Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C@@H:8]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:13]([N:15]1[CH2:19][CH:18]=[CH:17][C@H:16]1[C:20]#[N:21])=[O:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CC=C[C@H]1C#N)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](N)C(=O)N1CC=C[C@H]1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.2 %

Procedure:
(140 mg, 0.46 mmol) of (3) was dissolved in 0.5 ml of dichloromethane and the mixture was cooled to 0° C. 0.5 ml of trifluoroacetic acid was added and the reaction mixture was stirred at 0° C. for 1 hour. The solvent was evaporated and the crude product was purified by preparative HPLC, using acetonitrile/water as the eluent. Fractions containing the product were collected and the solvent was evaporated, to afford 25 mg of the title compound (1) as the trifluoroacetic acid salt. Oil, 17% yield. 1H-NMR (MeOH, 200 MHz) δ: 1.20 (s, 9H); 4.08 (s, 1H); 4.46-4.70 (m, 2H); 5.56-5.62 (m, 1H); 5.95-6.02 (m, 1H); 6.22-6.29 (m, 1H). LC-MS, m/z: 208.4 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH2:9]OC(=O)C3C=CC=CC=3C(O)=O)[CH2:7][S:8][C@H:3]12.[SH:27][C:28]1[N:32]([CH3:33])[N:31]=[N:30][N:29]=1.COC(C1C(Cl)=C(Cl)C(C(OC)=O)=C(Cl)C=1Cl)=O>C(#N)C>[NH2:1][CH:2]1[C:25](=[O:26])[N:4]2[C:5]([C:22]([OH:24])=[O:23])=[C:6]([CH2:9][S:27][C:28]3[N:32]([CH3:33])[N:31]=[N:30][N:29]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cn1nnnc1S
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3C(=O)O)CS[C@H]12
Agent: COC(=O)c1c(Cl)c(Cl)c(C(=O)OC)c(Cl)c1Cl
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
A 3.5 ml portion of acetonitrile was added to 0.946 g of 7-amino-3-(2-carboxybenzoyloxy)methyl-3-cephem-4-carboxylic acid and 0.32 g of 5-mercapto-1-methyl-1H-tetrazole, and the mixture was cooled over a dry-ice/ethanol bath, followed by adding through a dropping funnel 3.71 g of DCPA to it with stirring and rinsing the funnel with 1.0 ml of acetonitrile. The external bath was removed, and the reaction mixture was warmed to 0° C., whereby the starting materials dissolved. The solution was stirred at 14° to 16° C. for 40 minutes to allow the reaction to proceed, and the reaction solution was cooled with ice, and poured into ice-water, which was placed in a refrigerator overnight. The precipitate was filtered out and washed with 10 ml of water, and the filtrate and washing were combined and adjusted to pH 4.0 with 25% aqueous ammonia under ice cooling. The precipitated powder was recovered by filtration, washed with water and acetone successively, and dried, thereby affording 0.710 g (86.5% of yield) of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid. The IR and NMR values of the product were in accordance with those of the authentic sample.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1(=[O:23])[NH:21][C:20](=[O:22])[CH:19]=[CH:18]1>>[CH2:10]([N:8]([O:9][CH:19]1[CH2:18][C:17](=[O:23])[NH:21][C:20]1=[O:22])[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C=CC(=O)N1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1
Yield: 69.6 %

Procedure:
The procedure of Example 1 is repeated using 5.33 g (25 mmole) of N,N-dibenzylhydroxylamine and 2.42 g (25 mmole) of maleimide. The residue is purified by preparative HPLC (Silica gel: 4:1 heptane:ethyl acetate eluent) to give 5.4 g (74%) of a colorless gum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[CH3:8][C:7]1[C:2]([N:1]2[CH:12]=[CH:16][CH:15]=[CH:14]2)=[C:3]([OH:9])[CH:4]=[CH:5][CH:6]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1cccc(O)c1N
Solvent: CC(=O)O
Product: Cc1cccc(O)c1-n1cccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 82.5 %

