Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:5]=[CH:4][N:3]=1.[CH:23]1([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]1.C([O-])([O-])=O.[Cs+].[Cs+].[NH4+].[Cl-]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:23]1([C:26]([NH:28][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[C:11]([C:19]([O:21][CH3:22])=[O:20])[C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:4][N:3]=2)=[O:27])[CH2:25][CH2:24]1
Reactant: COC(=O)c1cc(Oc2ccnc(Cl)c2)cc2ccccc12
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cc(Oc2ccnc(NC(=O)C3CC3)c2)cc2ccccc12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 3-[[2-chloro-4-pyridinyl]oxy]-1-naphthalenecarboxylic acid, methyl ester (0.188 g, 0.60 mmol), cyclopropanecarboxamide (0.077 g, 0.90 mmol), Cs2CO3 (0.274 g, 0.84 mmol), 1,1′-(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[1,1-diphenylphosphine (0.035 g, 0.06 mmol; xantphos; Aldrich) and Pd2(dba)3 (0.018 g, 0.020 mmol) in dioxane (6 mL) is stirred at 90° C. for 16 h under an argon atmosphere. The cooled mixture is treated with saturated aqueous NH4Cl (50 mL) and extracted with ethyl acetate. The combined extracts are washed (brine), dried (Na2SO4) and the solvent is evaporated off under reduced pressure to give a crude product, which is purified by column chromatography (SiO2; ethylacetate/hexane 1:1) to afford the title compound as a viscous oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[F:10][CH:11]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33](O)=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[F:10][CH:11]1[CH2:14][N:13]([C:15]2[CH:16]=[C:17]([CH:21]3[C:30]([CH3:31])([CH3:32])[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:9][S:6]([CH:3]5[CH2:5][CH2:4]5)(=[O:8])=[O:7])=[O:34])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:12]1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CC(F)C2)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CC(F)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.8 %

Procedure:
To a suspension of 60% sodium hydride (165 mg, 4.1 mmol) in N,N-dimethylformamide (1.5 mL) was added cyclopropanesulfonamide (510 mg, 4.2 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 2-[3-(3-fluoro-azetidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 0.42 mmol) and 1,1′-carbonyldiimidazole (170 mg, 1.04 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {2-[3-(3-fluoro-azetidin-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (38 mg, 20%) as a white solid: LC/MS m/e calcd for C24H28FN3O3S (M+H)+: 458.57, observed: 458.1.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14])=O.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[CH3:1][NH:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COc1ccc([N+](=O)[O-])cc1NC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CNc1cc([N+](=O)[O-])ccc1OC
Temperature: 0 °C

Procedure:
To a 0.5M solution of 2-formamido-4-nitroanisole (745 mg, 3.8 mmol) in dioxane was added sodium borohydride (722 mg, 19 mmol) followed by dropwise addition of glacial acetic acid (1.09 mL, 19 mmol). The reaction mixture was refluxed for 40 minutes, then cooled to 0° C. and quenched slowly with MeOH. Excess MeOH was then added and the solution was concentrated under vacuum to yield 2-methylamino-4-nitroanisole. The crude product was dissolved in anhydrous MeOH (20 mL) and Pd/C (795 mg, 0.76 mmol) was added followed by bubbling hydrogen gas through the solution for 1 minute. The reaction mixture was then stirred for 1.5 h under 1 atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite and the filter pad was washed with MeOH (40 mL). To the combined filtrate and wash was added pentafluorophenylsulfonyl chloride (282 mL, 0.26 mmol). After stirring for 30 min the reaction mixture was concentrated under vacuum and purified by column chromatography (10–25% EtOAc in hexane) to yield 153 mg (21% for three steps) of the title compound as a pale yellow solid. 1H NMR (400MHz, DMSO-d6) δ 10.7 (s, 1H), 6.68 (d, J=8.4 Hz, 1H), 6.3 (dd, J=8.3, 2.5 Hz, 1H), 6.22 (d, J=2.2 Hz, 1H), 5.18 (bs, 1H), 3.7 (s, 3H), 2.6 (d, J=3 Hz, 3H). MS(EI): m/z 785 (35, 2M+Na-2H), 382 (20, M+), 381 (100, M−H).
Reaction SMILES: [BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=[CH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)[CH2:5][CH2:4]1.[Br:24]Br>C(O)(=O)C>[BrH:1].[CH3:2][N:3]1[CH2:8][CH2:7][C:6](=[C:9]2[C:10]3[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=3[CH:12]([Br:1])[CH:13]([Br:24])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: BrBr
Reactant: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Br
Solvent: CC(=O)O
Product: CN1CCC(=C2c3ccccc3C(Br)C(Br)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
1-Methyl-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine hydrobromide, 18.40 g. (0.05 mole) is dissolved with warming in 750 ml. of glacial acetic acid. This solution is cooled to room temperature and 8.0 g., 2.6 ml., (0.05 mole) of bromine dissolved in 75 ml. of glacial acetic acid is added dropwise with stirring. After completion of the addition the mixture is stirred overnight. The crystals are collected, washed with a small amount of cold glacial acetic acid, then with dry ether, and then dried for 2 hours in a vacuum oven at 70°C. to give 1-methyl-4-(10,11-dibromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine hydrobromide. Recrystallization from acetonitrile gives an analytical sample, m.p. 185°-186°C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][N:11]([C:26]([N:28]3[CH2:33][CH2:32][S:31][CH2:30][CH2:29]3)=[O:27])[CH2:10]2)[O:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>>[CH2:1]([O:3][C:4]1[N:8]=[C:7]([CH:9]2[CH2:14][CH:13]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:19][CH:20]=3)[CH2:12][N:11]([C:26]([N:28]3[CH2:33][CH2:32][S:31](=[O:42])[CH2:30][CH2:29]3)=[O:27])[CH2:10]2)[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCSCC3)C2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCOc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCS(=O)CC3)C2)n1
Yield: 29.6 %

