Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[CH:4].Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[C:4][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2
Reactant: C#CC(O)c1ccc(OC)c(O)c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1O

Procedure:
Using Method D above, 3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propyne (105 mg, 0.59 mmol) (from Example 34 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (122 mg, 0.38 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 64%).
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CS(C)=O>O>[N:15]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: C1CNCCN1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (221 mg, 1 mmol, Example 1c), piperazine (172 mg, 2 mmol, Aldrich) and DMSO (2 mL) was stirred at 80° C. for 24 h. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (30% in water) to give the title compound. MS (ESI, pos. ion) m/z: 271 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.CO>[Pd]>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]2[CH2:7][CH2:6][N:5]([CH2:4][C:3]([N:2]([CH3:1])[CH3:20])=[O:19])[CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: CN(C)C(=O)CN1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)CN1CCc2ccc(N)cc2CC1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
N,N-Dimethyl-2-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide (150 mg, 0.541 mmol) was placed in methanol (10.0 mL, 247 mmol) and 10% palladium on carbon (50% Wet) (5:45:50, palladium:carbon black:water, 15.0 mg) was added. The reaction was hydrogenated at 30 psi. for 1 hour, filtered through Celite, and then concentrated under reduced pressure to obtain 2-(7-Amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide as an orange solid (134 mg, 100%). LCMS (m/e) 248 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 6.88 (d, 1H, J=7.5 Hz), 6.50-6.44 (m, 2H), 3.54 (bs, 2H), 3.28 (s, 2H), 3.16 (s, 3H), 2.98 (s, 3H), 2.870-2.81 (m, 4H), 2.71-2.62 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][NH:9][C:10](=[O:20])[O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:20])[O:11][CH2:12][CH2:13][CH2:14][C:15]2[N:16]=[CH:17][NH:18][CH:19]=2)=[CH:21][CH:22]=1
Reactant: [H][H]
Reactant: O=C(NCc1ccc([N+](=O)[O-])cc1)OCCCc1c[nH]cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(CNC(=O)OCCCc2c[nH]cn2)cc1

Procedure:
2 mmol of the compound obtained in Example 67 are hydrogenated in 10 ml of methanol with 40 mg of palladium-on-charcoal (10%) with hydrogen. After absorption of the calculated amount of hydrogen, the solution is filtered, concentrated and purified by chromatography. The title compound obtained is crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10].[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[O:38][CH3:39].C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:19][O:20][C:21](=[O:40])[CH2:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:3]=2[CH2:4][N:5]2[CH2:9][CH2:8][O:7][C:6]2=[O:10])[CH:26]=[CH:25][C:24]=1[O:38][CH3:39]
Reactant: COC(=O)Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: O=C1OCCN1Cc1cc(C(F)(F)F)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc(-c2ccc(C(F)(F)F)cc2CN2CCOC2=O)ccc1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
3-(2-Bromo-5-trifluoromethyl-benzyl)-oxazolidin-2-one (0.085 g, 0.26 mmol), [2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (0.120 g, 0.39 mmol), potassium carbonate (0.091 g, 0.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.030 g, 0.03 mmol) were combined in DME:H2O (2:1; 10 mL), and the mixture was purged with N2. The reaction was stirred at 90° C. for 3 hours, until no starting material was seen by analytical LCMS. After cooling to room temperature, the mixture was worked-up with EtOAc and brine and purified by silica gel chromatography to give the title compound.
Reaction SMILES: FC(F)(F)S([C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][C:28](S(C(F)(F)F)(=O)=O)=[CH:27][CH:26]=3)[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:18]3[C:13]2=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][CH:7]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[Cl:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Cl:46][C:47]1[CH:52]=[CH:51][C:50]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3([C:25]4[CH:30]=[CH:29][C:28]([C:50]5[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][CH:49]=5)=[CH:27][CH:26]=4)[C:24]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:18]4[C:13]3=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:8][CH:7]=2)=[CH:49][CH:48]=1
Reactant: O=S(=O)(c1ccc(C2(c3ccc(S(=O)(=O)C(F)(F)F)cc3)c3ccccc3-c3ccccc32)cc1)C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C3(c4ccc(-c5ccc(Cl)cc5)cc4)c4ccccc4-c4ccccc43)cc2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
16 g of 9,9-bis[4-(trifluoromethylsulfonyl)phenyl]fluorene, 100 ml of tetrahydrofuran, 62 g of a 20% sodium carbonate aqueous solution, 8.54 g of 4-chlorophenylboronic acid, and 0.6 g of tetrakis(triphenylphosphine)palladium were placed in a 300 ml four-necked flask, and the mixture was heated at 70° C. The resulting mixture was aged at the same temperature for 18 hours, and the reaction mixture was then cooled to room temperature and subjected to liquid separation. An organic phase was washed with a saturated ammonium chloride aqueous solution and saturated salt water, and the resulting organic phase was concentrated and recrystallized from tetrahydrofuran to obtain 11.4 g of a white powder.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][OH:25])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[OH:11][CH2:12][CH2:13][N:14]([CH2:23][CH2:24][OH:25])[C:15]1[CH:22]=[CH:21][C:18]([C:19]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:4]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccccc1N
Reactant: O=Cc1ccc(N(CCO)CCO)cc1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: O=c1[nH]c(-c2ccc(N(CCO)CCO)cc2)nc2ccccc12
Yield: 42 %