Procedure:
A round bottom flask was charged with 2-amino-3-methyl-phenol (2.5 g, 20.3 mmol) and acetic acid (37.5 mL) which provided a very dark solution. Stirring was commenced and the vessel was charged with 2,5-dimethoxytetrahydrofuran (2.6 mL, 20.3 mmol) added neat dropwise over a period of 2 minutes. The dark mixture was then heated at 100° C. for 3 h then 80° C. for 12 hours. The solvent was evaporated under vacuum and the crude residue purified by column chromatography using a gradient of 0.5-50% EtOAc in hexanes to yield 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 83%). ESI-MS m/z calc. 173.1. found 174.3 (M+1)+. Retention time: 1.31 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[CH:9]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][CH:25]=1)/[CH:15]=[N:16]/[S@:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])([CH3:11])[CH3:10]>C1COCC1>[CH3:22][C:19]([S@@:17]([NH:16][C@H:15]([C:14]1[CH:23]=[CH:24][CH:25]=[C:12]([CH:9]([CH3:11])[CH3:10])[CH:13]=1)[C:2]([F:4])([F:3])[F:1])=[O:18])([CH3:20])[CH3:21]
Reactant: CC(C)c1cccc(/C=N/[S@@](=O)C(C)(C)C)c1
Reactant: C[Si](C)(C)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)c1cccc([C@@H](N[S@@](=O)C(C)(C)C)C(F)(F)F)c1
Reaction time: 2 h

Procedure:
Tetra-n-butylammonium difluorotriphenylsilicate (TBAT) (1.19 g, 2.13 mmol) and (trifluoromethyl)trimethylsilane (TMS-CF3) (0.371 mL, 2.33 mmol) was added to a solution of (S,E)-N-(3-isopropylbenzylidene)-2-methylpropane-2-sulfinamide (0.487 g, 1.937 mmol) in anhydrous THF (16 mL) at −20° C. under argon. The reaction was allowed to proceed for ˜2 h where the starting material appeared to have been consumed as determined by analytical-HPLC. A saturated solution of NH4Cl (20 mL) was added to quench and the mixture was extracted with EtOAc (100 mL×3) and dried over Na2 SO4. The organic partition was then concentrated to an oil and the title compound was isolated by flash chromatography using silica gel (EtOAc:Hexanes). ESI-MS (m/z): 321 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[N:18]=[C:17]2[CH2:19][O:20][C:21](=O)[C:16]2=[CH:15][CH:14]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:21]1[C:16]2[C:17](=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH2:19][O:20]1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1ccc2c(n1)COC2=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (752 mg, 4.98 mmol.) in THF (5 mL) is placed under an argon atmosphere and cooled in an ice bath. A solution of Li bis(trimethylsilyl)amide (13.2 mL of a 1M in THF, 13.2 mmol) is added slowly at 0° C. and the resulting solution is stirred at 0° C. for 10 min. The ice-bath is removed and a solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (495 mg, 3.32 mmol) in THF (6 mL) is added dropwise to the reaction mixture. The resulting solution is stirred for 4.5 h and then poured into 50 mL of aqueous 10% HCl solution. After 10 min at room temperature, the reaction is heated to ˜90° C. for 45 min and is then stirred at room temperature for 36 h. The solid which precipitated from solution is collected by filtration and washed sequentially with small volumes of MeOH (3×5 mL), EtOAc (3×5 mL) and Et2O (3×5 mL) followed by drying to give the title compound as a yellow solid (450 mg, 48%).
Reaction SMILES: [Br-].[OH:2][C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[O:5][NH+:4]=1.C(N(CC)CC)C.[K+].[Br-].CO>O.C(O)C>[O:5]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:11]=2[C:3]([OH:2])=[N:4]1
Reactant: Oc1[nH+]oc2c1CCNC2
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: Oc1noc2c1CCNC2
Reaction time: 2 h

Procedure:
To a solution of 3-hydroxy-4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridinium bromide (77 mg; 0.35 mmol) in water (0.6 ml) was added a solution of triethylamine (39 mg; 0.39 mmol) in ethanol (0.6 ml). The mixture was left at 25° C. for 2 hours. Ia (42 mg; 86%) was isolated as colourless crystals, m.p. 242°-244° C. (decomp.). IR (KBr): 3700-2900 (s), 2900-1900 (several bands, m-s), 1670 (s), 1625 (m) cm-1. UV [methanol (log ε)]: 212 (3.64) nm. pKA values (H2O, 25° C.): 4.44±0.03, 8.48±0.04.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[Na+].C1(C)C=CC(S(O[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:23]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1ccccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCCCNc1ccccc1C(=O)O
Temperature: 120 °C
Reaction time: 6 h
Yield: 43.1 %