Procedure:
37.1 mg (0.123 mmol) of the compound from Example 51 were reacted according to General Method 2 with 38.3 mg (0.111 mmol) of meta-chloroperbenzoic acid. Enantiomer separation of 37.7 mg of the racemate according to Method 4D gave 16.1 mg of the title compound from Example 52 (enantiomer 1) and 16.5 mg of the title compound from Example 53 (enantiomer 2).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(OCC)(=O)C>CC(N(C)C)=O.[Cu]I.O>[N:1]1([C:7]2[N:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Brc1ncccn1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: c1cnc(-n2cccn2)nc1
Temperature: 140 °C
Yield: 15.7 %

Procedure:
A reaction mixture containing pyrazole (2 g, 29 mmol), 2-bromopyrimidine (3.8 g, 24 mmol), copper (I) iodide (0.91 g, 4.8 mmol) and 1,10-phenanthroline (1.7 g, 9.6 mmol) in DMA was heated at 140° C. in a sealed tube for 6 hours. After the reaction, ethyl acetate (30 mL) was added, followed by water. The aqueous layer was extract three times (20 mL) and the organic layer was collected, dry over sodium sulfate. After concentration under vacuum, the crude product was purified using column chromatography (10% ethyl acetate in dichloromethane) to give 0.55 g of pure product. 15% yield. MS (ESMS, M+H 146).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[N:2]1.[H-].[Na+].Br[CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C)C=O>[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[N:2][N:1]2[CH2:15][C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:11]
Reactant: N#Cc1cccc2[nH]ncc12
Reactant: CCOC(=O)C(C)(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(C#N)cccc21
Temperature: 80 °C
Yield: 86 %

