Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6][N:7]([C:17](=[O:42])[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([O:25][CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[NH2:15].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>ClCCl>[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47].[CH3:1][O:2][C:3](=[O:43])[CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:16])[NH2:15])[C:17](=[O:42])[C:18]1[CH:19]=[C:20]([O:25][CH2:26][CH2:27][NH:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
A solution of 4-[{3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-carbamoyl-phenyl)-amino]-butyric acid methyl ester (0.031 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 1 h and then concentrated under reduced pressure to give the title compound (0.032 g) as a colourless gum.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:21][Zn]C>C1COCC1.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 65 °C
Yield: 14.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.200 g, 0.562 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol) were combined in THF (4 mL) and treated with dimethylzinc (1 M in heptane) (1.125 mL, 1.125 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 65° C. and stirred for 1 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated aqueous NaHCO3, the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was cooled in an ice bath and the resultant precipitate filtered off to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.023 g, 0.079 mmol, 14.07% yield) as a white solid. The mother liquor was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give a second batch of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.072 g, 0.248 mmol, 44.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45-7.53 (m, 2H), 7.42 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 3.76 (s, 2H), 2.33 (s, 3H), 1.99 (br. s., 2H). LC-MS (ES−) m/z 289.99, 291.15 [M−1]. LC-MS (ES+) m/z 290.98, 293.00 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:19][CH:18]3[CH:14]([CH2:15][NH:16][CH2:17]3)[CH2:13]1)[N:6]=[CH:5]2.[F:20][C:21]1[C:22]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>>[F:20][C:21]1[C:22]([N:30]2[N:34]=[CH:33][CH:32]=[N:31]2)=[C:23]([C:24]([N:16]2[CH2:17][CH:18]3[CH:14]([CH2:13][N:12]([C:7]4[N:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[N:8]=4)[CH2:19]3)[CH2:15]2)=[O:25])[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1ccc2nc(N3CC4CNCC4C3)ncc2c1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Product: O=C(c1cccc(F)c1-n1nccn1)N1CC2CN(c3ncc4cc(F)ccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 43 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): mass calculated for C23H19F2N7O, 447.16; m/z found 448.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.99 (s, 1H), 7.77 (d, J=15.8, 2H), 7.61 (dd, J=11.0, 5.5, 1H), 7.53-7.43 (m, 2H), 7.37-7.29 (m, 2H), 7.24 (s, 1H), 3.93 (d, J=9.9, 1H), 3.79 (dd, J=12.3, 7.4, 2H), 3.71-3.62 (m, 1H), 3.62 (s, 3H), 3.20 (dd, J=11.0, 5.3, 1H), 3.12-2.98 (m, 2H).
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][NH:7]C(=O)OC(C)(C)C)(=[O:4])=[O:3].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[CH3:1][S:2]([CH2:5][CH2:6][NH2:7])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCN
Reaction time: 1.5 h

Procedure:
In a dried reaction flask, tert-butyl 2-(methylsulfonyl)ethylcarbamate (0.906 g, 4.06 mmol) was dissolved in dichloromethane (60 mL). Trifluoroacetic acid (27.8 mL) was added dropwise at −10° C. The mixture was stirred for 1.5 hr, and was concentrated at reduced pressure to produce a crude brown oil (1.258 g).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.Cl.Cl[C:11]1[N:16]=[CH:15][N:14]=[C:13]([N:17]2[C:21](=[O:22])[C:20]([N:23]3[CH:27]=[CH:26][N:25]=[CH:24]3)=[CH:19][NH:18]2)[CH:12]=1.[OH-].[Na+]>O.C(O)C>[N:23]1([C:20]2[C:21](=[O:22])[N:17]([C:13]3[N:14]=[CH:15][N:16]=[C:11]([N:2]4[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]4)[CH:12]=3)[NH:18][CH:19]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: O=C(O)C1CNC1
Reactant: O=c1c(-n2ccnc2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CN(c2cc(-n3[nH]cc(-n4ccnc4)c3=O)ncn2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
46 mg (0.3 mmol) of azetidine-3-carboxylic acid hydrochloride are initially charged in a mixture of 1 ml of water and 0.3 ml of ethanol. 100 mg (0.3 mmol) of the compound from Example 13A are added, and the mixture is stirred at 100° C. for 1 h. The reaction mixture is then adjusted to pH=7 using aqueous 1 N sodium hydroxide solution and stirred at 100° C. for 16 h. Once more, the mixture is adjusted to pH=7 using aqueous 1 N sodium hydroxide solution and reacted in a single mode microwave (Emrys Optimizer) at 150° C. for 1 h. The reaction mixture is concentrated under reduced pressure and purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). Yield: 23 mg (21% of theory)
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:16]1[CH:20]=[C:19]([C:21]2[C:22]3[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=3[N:24]=[CH:25][N:26]=2)[CH:18]=[N:17]1>C(#N)C>[CH:1]1([CH:6]([N:16]2[CH:20]=[C:19]([C:21]3[C:22]4[CH:29]=[CH:28][N:27]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:23]=4[N:24]=[CH:25][N:26]=3)[CH:18]=[N:17]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 65 °C
Reaction time: 12 h
Yield: 97.8 %

