F:24])([F:23])[C:17]([C:19]([F:22])([F:21])[F:20])=[O:18].Cl>C1(C)C=CC=CC=1>[F:15][C:16]([F:24])([F:23])[C:17]([C:7]1[CH:6]=[C:5]([CH3:9])[C:4]([OH:10])=[C:3]([O:2][CH3:1])[CH:8]=1)([OH:18])[C:19]([F:22])([F:21])[F:20]
Reactant: COc1cccc(C)c1O
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O

Procedure:
To 2-methoxy-6-methylphenol (27.6 g=0.20 mol) in 300 ml toluene, add aluminum chloride (4.0 g=30 mmol). Bubble in hexafluoroacetone (47 g=0.28 mol) over 7 hours. Heat the reaction mixture in a steel bomb 16 hours at 120° C. Cool, and pour the contents onto 1.0 N HCl. Extract with ether. Wash the ether layer with 1.0 N NaOH. Acidify the basic aqueous layer with concentrated HCl, extract with ether, dry, concentrate and distill to obtain a fraction boiling at 71°-74° C./0.1 mm. Crystallize from cold hexane to obtain, as a solid, m.p. 44°-45° C., 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenol.
Reaction SMILES: [OH-:1].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][C:13]([CH:22]=[O:23])=[CH:12][C:11]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O.C1COCC1.[Ag-]=O>[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][O:9][C:10]1[C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:12][C:13]([C:22]([OH:1])=[O:23])=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [OH-]
Reactant: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Agent: O=[Ag-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOc1c(-c2ccccc2)cc(C(=O)O)cc1-c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
At ambient temperature, to a stirred mixture of silver (I) oxide (0.570 g, 2.46 mmol) in H2O (9.8 mL) was added NaOH (0.983 g, 24.6 mmol) and the reaction was heated at 50° C. After 0.5 h, to the reaction was added a solution of 2′-(2-methoxyethoxymethoxy)-[1,1′;3′,1″]terphenyl-5′-carbaldehyde (1.78 g, 4.92 mmol) in THF (9.8 mL) and the reaction was heated at 90° C. for 1 h. To the reaction was added silver (I) oxide (0.570 g, 2.46 mmol), NaOH (0.983 g, 24.6 mmol) and H2O (10.0 mL). The reaction was heated at 90° C. for 16 h. The reaction was filtered through a celite pad, rinsing with hot H2O (3×). The filtrate was washed with ether (3×), acidified with 2N HCl (pH 2) and extracted with EtOAc. The organic extracts were dried (MgSO4) and concentrated to give 1.73 g (93%) of the title compound. 1H NMR (DMSO-d6) δ 2.77-2.80 (m, 2H), 2.88-2.91 (m, 2H), 3.01 (s, 3H), 4.39 (s, 2H), 7.39-7.52 (m, 6H), 7.59-7.62 (m, 4H), 7.89 (s, 2H), 13.07 (s, 1H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[B:32]([O-])([O-:34])[O-:33]>C1COCC1.CCCCCC>[C:16]([O:20][C:21]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]1[B:32]([OH:34])[OH:33])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1ccc2ccccc21
Reactant: [O-]B([O-])[O-]
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (11.0 g; 78 mmols) in THF (170 ml), at -78° C. and under nitrogen, a 1.6M solution of BuLi (56.1 ml; 89.7 mmols) in hexane is added slowly in order to maintain the temperature below -65° C. The mixture is stirred at -75° C. for 10 min and is then warmed to 0° C. within 30 min. After cooling again to -78° C., a solution of 1-tert-butoxycarbonylindole (15.6 g; 72 mmols) in THF (300 ml) is added, keeping the temperature below -65° C. The mixture is stirred 1 hour at -75° C. and a solution of trimrthyl borate (7.5 g; 72 mmols) in THF (200 ml) is added dropwise. The reaction is allowed to warm up to room temperature overnight. A 0.25N solution of Hcl (200 ml) is added and the THF is removed under vacuum. The residue is extracted with ethyl ether (3×150 ml) and the combined organic phases are washed with water (2×100 ml) and dried over sodium sulphate. The solution is then concentrated, cooled to 0° C. and filtered to obtain crystalline (1-tert-butoxycarbonylindol-2-yl)boronic acid (6.95 g; 26.6 mmols). Yield: 37%.