Procedure:
1H-indazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd., 298 mg, 1.957 mmol) in dry N,N-Dimethylformamide (DMF) (1 ml), under nitrogen was treated with NaH (94 mg, 2.348 mmol). A solution of ethyl 3-bromo-2,2-dimethylpropanoate (D98) (450 mg, 2.153 mmol), in DMF (2 ml), was then added to the dark brown mixture. The reaction mixture was heated to 80° C. overnight then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water then brine, dried and concentrated to give a brown gum. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (217 mg, 86%) as a yellow oil. MS (ES) C15H15N3O2 requires 271, found 272 [M+H]+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@H:18]([OH:27])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:33]([Si:37]([CH3:40])([CH3:39])Cl)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C@H:18]([O:27][Si:37]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:40])[CH3:39])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]12CC[C@@H]3c4ccc(OCc5ccccc5)cc4CC[C@H]3[C@@H]1CC[C@H]2O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H]2[C@@H]3CCc4cc(OCc5ccccc5)ccc4[C@H]3CC[C@]12C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of 3-benzyloxyestra-1,3,5(10)-trien-17α-ol (49, 1.45 g, 4.0 mmol) in DMF (5.0 mL) were added imidazole (0.408 g, 6.0 mmol) and tert-butyldimethylchlorosilane (0.784 g, 5.2 mmol) at room temperature. The reaction mixture was stirred for 2 h, and quenched with saturated aqueous NaHCO3 at 0° C., and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:CHCl3 :EtOAc (50:50:1→20:20:1, v/v) to afford 1.91 g of 50 (100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:25][N:26]([CH3:36])[C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[O:22])[CH2:16]2)([OH:14])[CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@:8]([C@@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]([NH:23][C@@H:24]([CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:25][N:26]([CH3:36])[C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[O:22])[CH2:16]2)([OH:14])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCCO)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(C[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@](O)(CCCC=O)c2cccc(Cl)c2)C1)C(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A 100 mL, round-bottom flask was charged with (3R)-3-((S)-1-(3-chlorophenyl)-1,5-dihydroxypentyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propan-2-yl)piperidine-1-carboxamide (0.0544 g (0.0852 mmol), DMSO (2.5 mL) and Et3N (1 mL). The flask was cooled in an ice bath and a mixture of pyridine-sulphur trioxide complex (0.24 g, 1.51 mmol) and dry DMSO (2.5 mL) was added. After 10 min, the ice bath was removed. The reaction mixture was allowed to stir at rt for 3 h. The mixture was quenched with brine, extracted with EtOAc (3×) and dried over Na2SO4. Removal of the solvent left crude (3R)-3-((S)-1-(3-chlorophenyl)-4-formyl-1-hydroxybutyl)-N—((S)-3-cyclohexyl-1-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propan-2-yl)piperidine-1-carboxamide (0.1036 g), which was carried on to the next step without further purification. LC-MS (3 min) tR=2.43 min, m/z 658, 660 (MNa+), 636 (MH+), 618, 620.
Reaction SMILES: C([O:5][C:6](=[O:45])[C@@H:7]([NH:37]C(OC(C)(C)C)=O)[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[C:24]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH2:34][CH3:35])[N:23]=[C:22]([NH2:36])[N:21]=2)=[CH:15][CH:14]=1)=[O:10])(C)(C)C.Cl>>[NH2:36][C:22]1[N:21]=[C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:11][C:9](=[O:10])[CH2:8][C@H:7]([NH2:37])[C:6]([OH:45])=[O:5])=[CH:18][CH:17]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[O:33][CH2:34][CH3:35])[N:23]=1
Reactant: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2)nc(N)n1
Agent: Cl
Product: CCOc1ccc(Cl)cc1-c1cc(Nc2ccc(COC(=O)C[C@H](N)C(=O)O)cc2)nc(N)n1
Yield: 69 %

Procedure:
Following the method described in Example 64, (S)-2-tert-butoxycarbonylamino-succinic acid 4-{4-[2-amino-6-(5-chloro-2-ethoxy-phenyl)-pyrimidin-4-ylamino]-benzyl} ester 1-tert-butyl ester and hydrogen chloride provided the title compound (69% yield). 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J=7.0 Hz, CH3), 3.00-3.03 (m, 2H, CH2), 4.17 (q, 2H, J=6.9 Hz, CH2), 4.24 (s, 1H, CH), 5.16 (s, 2H, CH2), 6.74 (s, 1H, Ar), 7.28 (d, 1H, J=8.9 Hz, Ar), 7.43 (d, 2H, J=8.4 Hz, Ar), 7.61-7.68 (m, 2H, Ar), 7.88 (d, 2H, J=8.0 Hz, Ar), 8.52 (s, 3H), 11.23 (s, 1H), 12.77 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[N:17]1([CH:22]2[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]2)[CH:21]=[CH:20][N:19]=[N:18]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:25]1[CH2:24][CH2:23][CH:22]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:27][CH2:26]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Reactant: O=C1CCC(n2ccnn2)CC1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(n2ccnn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (example 9)(0.387 g, 1.6 mmol) and 4-[1,2,3]triazol-1-yl-cyclohexanone (0.27 g, 1.6 mmol) in dry THF is added dibutyltin dichloride (0.024 g, 0.080 mmol) followed by phenylsilane (0.276 ml, 2.2 mmol). The mixture is stirred overnight at room temperature. Solvent is evaporated under reduced pressure, and the residue is diluted with ethyl acetate. The organic layer is washed with water and brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica get using gradient 50-100% ethyl acetate in hexane to afford 5-(3,3-dimethyl-but-1-ynyl)-3-(4-[1,2,3]triazol-1-yl-cyclohexylamino)-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(NC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Yield: 74 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (4 ml), and 4-methoxyphenyl isocyanate (60 μl) was then added to the solution. The mixture was allowed to react at room temperature overnight. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of chloroform, and a large amount of ether was added to the solution. The resultant precipitate was collected by suction filtration to give 110 mg (yield 74%) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CNC.[Na].[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35](O)=[O:36])=[CH:23][CH:22]=3)=[CH:18][C:17]=2[CH:38]=1.[K].ClC1C=CC2OC(C3C=CC(C=CC4C=CC(C(O)=O)=CC=4)=CC=3)=CC=2C=1>>[CH3:12][C:13]1[CH:14]=[CH:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH:27]=[CH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:36])=[CH:25][CH:26]=3)=[CH:18][C:17]=2[CH:38]=1
Reactant: Cc1ccc2sc(-c3ccc(C=Cc4ccccc4C(=O)O)cc3)cc2c1
Reactant: C1CCNCC1
Agent: CNC
Agent: Cl
Agent: O=C(O)c1ccc(C=Cc2ccc(-c3cc4cc(Cl)ccc4o3)cc2)cc1
Product: Cc1ccc2sc(-c3ccc(C=Cc4ccccc4C(=O)N4CCCCC4)cc3)cc2c1