Procedure:
2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one was synthesized from anthranilamide and 4-[bis-(2-hydroxy-ethyl)-amino]-benzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(4-(Bis(2-hydroxyethyl)amino)phenyl)quinazolin-4(3H)-one (150 mg, 42%) was isolated as a brown solid. Selected data: MS (m/z): 326.03; MP 228-230° C.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][NH:21][CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.CCN(C(C)C)C(C)C.[CH3:38][N:39]=[C:40]=[O:41].Cl>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][N:21]([C:40]([NH:39][CH3:38])=[O:41])[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2
Reactant: CN=C=O
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNCc1ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)N1Cc2ccccc2C2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A vial was charged with N-(2-adamantyl)-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-carboxamide (15 mg, 40 μmol), i-Pr2NEt (11 μL, 60 μmol) and CH2Cl2 (1 mL). Methyl isocyanate (3 μL, 43 μmol) was added and the mixture was stirred overnight at rt. A 10-mL Chem-Elut cartridge was wetted with 5% aq HCl (6 mL) and allowed to stand for 5 min. The reaction mixture was applied to the cartridge and eluted with ether (20 mL). The eluate was evaporated to dryness and the residue was purified by preparative HPLC to afford N1′(2-adamantyl)-N2-methyl-1H-spiro[isoquinoline-4,4′-piperidine]-1′,2(3H)-dicarboxamide (7.7 mg, 44%). LC-MS Method 1 tR=1.77 min, m/z=437; 1H NMR (CDCl3) δ=1.60-2.10 (18H), 2.80 (1H), 2.88 (s, 3H), 3.25 (m, 2H), 3.77 (s, 2H), 3.88 (d, 2H), 3.98 (s, 1H), 4.52 (s, 2H), 4.87 (1H), 7.05-7.40 (4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:8]CC=C)[CH:5]=[CH:6][CH:7]=1.CN(C)[C:14]1[CH:19]=CC=C[CH:15]=1>>[CH2:19]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:8])[CH:14]=[CH2:15]
Reactant: C=CCOc1cccc(Br)c1
Reactant: CN(C)c1ccccc1
Product: C=CCc1c(O)cccc1Br

Procedure:
The title compound was synthesized from allyl 3-bromophenyl ether by an ortho Claisen rearrangement in dimethylaniline as described in Helvetica Chemica Acta, 5.6(1), 14, (1973).
Reaction SMILES: P(Br)(Br)[Br:2].N1C=CC=CC=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=1>C1COCC1>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][Br:2])=[CH:14][CH:13]=1
Reactant: BrP(Br)Br
Reactant: OCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Oc1ccc(CBr)cc1
Temperature: -20 °C
Reaction time: 18 h