Procedure:
Method B. Into a four-neck 250 mL round bottom flask equipped with a stir bar, thermocouple, condenser and nitrogen inlet was charged (3S)-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile ((S)-10, 13.9 g, 31.5 mmol), acetonitrile (84 mL) and 3-cyclopentylacrylonitrile (8, a mixture of E and Z isomers, 3.82 g, 31.5 mmol, 1.0 equiv) at room temperature. The resulting mixture was then treated with cesium carbonate (Cs2CO3, 2.57 g, 7.88 mmol, 0.25 equiv) at room temperature. The reaction mixture was warmed to 65° C. and checked after 12 hours by chiral HPLC to determine the enantiomeric ratio of compound (R)-10 to compound (S)-10. When the ratio of compound (R)-10 to compound (S)-10 reached to one to one, the reaction mixture was then allowed to cool to room temperature gradually and stirred at room temperature for 24 to 48 h. The reaction mixture was monitored by HPLC to determine the level of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5). The reaction was considered complete when the level of compound 5 was found to be ≦2% by HPLC area %. The reaction mixture was then filtered through a Celite pad to remove insoluble solids present in the reaction solution. The filtrates were then concentrated under reduced pressure to remove about 40 mL of solvent. The concentrated solution was diluted with ethyl acetate (40 mL) and washed with 1 N aqueous HCl solution (40 mL). The two layers were separated, and the aqueous acid wash solution was back extracted with ethyl acetate (20 mL). The combined organic fractions were washed with 1 M aqueous sodium bicarbonate (NaHCO3) solution (45 mL) and 20% (w/w) brine solution (40 mL). The organic fraction was dried over magnesium sulfate (MgSO4) and concentrated under reduced pressure to afford the crude racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 13.6 g, 13.9 g theoretical, 97.8%) as an amber oil, which was found to be identical to the material made by Method A. This crude product was found to be pure enough (>96 area % by HPLC) and was directly used in the subsequent chiral separation without further purification.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:16](C(OC(C)(C)C)=O)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=O>C(Cl)Cl>[C:20]([O:19][C:17]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:16])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (513 mg, 2.51 mmol), BOC2O (820 mg, 3.76 mmol) and TEA (0.698 ml, 5.02 mmol) in DCM (20 ml) was stirred at room temperature overnight. The resulting solution was concentrated in vacuo and then partitioned between water and AcOEt. The organic phase was dried over Na2SO4, evaporated in vacuo and the crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt) to give 701 mg of 4-(4-acetyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([N+:27]([O-:29])=[O:28])=[CH:9][C:10]2[O:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:12]([C:22](=[O:25])[NH:23][CH3:24])[C:11]=2[CH:26]=1)(=O)=O.[CH3:32][O:33][C:34]1[CH:43]=[CH:42][C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:14][C:10]3[CH:9]=[C:8]([N+:27]([O-:29])=[O:28])[C:7]([C:41]4[CH:42]=[CH:43][C:34]([O:33][CH3:32])=[C:35]([CH:40]=4)[C:36]([O:38][CH3:39])=[O:37])=[CH:26][C:11]=3[C:12]=2[C:22](=[O:25])[NH:23][CH3:24])=[CH:16][CH:17]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)OC)c3)cc12
Temperature: 100 °C

