Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH3:39])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[Cl:42]Cl>ClCCl>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:14]([CH:26]([C:37]([CH2:39][Cl:42])=[CH2:38])[C:27]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:13]1=[O:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCl
Reactant: C=C(C)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: C=C(CCl)C(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccccc1
Yield: 88 %

Procedure:
A 2.0 g quantity of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-methyl-3-butenate was dissolved in 10 ml of dichloromethane and to the solution was added 5 to ml of water. The mixture was cooled in an ice bath with stirring while thereto was added dropwise over 30 minutes about 10 ml of methylene chloride having dissolved therein 6.9 mmol of chlorine gas. After the addition, the organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer thus separated and the dichloromethane layer were washed successively with aqueous solutions each of NaHCO3, Na2S2O3 and NaCl and dried over anhydrous magnesium sulfate. The solvent was distilled off at reduced pressure. The resulting residue was separated and purified by silica gel column chromatography, giving 1.87 g of benzyl 2-(3-phenoxyacetamido-4-benzenesulfonylthio-2-azetidinone-1-yl)-3-chloromethyl-3-butenate in 88% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:20][S:21]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)(=[O:23])=[O:22]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[C@@H](O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of (3R)-3-hydroxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (9.0 g, 33.8 mmol) in methylene chloride (270 ml) were added methanesulfonyl chloride (2.88 ml, 37.2 mmol) and triethylamine (5.21 ml, 37.2 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1.5 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:2)→ethyl acetate as the eluant to afford (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)-pyrrolidine (11.5 g, yield 99%) as a pale yellow solid.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[O:21]=[C:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: CCCC(=O)Cl
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reaction time: 8 h

Procedure:
Butyryl chloride (0.31 mL, 2.94 mmol) was added to a solution of N-[4-(4-oxo-piperidin-1-yl)-phenyl]amine (which was obtained in Example 224) (0.70 g, 2.77 mmol) and triethylamine (1.9 mL, 13.9 mmol) in anhydrous methylene chloride(10 mL). The reaction was stirred overnight. The reaction was quenched with water (50 mL) and washed with methylene chloride (3×20 mL). The organic extracts were combined, dried (sodium sulfate) and concentrated. The desired product was isolated using silica gel flash chromatography to give the title compound as a yellow solid (0.41 g); 1H NMR (300 MHz, CDCl3) δ 1.01 (t, 3H, J=7.38 Hz), 1.72 (m, 2H), 2.29(t, 2H, J=7.62 Hz), 2.55(t, 4H, J=6.03 Hz), 3.55(t, 4H, J=5.97 Hz), 6.95(d, 2H, J=7.91), 7.42(d, 2H, J=8.97 Hz). MS (ES) m/z: 260.9(MH+); HRMS found for C15H20N2O2: 260.1511. Anal. Calcd. for C, 69.20; H, 7.74; N, 10.76. Found: C, 69.03; H, 7.94; N, 10.59.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1.C(N(CC)CC)C.[CH3:29][Si:30]([CH3:33])([CH3:32])Cl.[Na+].[I-]>C(#N)C>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:18]2[C@@H:17]3[C@H:8]([C@H:9]4[C@@:13]([CH2:15][CH2:16]3)([CH3:14])[C:12]([O:21][Si:30]([CH3:33])([CH3:32])[CH3:29])=[CH:11][CH2:10]4)[CH2:7][CH2:6][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(O[Si](C)(C)C)=CC[C@@H]12
Reaction time: 1.5 h

Procedure:
20.3 g (72 mmol) of 3-methoxy-estra-1,3,5(10)-trien-17-one is suspended with exclusion of moisture in 80 ml of acetonitrile (P2O5 and molecular sieve dried) and mixed with 17.4 ml of triethylamine (125 mmol, dried on KOH) as well as with 12.24 ml of trimethylchlorosilane (96 mmol) at an inner temperature of 35° C. Then, an NaI solution, which contains 15 g of NaI (96 mmol) in 100 ml of acetonitrile (NaI dried at 140° C. in a vacuum), is instilled in this suspension, so that the reaction temperature is kept at 35° C. without external heating. The reaction performed under nitrogen is performed with vigorous stirring. It is seen that after the addition has been completed, the amount of undissolved initial product becomes smaller. Later, the crystals completely disappeared. After 1.5 hours, the silyl enol ether begins to crystallize. After 4 hours, the crystal suspension is stirred in ice water, to which some triethylamine was added. Then, it is fritted, rewashed with water, sucked dry and the substance dried on P2O5 in a vacuum. 25.4 g of silyl enol ether, which can be recrystallized from hexane or methanol, is obtained.
Reaction SMILES: [CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25]O)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:32][NH:33][S:34]([CH:37]1[CH2:39][CH2:38]1)(=[O:36])=[O:35].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C:4]1([CH2:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][N:33]([CH3:32])[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Reactant: CNS(=O)(=O)C1CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCC1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 70 °C