Procedure:
To a stirred solution of PBr3 (1.38 g, 5.0 mmol) in dry THF (2 ml) at −5° C. was added a solution of dry pyridine (0.201 ml) in dry THF (0.4 ml). A solution of 4-Hydroxybenzyl alcohol (1.89 g, 15.2 mmol) in dry THF (23 ml) was added drop wise to the reaction mixture. The reaction mixture was allowed to stand at room temperature for 18 hours, then diluted with THF and filtered through celite pad. The filtrate was evaporated, the resulting semisolid was redissolved in dry toluene (16 ml). The solution was maintained at −20° C. for 2 hours, and then filtered through celite pad to provide the title compound as a light yellow solution which was used without further purification.
Reaction SMILES: O1CCOCC1.[ClH:7].C(OC([N:15]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1)C(OC(C)(C)C)=O)=O)(C)(C)C>>[ClH:7].[NH2:15][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C#N)cn1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: N#Cc1ccc(CN)nc1

Procedure:
2-Aminomethyl-5-cyanopyridine hydrochloride (EX-58A) was prepared by the deprotection with 4N HCl Dioxane of the intermediate 2-{N,N-bis-(tert-butoxycarbonyl)aminomethyl}-5-cyanopyridine used to prepare 2-aminomethyl-5-carbobenzyloxyamidinopyridine dihydrogen chloride salt in Example 56:1H NMR (400 MHz, DMSO) d 9.04 (s, 1H), 8.64 (br s, 2H), 834 (m, 1H), 7.69 (m, 1H), 4.25 (s, 2H); HRMS (EI) calcd for C7H8N3 134.0718, found 134.0699.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Cl)(=[O:3])[CH3:2].[OH:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([C:26]#[N:27])[C:23]3[N:28]=[CH:29][N:30](C)[C:22]=3[CH:21]=2)=[CH:16][C:15]=1[C:32]([F:35])([F:34])[F:33].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:25]=[C:24]([C:26]#[N:27])[C:23]3[N:28]=[CH:29][NH:30][C:22]=3[CH:21]=2)=[CH:16][C:15]=1[C:32]([F:35])([F:34])[F:33])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(CCl)c1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(O)c(C(F)(F)F)c3)cc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1cccc(COc2ccc(-c3cc4[nH]cnc4c(C#N)n3)cc2C(F)(F)F)c1
Temperature: 80 °C

Procedure:
A mixture of 3-acetylaminobenzylchloride (200 mg), 6-(4-hydroxy-3-(trifluoromethyl)-phenyl)-1-methyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile (350 mg), sodium iodide (16 mg) and potassium carbonate (300 mg) in acetonitrile (20 ml) was heated at 80° C. for 14 hours. After cooling to room temperature, water (30 ml) was added, the white precipitate collected by filtration was dissolved in DMSO (1 ml) and purified by HPLC to give 6-(4-(3-acetylaminobenzoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. 1H NMR (DMSO) δ: 8.71 (s, 1H), 8.64 (s, 1H), 8.43 (m, 2H), 7.74 (s, 1H), 7.51 (m, 2H), 7.33 (t, 1H), 7.15 (d, 1H), 5.34 (s, 2H), 3.98 (s, 3H), 2.04 (s, 3H). MS m/z 466 (M+1).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][SiH:11]([CH3:13])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CC([O-])(C)C.[K+]>>[C:1]1([C:7]2[Si:11]([CH3:13])([CH3:12])[O:10][CH2:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[SiH](C)OCC#CC1=CCCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C[Si]1(C)OCC=C1C1=CCCCC1
Yield: 51.9 %

