Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[C:10]#[C:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([C:11]1[C:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1)[CH3:13]
Reactant: N[n+]1ccccc1
Reactant: CCC#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CC)nn2ccccc12
Yield: 57.3 %

Procedure:
A solution of 1-aminopyridinium iodide (10 g, 40 mmol) [Aldrich 441503], ethyl 2-pentynoate (5.7 g, 45 mmol) [Aldrich 632112] and potassium carbonate (12.0 g, 90 mmol) were stirred in N,N-dimethylformamide (200 mL) at 20° C. for 16 h. The mixture was poured into water to give a tan suspension. The solid was filtered and washed with water to give the desired compound (5.0 g, 57%). LCMS for C12H15N2O2 (M+H)+: m/z=219.1. 1H NMR (300 MHz, DMSO-d6): δ 8.77 (m, 1 H), 8.00 (m, 1 H), 7.52 (m, 1 H), 7.05 (m, 1 H), 4.28 (m, 2 H), 3.00 (m, 2 H), 1.33 (m, 3 H), 1.24 (m, 3 H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH:12]1([CH2:18][CH2:19][OH:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.CCOCC>C(Cl)Cl>[CH:12]1([CH2:18][CH:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OCCC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCC1CCCCC1
Reaction time: 1 h
Yield: 55.5 %

Procedure:
A suspension of 100 g (0.46 moles) of pyridinium chlorochromate and 100 g of celite in 800 ml of methylene chloride was stirred vigorously while 38 g (0.3 moles) of 2-cyclohexylethanol in 200 ml of methylene chloride was added all at once. The reaction turned dark immediately and became mildly exothermic. After 1 hour, 1000 ml of ether was added and the reaction mixture was filtered through a bed of silica gel (ca. 250 g) on a fritted glass disk. The pad was rinsed with an additional liter of ether. The combined filtrates were reduced in volume to approximately 200 ml and the solution was washed with 2×40 ml of 6N HCl, 1×50 ml of saturated sodium bicarbonate, and 1×50 ml of saturated NaCl solution. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a light green oil. The residue was distilled in vacuo to afford 21 g (56%) of a colorless oil (bp 74°-76° C. at 23 mm of Hg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH:10]=O)(=[O:4])=[O:3].[NH2:15][NH:16][C:17]([NH2:19])=[S:18]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:8]=[CH:9][CH:10]=[N:15][NH:16][C:17]([NH2:19])=[S:18])(=[O:4])=[O:3]
Reactant: NNC(N)=S
Reactant: CS(=O)(=O)c1cccc(C=CC=O)c1
Product: CS(=O)(=O)c1cccc(C=CC=NNC(N)=S)c1
Yield: 70 %

Procedure:
The compound is prepared according to the method described in example 1A from 3-methylsulfonylcinnamaldehyde (3.8 mmoles) and from thiosemicarbazide (3.8 mmoles). Yield 70%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1.[CH2:25]([Sn:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:25]([Sn:29]([CH2:30][CH2:31][CH2:32][CH3:33])([O:34][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:17]=[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]2=[N:20]1)[O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:11][C:12]([CH3:13])([CH3:14])[CH3:15])([CH3:9])[CH3:10])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[N:17]1)[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Reactant: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCC[Sn](CCCC)(Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1)Oc1ccc(C(C)(C)CC(C)(C)C)cc1-n1nc2ccccc2n1
Temperature: 2.5 °C
Yield: 43.3 %

Procedure:
2-(2-Hydroxy-5-tert-octylphenyl)-2H-benzotriazole (64.6 g, 0.2 mol, TINUVIN® 329, CIBA), dibutyltin oxide (24.89 g, 0.1 mol) and toluene are charged to a laboratory reactor and the contents are heated to reflux and refluxed for seven hours. About half of the amount of toluene is removed by distillation. The reaction mass is cooled to 0-5° C. after the addition of 200 g of hexane. Any unreacted TINUVIN® 329 and dibutyltin oxide are removed by filtration. The solvent is then removed by distillation to yield the title compound (38 g, 43.3% yield) as a yellow resin whose structure is consistent with 1Hnmr analysis.