Procedure:
To a solution of anthranilic acid in toluene, n-octyl p-toluenesulfonate prepared according to the conventional method was added and the mixture was refluxed at 120° C. After 6 hours, an aqueous solution of sodium hydroxide was added and the toluene layer was concentrated. N-n-octylanthranilic acid was obtained from the remaining reactant after the purification by column chromatography with the yield of 43.1%.
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:11]OC(OC)N(C)C>>[N:1]12[CH:11]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][CH2:10]1)[CH2:3][CH2:2]2
Reactant: COC(OC)N(C)C
Reactant: C1CNCCNCCNC1
Product: C1CN2CCN3CCN(C1)C23

Procedure:
In a manner similar to that of Example 2 (A), 4.80 g (33.5 mmol) of 1,4,7-triazacyclodecane and 4.00 g of dimethylformamide dimethyl acetal were reacted to give 4.67 g (91%) of clear, colorless liquid, bp 96°-97.5° (4.0 mm). Redistillation in a molecular still at 70° (3.4 mm) gave an analytical sample of 1,4,7-triazatricyclo[5.3.1.04,11 ]undecane.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([C:9](Cl)=[CH:10]C=O)=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)C.[OH-].[Na+].Cl.[C]=O>C(O)(=O)C>[C:9]([C:8]1[CH:14]=[CH:15][C:5]([OH:4])=[C:6]([N+:16]([O-:18])=[O:17])[CH:7]=1)#[CH:10]
Reactant: CC(=O)Oc1ccc(C(Cl)=CC=O)cc1[N+](=O)[O-]
Agent: Cl
Agent: [C]=O
Agent: [Na+]
Solvent: CC(=O)O
Product: C#Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
In the third step of the process (equation 3), 4-acetoxy-3-nitro-β-chlorocinnamaldehyde is added to a solution of sodium hydroxide. The reaction mixture is maintained at 50° to 80° C. for about 15 to 30 minutes and then cooled at 0° C. In the reaction that occurs, the ester group is hydrolyzed, and hydrogen chloride and carbon monoxide are simultaneously eliminated. The mole ratio of sodium hydroxide to 4-acetoxy-3-nitro-β-chlorocinnamaldehyde is usually about 3 to 10:1. The cooled solution is neutralized with glacial acetic acid to give a precipitate which is separated by filtration. The precipitate is then purified to give crystals of 4-ethynyl-2-nitrophenol.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH:46]([S:79]CC2C=CC=CC=2)[CH2:47][NH:48][C:49]([C:51]2[NH:52][C:53]3[C:58]([CH:59]=2)=[CH:57][C:56]([O:60][CH2:61][CH2:62][CH2:63][S:64]([CH3:67])(=[O:66])=[O:65])=[CH:55][C:54]=3[N:68]([CH3:78])[S:69]([C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=2)(=[O:71])=[O:70])=O)[CH2:41][CH2:40]1)(=[O:38])[CH3:37].C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][CH:46]2[S:79][C:49]([C:51]3[NH:52][C:53]4[C:58]([CH:59]=3)=[CH:57][C:56]([O:60][CH2:61][CH2:62][CH2:63][S:64]([CH3:67])(=[O:66])=[O:65])=[CH:55][C:54]=4[N:68]([CH3:78])[S:69]([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][N:73]=3)(=[O:70])=[O:71])=[N:48][CH2:47]2)[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCN(CC(CNC(=O)c2cc3cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)SCc2ccccc2)CC1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CSc1ccccc1
Solvent: ClCCl
Product: CC(=O)N1CCN(CC2CN=C(c3cc4cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c5ccccn5)c4[nH]3)S2)CC1
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
To a solution of triphenylphosphine oxide (0.38 g) in dichloromethane (3 mL) Was slowly added trifluoromethanesulfonic anhydride (0.23 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[3-(4-acetylpiperazin-1-yl)-2-(benzylthio)propyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.34 g) and thioanisole (0.17 mL) in dichloromethane (5 mL) was added dropwise, and the mixture was stirred for 1 hr under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (ethyl acetate), and the obtained colorless oil was crystallized from ethyl acetate-hexane to give the title compound (109 mg, yield: 37%) as colorless crystals. MS:650(MH+). melting point 165-167° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@H:21]3[OH:29])[C:13]2=[N:12][C:11]=1[CH3:30])=[O:9].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:8]([C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][C@H:21]3[O:29][S:32]([CH3:31])(=[O:34])=[O:33])[C:13]2=[N:12][C:11]=1[CH3:30])=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3OS(C)(=O)=O)cccn2c1C=O