Procedure:
(3-Cyclohexenylprop-2-ynyloxy)dimethylsilane (2.77 g, 14.25 mmol) and KOtBu (0.160 g, 1.425 mmol) were used according to the general procedure. The brown oily crude reaction mixture was purified by flash chromatography using hexanes/Et2O (6:1) as eluant to produce 10e as a clear colorless oil (1.437 g, 7.394 mmol, 51.9%), which was used in Diels-Alder reactions without further purification. Analytical samples were prepared from this chromatographic compound (0.235 g, 1.209 mmol) by using a chromatotron (2.0 mm, silica gel) yielded the title compound as a colorless clear liquid in pure form (0.167 g, 0.859 mmol, 71.1%): Rf 0.34 (hexanes/Et2O, 8:1); 1H NMR (300 MHz, CDCl3) δ 6.49 (s, 1H, H-4), 5.61 (s, 1H, H-8), 4.64 (s, 1H, H-5), 2.04-2.26 (m, 4H, H-9, 12), 1.51-1.77 (m, 4H, H-10, 11), 0.32 (s, 6H, H-6); 13C NMR (300 MHz, CDCl3) δ 142.6 (C-3), 136.9 (C-4), 135.2 (C-7), 128.8 (C-8), 72.0 (C-5), 26.1 (C-9, 12), 22.6 (C-10/11), 22.4 (C-10/11), 0.74 (C-6); HRMS calcd for C11H18OSi (M+) 194.1127. found 194.1121.
Reaction SMILES: C(OCC)(=O)C.[CH2:7]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:18]([OH:20])=[O:19])/[C:13](/[O:17][C@H:8]12)=[CH:14]/[CH2:15][OH:16].S(=O)(=O)(O)O.C(C(CCCC)C([O-])=O)C.[K+:36]>C(C(C)=O)C(C)C>[CH2:7]1[C:10](=[O:11])[N:9]2[C@@H:12]([C:18]([O-:20])=[O:19])/[C:13](/[O:17][C@H:8]12)=[CH:14]/[CH2:15][OH:16].[K+:36]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: CCCCC(CC)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)CC(C)C
Product: O=C([O-])[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
100 ml of the solvent mixture of ethyl acetate and methyl isobutyl ketone (4:1) already cooled to 5° C. was added to 100 ml of aqueous solution containing clavulanic acid (12 mg/ml). While agitating the mixture, 50% sulfuric acid was slowly added in order to control pH at 1.5. After extracting the said mixture, the extracts are separated. The remaining aqueous solution was further extracted with 100 ml of the solvent mixture three times. Anhydrous magnesium sulfate (10 g) and activated carbon(10 g) were added to the combined extract, and the resultant mixture was agitated at 5° C. for 30 minutes. The mixture was suction-filtered through a filter, and the remaining material was washed with 50 ml of methyl isobutyl ketone. A solution of potassium 2-ethylhexanoate (1.5 equivalent) dissolved in methyl isobutyl ketone was slowly added to the said extract, and the mixture was agitated at 5° C. for 2 hours. The crystalline product was filtered and slurried with acetone at the same temperature for 2 hours. The crystalline was dried in a vacuum desiccator (30° C.) for about 5 hours to obtain 1.07 g of potassium clavulanate (yield: 73%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]1[O:8][C:9]2[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=2)[N:11]=1.[ClH:19].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:43][C@H:44]1[CH:49]2[CH2:50][CH2:51][N:46]([CH2:47][CH2:48]2)[CH2:45]1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[ClH:19].[N:46]12[CH2:51][CH2:50][CH:49]([CH2:48][CH2:47]1)[C@H:44]([NH:43][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[S:5][CH:4]=[N:3][C:2]=4[CH3:1])=[N:11][C:10]=13)=[O:18])[CH2:45]2
Reactant: Cc1ncsc1-c1nc2c(C(=O)O)cccc2o1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncsc1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39 %

Procedure:
A mixture of 2-(4-methylthiazol-5-yl)benzoxazole-4-carboxylic acid (80 mg, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (118 mg, 0.62 mmol), 1-hydroxybenzotriazole (84 mg, 0.62 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (73 mg, 0.39 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.18 mL, 4.0 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (50 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×100 mL). The combined organics were washed with water (2×50 mL) and brine (2×50 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford the desired product (49 mg, 45%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 9.28 (d, J=7.3 Hz, 1H), 8.90 (s, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.40-4.30 (m, 1H), 3.58-3.53 (m, 1H), 3.10-3.03 (m, 2H), 3.00 (s, 3H), 2.98-2.94 (m, 2H), 2.90-2.78 (m, 1H), 2.20-2.15 (m, 1H), 2.10-2.00 (m, 1H), 1.85-1.76 (m, 2H), 1.66-1.63 (m, 1H); MS (ESI+) m/z 369 (M+H).
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.Cl[C:13]([CH3:21])([CH2:15][CH2:16][C:17](Cl)([CH3:19])[CH3:18])[CH3:14].[Cl-].[Cl-].[Cl-].[Al+3].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>ClCCl.C1COCC1>[CH3:14][C:13]1([CH3:21])[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15]1)[NH:3][CH2:2][CH2:11][CH2:10]3
Reactant: O=C1CCc2ccccc2N1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc3c(cc21)CCCN3
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 6,6,9,9-tetramethyl-3,4,6,7-hexahydro-1H-benzo[g]quinolin-2-one (1.0 g, 3.9 mmol, prepared by Friedel-Crafts alkylation/annulation of 2-oxo-1,2,3,4-tetrahydroquinoline with 2,5-dichloro-2,5-dimethylhexane in the presence of aluminum trichloride at ambient temperature in dichloromethane) in THF (10 mL) at ambient temperature was added LiAlH4 (11.7 mmol). The reaction mixture was heated to 80° C. and allowed to stir for 30 minutes. The reaction mixture was poured into aqueous saturated sodium potassium tartrate (100 mL), extracted with EtOAc (100 mL), dried (MgSO4), and concentrated to give 6,6,9,9-tetramethyl-1,2,3,4,6,7,8,9-octahydrobenzo[g]quinoline 978 mg (99%): 1H NMR (400 MHz, CDCl3) δ 6.88(s, 1H ArH), 6.41(s, 1H, ArH), 3.26(t, 2H, J=6.2 Hz, ring CH2), 2.71(t, 2H, J=4.0 Hz, ring CH2), 1.92(m, 2H, ring CH2), 1.63(s, 4H, 2CH2), 1.23(s, 12H, 4CH3).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[F:21][C:22]1[CH:33]=[CH:32][C:25]([C:26](N(OC)C)=[O:27])=[CH:24][CH:23]=1.[Na+].[Cl-]>C(OCC)(=O)C.C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:26]([C:25]2[CH:32]=[CH:33][C:22]([F:21])=[CH:23][CH:24]=2)=[O:27])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Cc1ccnc(Cl)c1)c1ccc(F)cc1
Temperature: -50 °C
Reaction time: 0.92 h

Procedure:
n-BuLi (15% strength solution in n-hexane, 45 ml, 104 mmol) was added dropwise to a solution, cooled to −85° C., of diisopropylamine (15 ml, 106 mmol) in abs. THF (150 ml) in a double-necked flask which had been dried by heating and flushed with argon: temperature increase to −50° C. After the addition had ended, the light-yellow solution was stirred at −85° C for 55 min. At −85° C., a solution of 2-chloro-4-methylpyridine (2-chloro-γ-picoline, 8.6 g; 68 mmol) in abs. THF (75 ml) was added dropwise to this initial charge: temperature increase to −50° C., initial change of color to purple. After the addition had ended, the reaction mixture was stirred at −85° C. for 1 h, and a solution of 20 (12.4 g; 68 mmol) in abs. THF (75 ml) was added at this temperature over a period of 3 min: temperature increase to −60° C. The purple slurry of the reaction mixture was stirred at −85° C. for 1 h and then, over a period of 1 h, warmed to 0° C. The mixture was poured into saturated NaCl solution (300 ml) which had been covered with ethyl acetate (300 ml). The organic phase was removed and the aqueous phase was extracted with ethyl acetate (2×250 ml) and a little brown foamy precipitate of 1,3-bis-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)propan-2-ol separated off at the interface. The combined organic extract was washed with saturated NaCl solution, dried over NaSO4 and concentrated. The oily residue was taken up in a little tert-butyl methyl ether and stored at 4° C. overnight. The crystals were filtered off and dried.