Procedure:
(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (147 mg, 0.319 mmol; Example 202, Step B) and N-methylcyclopropanesulfonamide (129 mg, 0.958 mmol) were dissolved in toluene (2 mL). The mixture was evacuated and backfilled with argon (5×). Cyanomethylenetributylphosphorane (0.251 mL, 0.958 mmol) was added. The mixture was evacuated and backfilled with argon (5 X). The mixture was heated at 70° C. for 2 hours. The mixture was loaded onto silica gel and the product was eluted with 5 to 75% ethyl acetate/hexanes to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:33])=[C:4]([C:8]2[N:9]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([Cl:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=1[S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[Cl:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:22][CH2:21]3)=[N:9][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:42]([C:36]3[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=3[F:34])(=[O:44])=[O:43])[C:3]=2[F:33])[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(N)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4c(F)cccc4F)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(3-amino-2-fluorophenyl)-5-(2-chloro-4-pyrimidinyl)-1,3-thiazol-2-yl]-1-piperidinecarboxylate (300 mg, 0.612 mmol) in pyridine (3 mL) was added 2,6-difluorobenzenesulfonyl chloride (130 mg, 0.612 mmol), and the reaction mixture was stirred for 3 h. The reaction mixture was quenched with water (5 mL) and extracted with EtOAc (3×). The extracts were dried, filtered and concentrated. The residue was purified using column chromatography (40 to 100% EtOAc/hexane) to give 324 mg of the title compound. MS (ESI): 610.1 [M+1-56]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]3OCC[O:20]3)[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[C:14]([CH:19]=[O:20])[CH:13]=2)=[CH:7][C:6]=1[O:24][CH3:25])[CH3:2]
Reactant: CCOC(=O)c1ccc(Oc2ccc(Br)c(C3OCCO3)c2)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)cc1OC
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a solution of compound 6 (5.6 g, 13.23 mmol) in THF (50 mL) at 0° C. was added 2N HCl (50 mL). The resulting mixture was stirred at rt O/N. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to give crude product, which was purified by column chromatography (silica gel, 10% EtOAc in hexane) to afford the title compound 7 (3.0 g, 60%) as a pale yellow solid.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[N:27]1([C:33]([O:35][CH2:36]I)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: O=C(OCI)N1CCCCC1
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)N3CCCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 92.7 %

Procedure:
In the same manner as in Example 81, 192 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 130 mg of (piperidin-1-yl)carbonyloxymethyl iodide.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][N:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[N:10][CH:9]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)nc2)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 4-(6-(methoxycarbonyl)pyridin-3-yl)piperazine-1-carboxylate 49-3 (1.93 g, 6.01 mmol) and NaOH (530 mg, 13.26 mmol) in dioxane (15 mL) and H2O (15 mL) was stirred at 80° C. for 2 hours. Dioxane was removed by rotary evaporation and the resulting solution was acidified to pH around 4 by 1N HCl aqueous solution, followed by extraction with ethyl acetate (60 mL×3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation to afford 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)picolinic acid 49-4 as a yellow solid. MS m/z 308.1 (M+1)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C(#N)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: N#Cc1ccc2c(c1)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCN1CCc2ccc(C#N)cc2C1
Temperature: 70 °C
Yield: 93.5 %

Procedure:
7-cyano-1,2,3,4-tetrahydroisoquinoline (7 g; 44.3 mmol; 1 eq.) and potassium carbonate (10.4 g; 75.2 mmol; 1.7 eq.) were suspended in ACN (280 mL) to which was added t-butyl 3-bromopropionate (11.5 mL; 68.6 mmol; 1.05 eq.). The reaction mixture was heated to 70° C. for 24 h. Solvents were removed under vacuum and solid residue partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. Organic layers was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound (11.86 g; 94%) as a yellow oil. 1H NMR (DMSO-d6) δ 7.57-7.54 (m, 2H), 7.32-7.29 (m, 1H), 3.59 (s, 2H), 2.87-2.83 (t, J=5.94 Hz, 2H), 2.74-2.66 (m, 4H), 2.46-2.42 (t, J=7.01 Hz, 2H), 1.39 (s, 9H). LC/MS (Method B): 287.1 (M+H)+. HPLC (Method A) Rt 2.37 min (Purity: 96.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:25])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:49])[CH2:30][C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:25])[CH2:15][CH2:16]/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CC/C=C/c1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CC/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-5-phenyl-pent-4-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis-(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, waiter and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:methyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:19][F:20])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2[CH:14]=[C:15](I)[CH:16]=[CH:17][C:5]=2[O:4]1.[F:21][C:22]([F:34])([C:30]([F:33])([F:32])[F:31])[C:23]([F:29])([F:28])[C:24](I)([F:26])[F:25].CN(C)P(=O)(N(C)C)N(C)C.Cl>[Cu].C(OCC)(=O)C>[F:21][C:22]([F:34])([C:30]([F:31])([F:32])[F:33])[C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:5]2[O:4][C:3]([CH2:19][F:20])([CH2:2][F:1])[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]=2[CH:14]=1
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Agent: [Cu]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc21
Temperature: 70 °C
Yield: 51.3 %