Procedure:
When piperidine is substituted for the dimethylamine hydrochloride and the sodium salt of 5-methyl-2-[4-(2-carboxystyryl)phenyl]benzothiophene for the potassium salt of 5-chloro-2-[4-(4-carboxystyryl)phenyl]benzofuran in the procedure described in Example 29 above, there is obtained as the product 5-methyl-2-[4-(2-piperidinocarbonylstyryl)phenyl]benzothiophene.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)cc2)CC1
Yield: 9.5 %

Procedure:
Using (4-bromophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (240 mg) described in Preparation Example 185 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (24 mg) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[F-].[CH2:14]([N+:18](CCCC)(CCCC)CCCC)CCC.C[Si](C#N)(C)C>CC#N>[C:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:18]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C#N
Agent: [F-]
Solvent: CC#N
Product: COC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Yield: 42.8 %

Procedure:
To an ice-cold solution of methyl 3-bromomethylbenzoate (9.1 g, 40 mmol) in CH3CN (108 mL) was added tetrabutylammonium fluoride (17.3 mL, 60 mmol) and trimethylsilylcyanide (8.0 mL, 60 mmol), and the reaction mixture was heated at reflux for 20 h. The reaction mixture was cooled to room temperature, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1:1 EtOAc/hexanes) provided methyl 3-cyanomethylbenzoate as a clear oil (3.0 g, 43%): 1H NMR (300 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.92 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz, 1H), 7.56 (t, J=8 Hz, 1H), 4.16 (s, 2H), 3.87 (s, 3H)
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C@@H:7]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])[C:8](=O)[CH2:9][C@H:5]12)[CH3:3].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O)(=O)=O.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)[C:64]1[S:68][C:67]2=[CH:69][N:70]=[CH:71][N:66]2[CH:65]=1)CCC>C(#N)C.C(OCC)(=O)C.CN1CCCC1=O.O.[Cl-].[Zn+2].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:8]([C:64]3[S:68][C:67]4=[CH:69][N:70]=[CH:71][N:66]4[CH:65]=3)[CH2:9][C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cncc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cncc4s3)C[C@H]12
Reaction time: 0.5 h
Yield: 19.8 %

Procedure:
To ice-cooled solution of 149 mg of 4-nitrobenzyl (3R,5R,6S)-6-((1R)-1-hydroxyethyl)-2-oxo-1-carbapenam-3-carboxylate in 4 ml of dry acetonitrile was added dropwise 0.187 ml of N,N-diisopropylethylamine, followed by 0.071 ml of anhydrous trifluoro-methanesulfonic acid under the atmosphere of argon. The solution was stirred at the same temperature for 30 minutes, diluted with ethyl acetate, and washed sequentially with a mixed solvent of semi-saturated aqueous saline and saturated aqueous sodium hydrogen carbonate (pH 8.9), and semi-saturated aqueous saline. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residue thus obtained was dissolved in 2 ml of dry N-methylpyrrolidinone, added with 12 mg of tri-2-furylphosphine, 116 mg of zinc chloride, 12 mg of tris(dibenzylideneacetone)dipalladium (0), and a solution of 306 mg of 2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole in 1 ml of dry N-methylpyrrolidinone, and the mixture was stirred under the atmosphere of argon at 50° C. for 2 hours. The reaction mixture was diluted with 50 ml of ethyl acetate and 50 ml water, and insolubles were removed by filtration, and washed with ethyl acetate. The organic layer of the filtrate was separated, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1). The fraction containing the aimed product was concentrated under reduced pressure, and triturated with 13 ml of diethyl ether to collect insolubles and thus to give 38.5 mg of 4-nitrobenzyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate.