Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](O)=[O:15])[CH:5]=[CH:4][C:3]1=2.CN(C=O)C.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2 (0.20 g, 0.86 mmol) was dissolved in SOCl2 (4.3 mL) at 0° C. A drop of DMF was added and the mixture was stirred for 0.5 h. The SOCl2 was removed under vacuum and the crude acid chloride was dissolved in pyridine (10 mL). Methyl 4-aminobenzoate (0.143 g, 0.947 mmol) and DMAP (0.010 mg, 0.086 mmol) were added and the mixture was heated at 60° C. for 2 h with stirring. The mixture was poured into H2O and the product was extracted with EtOAc; The organic layer was washed successively with HCl (2M), saturated NaHCO3, saturated NaCl, dried over MgSO4, filtrated to give after evaporation methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate 3 (0.23 g, 73% yield) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[C:27]1([OH:31])[CH2:30][O:29][CH2:28]1>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:33]([NH:32][C:23]3[CH:24]=[CH:25][C:26]([C:27]4([OH:31])[CH2:30][O:29][CH2:28]4)=[C:21]([F:20])[CH:22]=3)=[O:34])=[CH:12][C:11]([C:16]([F:17])([F:18])[F:19])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(C2(O)COC2)c(F)c1)Oc1ccccc1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)Nc1ccc(C2(O)COC2)c(F)c1
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a stirred solution of (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (0.206 mg, 0.66 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.13 g, 1.32 mmol, 2.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyoxetan-3-yl)phenylcarbamate (0.2 g, 0.66 mmol, 1.0 eq) at RT and stirred for 16 h. The reaction mixture was extracted with DCM (20 mL), washed with water (15 mL), brine (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was purified by CC using EtOAc/PE (7:3) to get 1-((1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(3-hydroxyoxetan-3-yl)phenyl)urea (0.075 g; 23%) as off white solid (TLC system: EtOAc/PE (1:1); Rf: 0.55).
Reaction SMILES: [CH2:1]=[O:2].[CH:3]1([OH:10])[NH:8][C:6](=[O:7])[NH:5][CH:4]1[OH:9]>O>[CH2:1]([N:5]1[CH:4]([OH:9])[CH:3]([OH:10])[NH:8][C:6]1=[O:7])[OH:2]
Reactant: C=O
Reactant: O=C1NC(O)C(O)N1
Solvent: O
Product: O=C1NC(O)C(O)N1CO
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Formaldehyde (8.85 parts of 37.3 percent solution; 0.11 mole), adjusted to pH 7-8.5, is diluted with water (20 parts). While stirring, 11.8 parts (0.1 mole) of dihydroxyethyleneurea powder are added. The temperature is raised to 55° C., held at 55° C. for 30 minutes, cooled to room temperature, and refrigerated. The sample is recovered as an 80 percent aqueous solution.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH2:11])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[H][H].[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[CH:29]=O>[Pd].CO>[I:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([O:27][CH3:28])[C:22]=1[C:29]1[NH:11][C:6]2[CH:5]=[C:4]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:3]=[C:2]([CH3:1])[C:7]=2[N:8]=1
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1nc(N2CCOCC2)cc(N)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1nccc(I)c1-c1nc2c(C)nc(N3CCOCC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To 2-methyl-6-morpholin-4-yl-3-nitro-pyridin-4-ylamine (220 mg, 0.924 mmol) and 10% palladium on carbon (50 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 18 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount of MeOH. The product in MeOH was concentrated and used for the next step without purification; LCMS (+ESI, M+H+) m/z 209. To the crude diamino in MeOH (5 mL) was added a solution of 4-iodo-2-methoxy-pyridine-3-carbaldehyde (267 mg, 1.02 mmol) in MeOH (5 mL) at 0° C. and stirred for 0.5 hour. The resulting mixture was allowed to warm to ambient temperature and stirred for 4 days in an open system exposed to air. The reaction mixture was then heated to 50° C. and stirred for 2 days. MeOH was evaporated in vacuo and the crude was purified on silica gel column using CH2Cl2:MeOH (95:5 gradient) to give the title compound as a yellow solid (332 mg, 80%): IR (KBr, cm−1) 1624, 1554, 1458, 1378; 1H NMR (400 MHz, DMSO) δ 12.46 (s, 1H), 8.00 and 7.64 (d, J=5.5, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 3.74-3.72 (m, 4H), 3.38-3.36 (m, 4H), 2.58 (s, 3H); LCMS (+ESI, M+H+) m/z 452; HPLC: 97% (220 nm).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][C:7](=[O:10])[CH2:8]Cl.[CH2:11]1[C:19]2[C:14](=[CH:15]C=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20](=[O:25])[C:21]([F:24])([F:23])[F:22].Cl>ClCCCl>[Cl:5][CH2:6][C:7]([C:8]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[CH2:11][N:12]([C:20](=[O:25])[C:21]([F:23])([F:24])[F:22])[CH2:13]2)=[O:10]
Reactant: O=C(N1Cc2ccccc2C1)C(F)(F)F
Reactant: O=C(CCl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: O=C(CCl)c1ccc2c(c1)CN(C(=O)C(F)(F)F)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 5.00 g (37.5 mmol) aluminium(III)-chloride in 20 mL 1,2-dichloroethane is added at 0° C. dropwise 2.24 mL (28.1 mmol) 1,3-dichloro-propan-2-one keeping the temperature below 15° C. Then 4.48 g (18.7 mmol) 1-(1,3-dihydro-isoindol-2-yl)-2,2,2-trifluoro-ethanone in 5 mL 1,2-dichloroethane is added dropwise at RT keeping the temperature between 40-45° C. The reaction is stirred for 18 h at RT and is poured onto aqueous HCl-solution. The aqueous phase is extracted twice with DCM, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated with PE and the precipitate is collected.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.045 g, 0.219 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.049 g, 0.241 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.178 mL, 0.877 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (35 mg). MS (ESI pos. ion) m/z: 387.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (d, J=9.06 Hz, 6H) 3.06 (s, 3H) 3.33 (s, 3H) 6.96 (dd, J=7.60, 4.68 Hz, 1H) 7.75 (br. s., 1H) 7.87 (br. s., 1H) 8.27-8.41 (m, 2H) 8.67 (d, J=2.05 Hz, 1H) 8.79 (dd, J=7.82, 1.53 Hz, 1H) 9.30 (br. s., 1H) 12.03 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH:66](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.C(OCC)(=O)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C@H:21]3[S:20](=[O:64])[CH2:19][C:18]=2[S:65][CH2:66][S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SC(Sc4nc[nH]n4)C(c4ccccc4)(c4ccccc4)c4ccccc4)CS(=O)[C@H]23)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(SCSc4nc[nH]n4)CS(=O)[C@H]23)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(trityl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (11.3 g) in acetone (60 ml) under ice cooling is added toluene-p-sulfonic acid monohydrate (1.68 g: 8.83 mMol.), and the mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with ethyl acetate, washed with aqueous 5% sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel chromatography (toluene: ethyl acetate=1:1-1:2) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (2.84 g) as brown foam. Yield: 31%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[C:16]([O-:19])(=[O:18])[CH3:17].[K+]>C(O)(=O)C>[C:16]([O:19][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Agent: [K+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc([N+](=O)[O-])c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer and nitrogen inlet, was placed 411 g of the previously prepared methyl 3-bromomethyl-4-nitrobenzoate, 441 g of anhydrous potassium acetate and 2 l of glacial acetic acid. The resulting mixture was refluxed for 4 hours, cooled to room temperature and stirred overnight. The solvent was removed in a rotary evaporator and the resulting light yellow solid treated with a mixture of 2 l of ethyl acetate and 1 l of water.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[CH:47]1([C:53]2[C:54]3[CH:55]=[CH:56][C:57]([C:77]([O:79][CH3:80])=[O:78])=[CH:58][C:59]=3[N:60]3[C:67]=2[C:66]2[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=2[O:64][CH2:63][CH:62]([CH2:72][CH2:73][C:74](O)=[O:75])[CH2:61]3)[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[C:34]([O:33][C:31]([N:25]1[CH2:30][CH2:29][N:28]([C:74](=[O:75])[CH2:73][CH2:72][CH:62]2[CH2:61][N:60]3[C:59]4[CH:58]=[C:57]([C:77]([O:79][CH3:80])=[O:78])[CH:56]=[CH:55][C:54]=4[C:53]([CH:47]4[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52]4)=[C:67]3[C:66]3[CH:68]=[CH:69][CH:70]=[CH:71][C:65]=3[O:64][CH2:63]2)[CH2:27][CH2:26]1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)O)COc1ccccc1-3
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Temperature: 50 °C

Procedure:
HATU (1.1 eq) was added to a stirred mixture of tert-butyl piperazine-1-carboxylate (1.1 eq), DIPEA (2.5 eq) and 3-[14-cyclohexyl-11-(methoxycarbonyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocin-7-yl]propanoic acid (0.03 M) in DMF under N2 at RT. The reaction was warmed at 50° C. for 10 min. The reaction was allowed to cool to RT before being partitioned between EtOAc and 1N HCl (aq). The organics were washed with 1N HCl (aq), sat. aq. NaHCO3, water and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The material was taken on without further purification (88%). (ES+) m/z 630 (M+H)+; 652 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:20])(=[O:19])[NH2:18])[C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:5]([OH:7])=[O:6].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH2:29](O)[CH3:30]>>[CH2:21]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:17](=[O:19])(=[O:20])[NH2:18])[C:10]=1[O:11][CH2:12][C:13]([F:14])([F:16])[F:15])[C:5]([O:7][CH2:29][CH3:30])=[O:6])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1OCC(F)(F)F
Reactant: BrCc1ccccc1
Reactant: CCO
Product: CCOC(=O)c1cc(NCc2ccccc2)c(OCC(F)(F)F)c(S(N)(=O)=O)c1

Procedure:
A mixture of 3-amino-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoic acid (0.6 g), benzyl bromide (1.2 g), and dry ethanol (8 ml) was refluxed for 5 hours. After cooling, the precipitated ethyl 3-benzylamino-5-sulphamyl-4-(β, β, β-trifluoroethoxy)-benzoate was collected by suction and recrystallized from dry ethanol. After drying, the compound had a melting point of 163-165°C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].C1N2CCN(CC2)C1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[S:28]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:27](=[S:28])[N:26]([CH3:30])[CH3:25])=[CH:13][CH:14]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
A DMF (100 mL) solution of 2-(4-hydroxyphenoxy)-2-methyl propionic acid ethyl ester (15.2 g, 67.7 mmol) and DABCO (15.2 g, 135.5 mmol) was charged dropwise with N,N-dimethylthiocarbamoyl chloride (16.7 g, 135.5 mmol) in 20 mL DMF over 15 min. The reaction was stirred at room temperature for 18 h and then quenched with water. The reaction was partitioned between water (1L) and ethyl acetate (500 mL) and the organic layer washed with 1N HCl (500 mL). After drying (MgSO4) and concentration, the crude product was obtained as a tan oil. Purification by flash chromatography (15% ethyl acetate/hexane) provided the product (15.8 g, 75%) as a pale yellow oil: 1H NMR (CDCl3) δ1.32 (t, 3H), 1.65 (s, 6H), 3.37 (s, 3H), 3.50 (s, 3H), 4.30 (q, 2H), 6.93 (dd, 4H); MS (m/e) 312.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[O:24][C:25]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([O:33]C)=[O:32])=[CH:26][N:27]=3)[CH2:10]2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>CO.C1COCC1>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23]3[O:24][C:25]([C:28]4[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=4)[C:31]([OH:33])=[O:32])=[CH:26][N:27]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4ccc(C(F)(F)F)cc4)C3)o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4ccc(C(F)(F)F)cc4)C3)o2)c1
Yield: 71 %

Procedure:
Methyl 3-(2-(((1R,2R)-2-(((S)-1-(4-(trifluoromethyl)phenyl)piperidin-3-yl)amino)cyclohexyl)amino)oxazol-5-yl)benzoate (470 mg, 0.866 mmol) was dissolved in a mixed solvent of MeOH (3.5 mL) and THF (3.5 mL), then 2 M of aqueous LiOH (7 mL, 14 mmol) was added. The resultant mixture was stirred at rt for 16 h. LC/MS check showed the reaction was completed. The reaction was cooled in an ice-bath, 3 M HCl was added dropwise to adjust pH ˜3. The reaction mixture was concentrated. The resulting residue was purified using prep HPLC (Phenomenex Luna Axia, 5μ, 30×100 mm, 40-80% B, gradient over 10 min, hold at 80% B for 2 min). The desired fractions were concentraed to almost dryness, and the residue was lyophilized in CH3CN—H2O to afford the title compound (2 TFA salt) as a beign colored powder (465 mg, 0.615 mmol, 71.0% yield). Anal. Calcd. for C28H31F3N4O3 m/z 528.2, found: 529.1.
Reaction SMILES: [Al:1].[O-:2][CH2:3][CH3:4].[Mg+2:5].[O-:6][CH2:7][CH3:8]>>[O-:2][CH2:3][CH3:4].[Mg+2:5].[O-:6][CH2:7][CH3:8].[CH3:4][CH:3]([CH3:7])[O-:2].[Al+3:1].[CH3:4][CH:3]([CH3:7])[O-:2].[CH3:4][CH:3]([CH3:7])[O-:2]
Reactant: [Al]
Agent: CC[O-]
Agent: [Mg+2]
Product: CC(C)[O-]
Product: [Al+3]

Procedure:
One gram (5 mmoles) of aluminum ispropoxide was dissolved in 10 ml of Freon TF solvent and 0.7 grams (6 mmoles) of magnesium ethoxide added. After mixing in an ultra-sonic bath, followed by settling of suspended matter, 3 ml of the clear solution was analyzed for Mg and Al. Theory Al: 1.5 mmole, Found Al: 1.5 mmole. Theory Mg: 1.8 mmoles, Found Mg: 0.08 mmoles. Conclusion: Little effect of Aluminum alkoxide on solubility of Magnesium alkoxide in Freon TF, and therefore not a useful system for deacidification of books.
Reaction SMILES: [NH2:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)=[O:4].C1C[O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.C(Cl)(=O)C>O>[C:38]([NH:1][CH:2]([C:22]1[CH:31]=[CH:30][C:29]2[C:28]([CH3:33])([CH3:32])[CH2:27][CH2:26][C:25]([CH3:35])([CH3:34])[C:24]=2[CH:23]=1)[C:3]([NH:5][C:6]1[CH:21]=[CH:20][C:9]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:8][CH:7]=1)=[O:4])(=[O:39])[CH3:37]
Reactant: C1CCOC1
Reactant: CC1(C)CCC(C)(C)c2cc(C(N)C(=O)Nc3ccc(C(=O)OCc4ccccc4)cc3)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)Cl
Product: CC(=O)NC(C(=O)Nc1ccc(C(=O)OCc2ccccc2)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
1.5 g (3.2 mmol) of benzyl 4-[α-amino-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)acetamido]benzoate, 75 ml of THF and 490 μl (3.5 mmol) of triethylamine were introduced into a round-bottomed flask. 250 μl (3.5 mmol) of acetyl chloride were added dropwise and the mixture was stirred at room temperature for 2 hours. The reaction medium was poured into water, extracted with ethyl acetate, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was triturated in hexane, filtered and dried. 1.6 g (94%) of the expected compound of melting point 258°-259° C. was obtained.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:20]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)C(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of anhydrous ethanol (500 mL) was added sodium (9 g, 0.39 mol) in pieces. After all the sodium dissolved, diethyl malonate (50 g, 0.31 mol) was added dropwise at 0° C., and the mixture was stirred at 0° C. for another 30 minutes, followed by the addition of (±)-ethyl 2-bromopropanoate (56.5 g, 0.31 mol) dropwise. The mixture was warmed to room temperature for 1 hour and then heated at reflux for 12 hours. After cooling to room temperature, most of solvents were removed, and the residue was diluted with ethyl acetate. The organic phase was washed by brine, dried over anhydrous sodium sulfate and evaporated to afford the product (±)-triethyl propane-1,1,2-tricarboxylate (67.8 g, yield 83.4%), which was used for the next step without purification.
Reaction SMILES: [C:1]12([CH3:11])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[OH:10].[CH2:12]([OH:14])[CH3:13]>>[C:1]12([CH3:11])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][C:2]2([CH2:13][CH2:12][OH:14])[OH:10]
Reactant: CC1(C)C2CCC1(C)C(O)C2
Reactant: CCO
Product: CC1(C)C2CCC1(C)C(O)(CCO)C2

Procedure:
combining Borneol with ethanol to produce a Borneol-ethanol mixture,
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)[nH]ncc2c1C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 75.6 %

Procedure:
A solution of trifluoromethanesulfonic acid 6-methoxy-1-oxo-1,2-dihydro-phthalazin-5-yl ester (4.52 g, 13.94 mmoles), prepared as described in example 59, trimethylsilylethyne (3.94 ml, 27.88 mmoles), bis(triphenylphosphine)PdCl2 (245 mg, 0.384 mmole) and triethylamine (6.56 ml) in DMF (30 ml) was heated at 60° C. for 4 hours. Further trimethylsilylethyne (2 ml) was added and the mixture was heated at 90° C. for 3 hours. After evaporation of the solvent, the residue was taken up in ethyl acetate and the solid was filtered off. After evaporation, the residue was taken up in diethylcarbonate, washed with water, dried, evaporated again, taken up in ethyl ether and filtered giving 2.87 g of the title compound (yield: 75.6%).