Procedure:
A mixture of 0.30 g of ethyl 2,2-bis(fluoromethyl)-6-iodo-2H-1-benzopyran-4-carboxylate, 3.50 g of nonafluoro-butyl iodide, 0.30 g of copper powder, 0.32 g of cuprous iodide and 3 ml of hexamethylphosphoric triamide was stirred with heating at 70° C. for 22 hours, added another 1.75 g of nonafluorobutyl iodide, and stirred with heating at 150° C. for 5 hours. A mixture of 2N HCl and ethyl acetate was added to the reaction mixture, and insoluble materials were separated off using a celite. An organic layer was taken up, and an aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The resultant residue was purified with silica gel column chromatography (developing solution, methylene chloride:hexane=5:1) to obtain 0.19 g of ethyl 6-nonafluorobutyl-2,2-bis(fluoromethyl)-2H-1-benzopyran-4-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH:11](OS(C)(=O)=O)[CH3:12])=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+].ClCCl>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH:11]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C

Procedure:
To solution of methanesulfonic acid 1-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-ethyl ester (640 mg) and 1-methanesulfonyl-piperazine hydrochloride salt (described above) (511 mg) in acetonitrile (50 mL) was added potassium carbonate (1.170 g) and the reaction mixture was stirred at reflux for 16 h. After cooling to room temperature the reaction mixture was reduced in vacuo, redissolved into dichloromethane and washed with saturated aqueous sodium hydrogencarbonate solution and then brine. The organics were dried (MgSO4), reduced in vacuo and purified on silica to yield 2-chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([O:12][C:13](=[O:18])[CH2:14][C:15](=[NH:17])[NH2:16])[CH3:11]>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:18])=[C:15]([NH2:16])[NH:17][C:15]=1[NH2:16])=[O:18])[CH3:11]
Reactant: O=Cc1ccccc1F
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1F
Yield: 49 %

Procedure:
Upon boiling a solution of 6.2 g 2-fluorobenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 1 hour, 2,6-diamino-4-(2-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 128°-130° C (ethanol) is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4](F)[N:3]=1.CO.[CH3:12][NH:13][CH3:14]>[Cl-].[Na+].O>[Br:1][C:2]1[N:3]=[C:4]([N:13]([CH3:14])[CH3:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(F)c(Br)n1
Reactant: CNC
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc(F)c(Br)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
2-Bromo-3,6-difluoro-pyridine (300 mg, 1.5 mmol) was dissolved in a 2M solution of dimethylamine in MeOH (7.8 mL, 15.56 mmol) and stirred at 80° C. in a sealed tube for 16 hours. The mixture was treated with brine and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo to yield (6-bromo-5-fluoro-pyridin-2-yl)-dimethyl-amine as a dark oil that was used in the next step without further purification.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 73 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) was reacted with methyl 4-aminobenzoate (0.055 g, 0.36 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.100 g, 80%) as a white solid. MW=415.31. 1H NMR (DMSO-d6, 500 MHz) δ 9.94 (s, 1H), 8.05 (d, J=8.5 Hz, 2H), 7.98-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.68-7.64 (m, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.33 (s, 1H), 3.86 (s, 3H), 3.18 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH2:4][CH2:3]1.CN1CCOCC1.[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26](Cl)=[O:27]>CCOCC>[CH3:20][C:21]1[O:22][C:23]([CH3:29])=[CH:24][C:25]=1[C:26]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH2:4][CH2:3][C:2]2([CH3:12])[CH3:1])=[O:27]
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Reactant: CC1(C)CCc2c(N)cccc21
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: Cc1cc(C(=O)Nc2cccc3c2CCC3(C)C)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To 15 ml of an ether solution of 1.5 g (8.57 mmols) of 1,1-dimethylindane-4-amine,2 ml of N-methyl morpholine and 1.4 g (8.83 mmols) of 2,5-dimethyl-3-furan carboxylic acid chloride were added under cooling. The mixture was stirred at room temperature for 1 hour and then washed sequentially with water and brine. The solution was dried with magnesium sulfate. The resultant concentrate was purified with silica gel column chromatography (solvent for elution; ethyl acetate/ n-hexane =1/4), thereby obtaining 2.1 g of light yellow crystals (Compound No. 20 shown in Table 6). The yield was 85.8%.