Procedure:
To a mixture of 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (750 mg, 1.622 mmol), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (569 mg, 1.947 mmol) and cesium carbonate (1057 mg, 3.24 mmol) in dioxane (20 mL)/water (1.0 mL) at rt under nitrogen was added Pd(PPh3)4(0) (187 mg, 0.162 mmol). The reaction mixture was heated to 100° C. and maintained at the same temperature for overnight. The reaction mixture was filtered through celite, and the celite bed washed with ethyl acetate. The filtrate was concentrated and the residue purified by Combiflash using MeOH/CHCl3 as eluant. The desired fraction was collected at 2.5% MeOH in CHCl3. Yield: 0.650 g (83%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([CH3:16])=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][CH:7]([CH3:16])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=1)[CH3:2]
Reactant: CCOC(=O)CCC(C)=Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(C)Cc1ccc(F)cc1

Procedure:
A slurry of palladium on charcoal (10%, 1.00 g) and 5-(4-fluoro-phenyl)-4-methyl-pent-4-enoic acid ethyl ester (1.01 g) in ethanol (20 ml) was stirred for 2 h under an atmosphere of hydrogen. The reaction mixture was filtered (dicalite), and the solvent was evaporated. Upon evaporation of the solvent, 5-(4-fluoro-phenyl)-4-methyl-pentanoic acid ethyl ester was obtained; the compound was used in the next step without further purification. MS: m/e=239.3 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[O:19][CH3:20].[F:21][C:22]([F:38])([F:37])[C:23]1[CH:36]=[CH:35][C:26]([O:27][C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>>[CH3:18][O:17][CH:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:34][C:31]2[CH:32]=[CH:33][C:28]([O:27][C:26]3[CH:35]=[CH:36][C:23]([C:22]([F:21])([F:37])[F:38])=[CH:24][CH:25]=3)=[CH:29][CH:30]=2)=[C:7]([O:19][CH3:20])[CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1cc(CC(OC)C(=O)O)ccc1OCCCBr
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Product: COc1cc(CC(OC)C(=O)O)ccc1OCCCOc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 3-[4-(3-Bromo-propoxy)-3-methoxy-phenyl]-2-methoxy-propionic acid (Example 175, Step B) and 4-(4-Trifluoromethyl-phenoxy)-phenol following the Standard Procedure J. MS (ES) for C27H27F3O7 [M+Na]+: 543.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=O)=[CH:5][CH:4]=1.Cl.[NH2:31][OH:32].C([O-])(O)=O.[Na+]>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]=2[CH3:28])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:31][OH:32])=[CH:5][CH:4]=1
Reactant: Cc1[nH]c2ccccc2c1C(CC(=O)c1ccncc1)c1ccc(N(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1[nH]c2ccccc2c1C(CC(=NO)c1ccncc1)c1ccc(N(C)C)cc1

Procedure:
In analogy to example 1, step 2, from 3-(4-dimethylamino-phenyl)-3-(2-methyl-1H-indol-3-yl)-1-pyridin-4-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (8.8:1) as a yellow foam, MS (ESI+): m/z=399.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([O:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.CS(O)(=O)=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[CH2:8][C:9](=[O:11])[C:14]3[C:15]([O:21][CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=3[O:12][C:4]=2[CH:3]=1
Reactant: COc1cc(OC)cc(Oc2cc(Br)ccc2CC(=O)O)c1
Agent: CS(=O)(=O)O
Product: COc1cc(OC)c2c(c1)Oc1cc(Br)ccc1CC2=O
Temperature: 40 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
To 27.3 g (F.W. 367.195, 74.3 mmol) of carboxylic acid (26) was added 140 mL of methanesulfonic acid to dissolve carboxylic acid (26). This solution was stirred at 40° C. for three days. To the resulting reaction solution was added 300 mL of ice water to deposit a cyclized compound. The cyclized compound was separated by filtration and extracted with ethyl acetate and treated according to the conventional method to obtain a crude product. This crude product was purified by silica gel column chromatography (developing solvent; ethyl acetate:hexane=1:2) and recrystallized from hexane-ethyl acetate to obtain 17.1 g (66%) of cyclized compound (27). (TLC; ethyl acetate:hexane=1:2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn](CCCC)(CCCC)CCCC)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:36]([NH:40][S:41]([C:44]1[S:48][C:47](Cl)=[N:46][CH:45]=1)(=[O:43])=[O:42])([CH3:39])([CH3:38])[CH3:37].[F-].[K+].O>C1(C)C=CC=CC=1>[C:36]([NH:40][S:41]([C:44]1[S:48][C:47]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=3)[CH:22]=2)=[N:46][CH:45]=1)(=[O:42])=[O:43])([CH3:39])([CH3:37])[CH3:38]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(Cl)cc3)cc(C(F)(F)F)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 4-(4-chloro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.2) (0.28 g, 0.46 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.128 g, 0.5 mmol), tetrakis(triphenyl-phosphine)palladium (0.032 g, 0.028 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.094) as a light brown solid. Mp 261° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:11][CH:12]([F:16])[C:13](Cl)=[O:14].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:13](=[O:14])[CH:12]([Cl:11])[F:16])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1N
Reactant: O=C(Cl)C(F)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cscc1NC(=O)C(F)Cl
Temperature: -15 °C