Procedure:
8.5 ml triethylamine is added, while stirring and excluding any moisture, to 10 g 3-formyl-8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-imidazo[1,2-a]pyridine, suspended in 200 ml dry dichloromethane. This is cooled in an icebath and 5 ml methane sulfonyl chloride dissolved in 10 ml dry dichloromethane is added dropwise. This is stirred for 1 hour while cooling with ice, and the solution is poured onto icewater and extracted several times with dichloromethane. The organic phases are washed with water and dried, and the solvent is stripped off in vacuo. The yellowish residue is stirred with diethyl ether, filtered off under suction and dried. 12 g of the title compound of m.p. 158°-160° C. is obtained. By analogous methods 2-methyl-8-(2-(trans)methylsulfonyloxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine is obtained from 2-methyl-8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-imidazo[1,2-a]pyridine and methane sulfonyl chloride. M.p. 122°-125° C. (decomposition).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].[C:36]1(B(O)O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: OB(O)c1ccccc1
Product: Cc1ccccc1N1C(C)N(c2ccccc2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=576.0 (M+H+), was prepared in accordance with the general method of example 62 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 4 phenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9](B(O)O)[CH:8]=[CH:7]2.Cl[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[C:24]2[CH3:28])[N:19]=[N:20][CH:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([C:16]1[CH:17]=[C:18]([CH2:22][N:23]3[CH:27]=[CH:26][N:25]=[C:24]3[CH3:28])[N:19]=[N:20][CH:21]=1)[CH:8]=[CH:7]2
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: OB(O)c1ccc2cccc(F)c2c1
Product: Cc1nccn1Cc1cc(-c2ccc3cccc(F)c3c2)cnn1

Procedure:
The title compound, MS: m/e=319 (M+H+), was prepared from 8-fluoro-naphthalene-2-boronic acid and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(N(CC)CC)C.C(Cl)Cl>[CH2:14]([N:13]([C:26](=[O:27])[NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(C)(C)N=C=O
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCN=C(SCC)N(CCCCCCC)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The equipment was the same as used in Example 26. 3.0 g (0.01 mole) 1,3-di-n-heptyl-2-S-ethyl isothiourea was mixed with 30 ml of methylene chloride. Two drops of triethylamine and 1 drop of dibutyltindilaurate were added to the mixture followed by 1.0 g (0.01 mole) tert-butyl isocyanate. The temperature rose from 24° to 39° C. The reaction mixture was stirred overnight at ambient temperature and then heated for one-half hour at 35° to 40° C. to complete the reaction. The reaction mixture was vacuum evaporated to produce 3.83 g (96 weight percent of theory yield) of a clear liquid having a nD30 of 1.4750. The product was identified as the title product by IR and NMR spectra analyses. Compound No. 40 in Table I.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:4][N:3]=[CH:2]1.[CH3:21]I>>[CH3:21][N:1]1[C:5]([CH2:6][O:7][CH2:8][CH:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[OH:10])=[CH:4][N:3]=[CH:2]1
Reactant: OC(COCc1cnc[nH]1)c1cccc2ccccc12
Reactant: CI
Product: Cn1cncc1COCC(O)c1cccc2ccccc12

Procedure:
2-(Imidazol-5-yl)methoxy-1-(1-naphthyl)ethanol was reacted with methyl iodide to obtain oily 2-(1-methylimidazol-5-yl)methoxy-1-(1-naphthyl)ethanol (compound No. 283).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:23])C(=O)C1>C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Br:23]
Reactant: CN1CCC(c2ccc(N)nc2)CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CN1CCC(c2cnc(N)c(Br)c2)CC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (+/−)-4-(6-aminopyridin-3-yl)-1-methylpiperidin-2-one (291 mg, 1.418 mmol) in acetonitrile (14.200 mL) was added NBS (202 mg, 1.134 mmol) at 0° C. The reaction mixture was stirred for 30 min upon warming-up to room temperature. After quenched with Na2S2O3 solution, the reaction mixture was extracted with EtOAc, which was washed with NaHCO3 solution and brine. The organic layer was dried over anhydrous Na2SO4, filtered off, concentrated in vacuo. The crude product (+/−)-4-(6-amino-5-bromopyridin-3-yl)-1-methylpiperidin-2-one (98%) was used for the next step. LCMS (m/z): 284/286 (MH+), 0.34 min.
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH2:11][C:12](C)([CH3:15])[CH2:13]O.O>C1(C)C=CC=CC=1>[CH3:13][C:12]1([CH3:15])[CH2:10][O:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[N:11]1
Reactant: COC(=O)c1cccnc1
Reactant: CC(C)(N)CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)COC(c2cccnc2)=N1
Reaction time: 8 h