Reaction SMILES: N(CCO)(CCO)CCO.Cl.[C:12]([O:20]C(=O)C1C=CC=CC=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>OCC(CO)O.O>[C:12]([OH:20])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: OCC(O)CO
Solvent: OCCN(CCO)CCO
Product: O=C(O)c1ccccc1

Procedure:
Standard reaction conditions for the rate determinations in Table 1 are as follows: 60% glycerol/water (w/w), 120 ppm hardness (2:1 Ca:Mg), 10 mM Triethanolamine adjusted to pH 7 with HCl, and 50 umol benzoic anhydride. All incubations were at -10 deg. centigrade for 5 mins. Benzoic acid produced was measured by HPLC via an internal standard (acenaphthylene).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:55]=[CH:54][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:50]=[C:49]([CH3:51])[C:39]([NH:40][C:41](=[O:48])[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[N:38][C:36]3=[O:37])[C@H:32]([OH:52])[C@@H:31]2[OH:53])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.[Si:56](Cl)([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57]>C1COCC1.[N+]([O-])([O-])=O.[Ag+]>[CH3:7][O:8][C:9]1[CH:55]=[CH:54][C:12]([C:13]([O:28][CH2:29][C@H:30]2[O:34][C@@H:33]([N:35]3[CH:50]=[C:49]([CH3:51])[C:39]([NH:40][C:41](=[O:48])[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)=[N:38][C:36]3=[O:37])[C@H:32]([O:52][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[C@@H:31]2[OH:53])([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(NC(=O)c4ccccc4)nc3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(NC(=O)c4ccccc4)nc3=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
Anhydrous pyridine (3.6 mL) was added to a solution of 5′-O-(4,4′-dimethoxitrityl)-N-benzoyl-5-methylcytidine (7.06 g, 10.64 mmol) and AgNO3 (2.17 g, 12.75 mmol) in dry THF (71 mL) and stirred at room temperature for 20 min under an argon atmosphere. Followed by addition of tert-butyldimethylsilyl chloride (1.89 g, 12.81 mmol) in dry THF (6 mL) and stirred at the same temperature for 2-3 h. The solids were filtered off and the filtrate was concentrated to a crude residue which was applied to a column of silica gel eluted with hexane-ethyl acetate (3:1) to give a pure title compound (3.04 g, 37%), and a mixture of 2′- and 3′-isomers (3.04 g) as amorphous solid. 1H-NMR (DMSO-d6, 400 MHz): δ 12.96 (br, 1H), 8.20-7.81 (m, 2H, ArH), 7.82 (s, 1H), 7.58-7.22 (m, 12H, ArH), 6.92-6.90 (m, 4H, ArH), 5.80 (d, 1H, J=3.6 Hz, H-1′), 5.20 (d, 1H, J=6.4 Hz, 3′-OH), 4.32 (dd, 1H, H-2′), 4.16-4.13 (dd, 1H, H-3′), 4.08 (m, 1H, H-4′), 3.78 (s, 6H, 2OCH3), 3.38-3.25 (m, 2H, H-5′), 1.80 (s, 3H, 5-CH3), 0.86 (s, 9H, t-Bu), 0.08 (s, 6H, 2 CH3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.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].C(O)C.C1(C)C=CC=CC=1>[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: OB(O)c1cccs1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nc(-c2cccs2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo-[3,2-d]pyrimidine (Example 1(e)) (50 mg, 0.21 mmol), thiophene-2-boronic acid (37 mg, 0.287 mmol), tris(dibenzylidene-acetone)dipalladium(0) (Aldrich Chemical Company) (4.7 mg, 0.0051 mmol) and triphenylphosphine (Aldrich Chemical Company) (10.8 mg, 0.041 mmol) in a mixed solvent (600 μL of toluene, 300 μL, 1.0 M Na2CO3 and 150 μL of ethanol) was heated at reflux under N2 for 36 h. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with CHCl3 (3×20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 37.2 mg (62%) of the title compound as a yellow solid. Mp: 178-179° C. 1H NMR (Acetone-d6; 400 MHz): δ 10.61 (s, 1), 8.21 (d, 1, J=4.5), 8.00 (d, 2, J=7.3), 7.73 (d, 2, J=4.5), 7.54 (t, 2, J=7.3), 7.48 (t, 1, J=7.3) 7.28 (t, 1, J=4.5), 6.96 (s, 1), 2.68 (s, 3). MS m/z: 292 (M+1), 290 (M−1). HRMS (NBA-NaI) m/z Calcd for M+H, C17H13N3S: 292.0908. Found: 292.0900.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:18]2[CH2:19][CH2:20][CH:9]1[CH2:10][C:11]1[CH:12]=[C:13]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH:27]([C:30]([F:33])([F:32])[F:31])[CH2:26][CH2:25]3)[CH:14]=[CH:15][C:16]=1[CH2:17]2)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:32][C:30]([F:31])([F:33])[CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][CH2:21][C:13]2[CH:14]=[CH:15][C:16]3[CH2:17][CH:18]4[CH:8]([NH2:7])[CH:9]([CH2:20][CH2:19]4)[CH2:10][C:11]=3[CH:12]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1C2CCC1Cc1cc(CCCN3CCC(C(F)(F)F)CC3)ccc1C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
The Boc protecting group was removed by dissolving the product of Step 3 (87 mg, 0.181 mmol) in 3:1 DCM-TFA (4 ml) and stirring at 0° C. for 1 hour. The mixture was concentrated to dryness, and a solution of the residue in DCM washed with sodium carbonate solution (sat). The organic phase was dried and evaporated to give a colourless oil 66 mg (96%). 1H NMR (CDCl3, 360 MHz) δ 6.99 (1H, d, J=8.4 Hz), 6.90 (2H, m), 3.36 (1H, t, J=6.1 Hz), 3.21 (2H, m), 2.99 (2H, m), 2.45–2.59 (4H, m), 2.35 (2H, m), 2.23 (2H, m), 1.57–2.04 (11H, m), 1.17 (2H, m).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.34 g of product m.p. 114-16° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H); 1.72 (s, 3H); 2.44 (d, 3H, J=1.22 Hz); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (d, 1H, J=1.2 Hz); 6.95 (d, 1H, J=8.8 Hz); 7.00 (d, 1H, J=18 Hz); 7.10 (d, 1H); 7.30-7.40 (m, 3H); 7.45-7.52 (m, 12H); 7.61 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.CCCCCC.CN(C)CCN(C)C.[CH2:27]([N:34]1[CH2:38][CH:37]([C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1OC1.C(=O)([O-])O.[Na+]>CCOCC>[CH2:27]([N:34]1[CH2:35][CH2:36][C:37]2([C:39](=[O:40])[O:41][CH2:42][CH2:1]2)[CH2:38]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C1CCN(Cc2ccccc2)C1
Reactant: CC(C)NC(C)C
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CO1
Solvent: CCOCC
Product: O=C1OCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diisopropylamine (6.6 ml, 0.047 mole) in dry ether (100 ml) at -65° C. under nitrogen was treated with 1.6 M n-butyllithium in hexane (26.2 ml, 0.042 mole) and the solution stirred for 15 min, before treating with N,N,N',N'-tetramethylethylenediamine (12.3 ml). After stirring for a further 10 min, the solution was treated dropwise over 10 min with a solution of (±) methyl 1-benzyl-4-pyrrolidylcarboxylate (D17, 7.50 g, 0.034 mole) in dry ether (20 ml) and stirring continued at -65° C. for 15 min. Ethylene oxide (3.1 g, 0.070 mole) was then bubbled into the solution over 20 min and the mixture was allowed to warm to room temperature over 2 h followed by 40 min at reflux. The reaction mixture was treated with saturated sodium hydrogen carbonate solution (50 ml) and extracted with ether (3×100 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave an orange oil. The unreacted starting material was removed by heating under reflux in 8 M hydrochloric acid (50 ml) for 2 h, followed by basifying to saturation with sodium hydrogen carbonate and extraction with ether. The organic extract was dried (Na2SO4) and concentrated in vacuo to leave an orange oil, which was distilled in a Kugelrohr apparatus (b.p. 190° C.-210° C./0.2-0.5 mmHg) followed by column chromatography on silica gel eluting with ether, to give the title compound (D18) as a pale yellow oil (2.50 g, 36%).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].Cl.Cl.[NH2:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:36])([F:37])[F:38])=[O:9])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(F)(F)F)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (100 mg, 0.91 mmol) in DMSO (2.4 mL) was added PyBOP (248 mg, 1.05 mmol) and hunig base (166 ul, 2.10 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was triturated from ethylacetate/hexane. The resulting solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (75.0 mg, 44% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.32 (s, 1H), 7.26 (s, 1H), 6.86-6.89 (m, 1H), 6.34 (s, 1H), 4.73 (d, J=6.4 Hz, 2H), 3.08 (q, J=7.2 Hz, 2H), 2.80-2.85 (m, 2H), 2.70-2.78 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.85-1.89 (m, 2H), 1.69-1.72 (m, 4H), 0.84 (t, J=7.2 Hz, 3H); MS (ES) [M+H] 533.1, [M+Na] 555.2; HPLC 95.8% purity.
Reaction SMILES: [OH:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4].[H-].[Na+].[CH2:15](I)[CH3:16].O>CN(C)C=O>[CH2:15]([O:1][CH2:2][CH:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7][C@H:6]1[OH:12])[CH3:4])[CH3:16]
Reactant: CCI
Reactant: CC(CO)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
20.0 g (0.12 mol) of (1R, 2S, 5R)-2-(2-hydroxy-1-methylethyl)-5-methylcyclohexanol was dissolved in 100 ml of dimethylformamide, and 3.3 g (0.14 mol) of sodium hydride was added to the solution. The mixture was agitated for 30 min, and 21.8 g (0.14 mol) of ethyl iodide was dropped thereinto and continued to agitate at room temperature for 24 hr. After the completion of the reaction, 300 ml of water was added to the reaction fluid and agitated. The reaction product was extracted with ether. The resultant ether phase was dried over anhydrous magnesium sulfate, and the solvent was distilled off, thereby obtaining 20.1 g (yield: 86.4%) of (1R, 2S, 5R)-2-(2-ethoxy-1-methyl-ethyl)-5-methylcyclohexanol in the form of a colorless liquid. The mass spectrometry and NMR data of the obtained compound are as follows:
Reaction SMILES: [OH-].[Na+].C1(C)C=CC=CC=1.[OH:10][CH:11]1[CH2:16][C:15]([CH3:18])([CH3:17])[NH:14][C:13]([CH3:20])([CH3:19])[CH2:12]1.[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][C:15]1([CH3:18])[CH2:16][CH:11]([O:10][CH2:21][CH:23]2[O:25][CH2:24]2)[CH2:12][C:13]([CH3:20])([CH3:19])[NH:14]1
Reactant: ClCC1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(OCC2CO2)CC(C)(C)N1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In a 750 ml sulfonating flask with mechanical stirrer, condenser and 100 ml dropping funnel 64.0 g (1.6 mol) of sodium hydroxide are dissolved in 64 ml of water under an argon atmosphere. 170 ml of toluene, 10.3 g (31.8 mmol) of tetrabutylammonium bromide and 50 g (318 mmol) of 4-hydroxy-2,2,6,6-tetramethylpiperidine are added. 58.8 g (636 mmol) of epichlorohydrin are added dropwise at 45° C. The mixture is then stirred at 50° C. for 4 hours. The reaction mixture is cooled to room temperature and then poured into 1 l of ice-water, the organic phase is separated off and dried over sodium sulfate, and the residue is concentrated on a rotatory evaporator. The residue is distilled at 8·10-3 torr. Boiling point: 48° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:12])=[CH:9]2)=[CH:4][CH:3]=1.[C:13]([OH:17])(=[O:16])[CH2:14]S.[OH-].[Na+].C(O)CO>O>[OH:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9]=1[CH2:14][C:13]([OH:17])=[O:16]
Reactant: O=C(O)CS
Reactant: Cc1ccc2ccc(O)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1ccc2ccc(O)c(CC(=O)O)c2c1
Reaction time: 20 h

Procedure:
A mixture of 7-methylnaphth-2-ol (5 g), thioglycolic acid (3 g), sodium hydroxide (2 g) and ethylene glycol (10 ml) was stirred at 145° under an atmosphere of argon for 20 h. The mixture was cooled, water (100 ml) was added, and the mixture was heated at 90° for 2 h. The mixture was then washed with ethyl acetate and the aqueous phase was separated, acidified with concentrated hydrochloric acid, and extracted twice with ethyl acetate. The ethyl acetate extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was triturated with toluene. The insoluble solid thus produced was filtered off, washed with toluene and dried to give 2-hydroxy-7-methyl-1-naphthylacetic acid, m.p. 138°-140°.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1.