Procedure:
To a suspension of 4-amino-thiophene-3-carboxylic acid methyl ester (2 g) in dichloromethane (25 mL) was added chlorofluoroacetyl chloride (1.16 mL) and the reaction mixture was stirred to −15° C. Then a solution of triethylamine (3.2 mL) in dichloromethane (5 mL) was added slowly to the cold reaction mixture which was then allowed to warm up and stirred at room temperature for one hour. The reaction mixture was then diluted with further methylene chloride and washed several times with water, dried with sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a light yellow solid. MS (EI): 251.1; mp=51-54° C.
Reaction SMILES: [C@@H]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[I-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Cl:30])=[CH:27][CH:26]=1.[ClH:33]>CS(C)=O.CO>[ClH:30].[ClH:33].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:12]2[C:13]3[C:14](=[O:15])[NH:16][C:17]([NH2:18])=[N:19][C:20]=3[N:10]=[CH:11]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1ccc(Cn2cnc3nc(N)[nH]c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.8 %

Procedure:
Guanosine (5.7 g; 20.0 mmol) was dissolved in 13.2 ml of dimethylsulfoxide. To this solution were added sodium iodide (0.6 g; 4 mmol) and 4-methoxybenzyl chloride (6.8 ml; 50.2 mmol), and the mixture was stirred at room temperature for 19 h. Conc. hydrochloric acid (10 ml) was added thereto, and stirred at 45° C. for 1 h. The mixture was cooled down to room temperature. Methanol (50 ml) was added thereto, and the mixture was stirred at room temperature for 3 h. The crystals precipitated were filtered, washed well with methanol (20 ml×3), and then dried at 50° C. under reduced pressure to obtain 2.5 g of 7-(4-methoxybenzyl)guanine dihydrochloride (34.8%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C1(c2ccc(C)cc2)CC1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(CBr)cc2)CC1
Yield: 97.7 %

Procedure:
To a solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (622 mg, 3.27 mmol) in carbon tetrachloride (16 mL) was added N-bromosuccinimide (611 mg) followed by benzoyl peroxide (40 mg). The resulting solution was heated at reflux overnight, and then diluted with methylene chloride. The mixture was washed with brine, dried on MgSO4, and concentrated to afford a colorless oil (860 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[NH2:15][C:16]1[CH:35]=[CH:34][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:22]=2)=[CH:18][CH:17]=1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:15][C:16]2[CH:35]=[CH:34][C:19]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH:22]=3)=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
At room temperature, 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene (656 mg, 2.96 mmol, 1.05 eq) was dissolved in dichloromethane (5 mL). To the resulted solution, a solution of tert-butyl 4-(4-aminophenoxy)picolinate (805 mg, 2.81 mmol, 1 eq) in dichloromethane (5 mL) was slowly added dropwise. The mixture was stirred for 16 hours at room temperature. The solvent was removed under reduced pressure, and the resulted solid was purified by column chromatography (dichloromethane:methanol=30:1) to give the title compound (1.4 g, purity 95%, yield 85%) as a white solid.