Procedure:
A solution of 69 g (0.500 mol) of methyl nicotinoate and 45 g (0.500 mol) of 2-amino-2,2,dimethyl-ethanol in 600 ml of toluene was refluxed with a water separator overnight. The solvent was removed in vacuo, 300 ml of water added, and the aqueous solution extracted with 3×300 ml of dichloromethane. Drying of the organic phase over magnesium sulphate and evaporation in vacuo gave a red oil which was filtered through silica gel (eluent: methanol/ether=1/19). Removal of solvents in vacuo gave a yellow oil, 86. Yield: 30.0 g (0.170 mol, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]([O:24][CH2:25][CH3:26])(=[O:23])C>>[CH2:25]([O:24][C:21](=[O:23])[NH:1][CH2:2][CH2:10][CH2:9][CH2:8][CH2:7][C:6](=[O:11])[NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11])[C:26]1[CH:15]=[CH:16][CH:17]=[CH:12][CH:13]=1
Reactant: CCOC(C)=O
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)CCCCCNC(=O)OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 48 %

Procedure:
A solution of 6-benzyloxycarbonylamino-hexanoic acid(2.65 g, 10 mmol) in thionyl chloride (15 ml) was heated to reflux 1 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo to give (5-chlorocarbonyl-pentyl)-carbamic acid benzyl ester as tan oil. The oil was used without further purification. (5-Chlorocarbonyl-pentyl)-carbamic acid benzyl ester was dissolved in THF (50 ml). To this solution was added 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.37 g, 5 mmol). The resulting suspension was to reflux for 4 hours. The solvent was evaporated in vacuo and the resulting solid was partially purified by flash chromatography (60/40 ethyl acetate/hexane) to give a light yellow solid. The solid was recystallized from minimal ethyl acetate to give 1.24 g (48%) of product as an off-white solid: mp 122-125° C.; 1H NMR (DMSO-d6) 11.18 (s, 1H), 9.70 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.83 (t, J=7.7 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.34-7.24 (m, 6H), 5.16 (dd, J=5.1 and 12.6 Hz, 1H), 5.00 (s, 2H), 3.02-2.84 (m, 3H), 2.65-2.43 (m, 4H), 2.12-2.05 (m, 1H), 1.65-1.15 (m, 6H; 13C NMR (DMSO-d6) 172.75, 171.95, 169.77, 167.72, 166.67, 156.08, 137.29, 136.57, 136.09, 131.43, 128.32, 127.70, 126.21, 118.25, 116.90, 65.08, 48.92, 36.47, 30.94, 30.67, 29.14, 25.77, 24.47, 21.99; Anal. Calcd. For C27H28N4O7: C, 62.30; H, 5.42; N, 10.76. Found: C, 62.40; H, 5.31; N, 10.48.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[K].[OH:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21]>CC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:21])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: COc1ccc(C(=O)Cc2cc([N+](=O)[O-])ccc2O)cc1
Reactant: CCCCC(=O)Cl
Agent: [K]
Solvent: CC(C)=O
Product: CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1CC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
4.23 g (35.0 mmol) of valeroyl chloride (compound of the formula VI) were added with cooling at −10° C. to 20° C. to a stirred suspension of 11.3 g (34.7 mmol) of 2-(2-hydroxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone potassium salt (example 1) in 50 ml of dry acetone. After 30 minutes the reaction was complete, as monitored by LC-MS, and the mixture was filtered through a layer of Celite to remove the precipitated potassium chloride. The solution was evaporated to dryness to give 9.23 g (98%) of a yellow oil which slowly crystallized while standing at room temperature.