[C:13]1([N:19]2[C:23]([SH:24])=[N:22][N:21]=[N:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+].O>CCO>[O:10]1[C:6]2([CH2:11][CH2:12][CH:3]([CH2:2][S:24][C:23]3[N:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:20]=[N:21][N:22]=3)[CH2:4][CH2:5]2)[O:7][CH2:8][CH2:9]1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: ICC1CCC2(CC1)OCCO2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(-n2nnnc2SCC2CCC3(CC2)OCCO3)cc1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (prepared according to WO 2003/095438, 26 g, 92 mmol) was dissolved in EtOH (200 ml), 1-phenyl-1H-tetrazole-5-thiol (18.9 g, 106 mmol) and KOH (6.7 g, 120 mmol) was added and the mixture stirred at 80° C. for 2.5 h. A little water was added and the mixture concentrated in vacuo. The residue was taken up in water and EA. The yield after work up was 30.9 g (100%; yellowish oil).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([CH:10]([C:16]([O:18]CC)=O)[C:11]([O:13]CC)=O)=[O:9])=[CH:4][CH:3]=1.[N:23]1([CH2:29][C:30]2[S:34][C:33]([NH2:35])=[N:32][N:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:13])[N:35]=[C:33]3[S:34][C:30]([CH2:29][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:31][N:32]3[C:16]=2[OH:18])=[O:9])=[CH:21][CH:22]=1
Reactant: Nc1nnc(CN2CCOCC2)s1
Reactant: CCOC(=O)C(C(=O)NCc1ccc(Cl)cc1)C(=O)OCC
Solvent: Cc1ccccc1C
Product: O=C(NCc1ccc(Cl)cc1)c1c(O)n2nc(CN3CCOCC3)sc2nc1=O
Yield: 39.1 %

Procedure:
Diethyl 2-(((4-chlorobenzyl)amino)carbonyl)malonate (Preparation 5, 33 mg) and 5-(4-morpholinylmethyl)-1,3,4-thiadiazol-2-ylamine (Preparation 4, 20 mg) are dissolved in xylene and heated to reflux for 5 h. The solvent is evaporated and the residue is triturated with ether. The resulting percipitate is filtered and dried to afford 17 mg of the title compound as a brown solid. Physical characteristics: MS (ESI+) m/z 438 (M+H)+. 1H NMR (DMSO) δ 7.42, 7.38, 4.60, 3.92, 3.62, 2.62.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.CO>C1COCC1.Cl.CCOCC>[CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Cc1nccc2ccccc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1NCCc2ccccc21
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 1-methylisoquinoline (133 μL, 1.0 mmol) in THF under nitrogen was added dropwise a solution of LiBEt3H in THF (1.0M, 2.2 mL, 2.2 mmol) to give a yellow solution. After stirring 1.5 h, MeOH (1.2 mL) was added dropwise to produce a clear colorless solution, which was then diluted with 1M aq. HCl and ether. The aqueous layer was extracted three times with ether, then made basic (pH 14) by addition of 1M aq. NaOH. The aqueous layer was extracted five times with DCM, dried over MgSO4, filtered and concentrated to give the desired product in 77% yield, which was used without further purification. LC/MS (10-99%) M/Z: M+1 obs=148.3; tR=0.62 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C1(C2C=CC([C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22])=CC=2)C=CC=CC=1>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:22])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccccc1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccccc2)cc1
Product: CCOC(=O)C(=O)c1ccc(CC(C)C)cc1
Yield: 81 %

Procedure:
A mixture of 27 g (200 mmol) of isobutylbenzene and 24 mL (215 mmol) of ethyl oxalylchloride underwent Friedel-Crafts acylation reaction in an analogous fashion as described for the synthesis of ethyl 4-phenylbenzoylformate to yield 38 g (81% yield) of ethyl 4-isobutylbenzoylformate as a colorless oil.