Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2.O>CC(N(C)C)=O>[OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[C:3]([NH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:29](=[O:30])[O:28][CH2:27]2)=[O:5]
Reactant: Nc1ccc2c(c1)COC2=O
Reactant: CC(CC(O)(C(=O)O)C(F)(F)F)c1ccccc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(CC(O)(C(=O)Nc1ccc2c(c1)COC2=O)C(F)(F)F)c1ccccc1
Temperature: -15 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
500 mg of 2-hydroxy-4-phenyl-2-trifluoromethyl-valeric acid (Eur. Appl. 0 253 500 (Imperial Chemical Industries)) in 10 ml of dimethylacetamide is mixed at −15° C. with 0.14 ml of thionyl chloride. After 3 hours of stirring at −15° C., 600 mg of 5-aminophthalide (test) is added. The solution is stirred for 2 hours at −15° C. and then left for 18 hours at room temperature, then mixed with water and extracted with ethyl acetate. The ethyl acetate phase is dried (Na2SO4) and concentrated by evaporation. The residue is stirred with diethyl ether and suctioned off. 290 mg of 5-(2-hydroxy-4-phenyl-2-trifluoromethyl-valeroylamino)-phthalide, melting point 166-168° C., is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[C:13]1([CH:19]([O:21][C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([NH:6][C:7]([NH:26][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:20])=[CH:28][CH:27]=1)=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1ccccc1Cl
Reactant: CC(Oc1ccc(N)cc1)c1ccccc1
Solvent: CC#N
Product: CC(Oc1ccc(NC(=O)NC(=O)c2ccccc2Cl)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
18.7 g of 2-chlorobenzoylisocyanate were added to 150 ml of a solution of 23.4 g of 4-(1-phenylethoxy)aniline in dry acetonitrile. After stirring at room temperature for a few hours, the crystalline precipitate was sucked off, washed with successively acetonitrile, ethanol and petroleum ether and dried in air. The desired product was obtained in a yield of 32.8 g; melting point 166°-167° C. The starting aniline was obtained from the corresponding nitro compound by hydrogenation with hydrogen under the influence of Raney nickel as a catalyst in alcohol as a solvent. α-Methylbenzyl-4-nitrophenyl ether was prepared from a reaction of 1-bromo-1-phenyl-ethane and 4-nitrophenol under the influence of anhydrous potassium carbonate in acetone as a solvent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:39])([F:38])[C:27]1[CH:28]=[C:29]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[NH2:30]>>[F:25][C:26]([F:38])([F:39])[C:27]1[CH:28]=[C:29]([NH:30][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:15][C@@H:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12][C@@H:11]4[CH2:13]3)[CH:17]=[N:18][CH:19]=2)=[O:22])[CH:31]=[C:32]([C:34]([F:35])([F:37])[F:36])[CH:33]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(C(F)(F)F)cc(C(F)(F)F)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,5-bis(trifluoromethyl)aniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 545 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:26]([OH:29])([CH3:28])[CH3:27])[N:18]=[C:17]2[CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)#[N:2].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[OH:29][C:26]([C:19]1[N:18]=[C:17]([CH2:30][CH2:31][CH3:32])[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:48][N:47]=[N:46][N:2]=3)=[CH:10][CH:11]=2)[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:27])[CH3:28]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.00 g of ethyl 1-(2'-cyanobiphenyl-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate [prepared as described in Example 71(b)] and 1.00 g of tributyltin azide in 7.5 ml of toluene was stirred at 100° C. for 5 days. 2.5 g of sodium hydrogencarbonate and 20 ml of water were then added to the mixture, and the resulting mixture was stirred at room temperature for 8 hours. At the end of this time, the mixture was diluted with ethyl acetate and acidified with 3N aqueous hydrochloric acid to a pH value of 3. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate as a syrup. 0.80 g of trityl chloride was added to a solution of the whole of this syrup in 15 ml of pyridine, and the mixture was stirred at 60° C. for 4 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent; it was then crystallized in diisopropyl ether, to give 1.15 g of the title compound as crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].[H-].[Na+].O1CCCC1.Br[CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][CH3:23]>CCCCCC.O>[CH2:20]([O:19][CH2:18][CH2:17][O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:21][CH2:22][CH3:23]
Reactant: OCCc1cccs1
Reactant: CCCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOCCOCCc1cccs1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.8 %

Procedure:
6.1 g of 2-thiopheneethanol was cooled to 0° C., and to this, a suspension formed by adding 2.8 g of sodium hydride (60% in oil) to 50 ml of tetrahydrofuran was added dropwise. The solution was stirred at 0° C. for 20 minutes under a nitrogen atmosphere, and to this, 8.2 g of 1-(2-bromo-ethoxy)-butane was added dropwise. Thereafter, the solution was heated to 90° C. and stirred for 9 hours. 100 ml of water and 100 ml of hexane were added to the reaction solution to separate the organic layer. The organic layer was washed with 300 ml of water and then dried over anhydrous magnesium sulfate. The resulting solution was concentrated by a rotary evaporator and purified by a column chromatography (filler: silica gel, eluent: hexane/dichloromethane) to obtain 3.5 g of 2-[2-(2-butoxy-ethoxy)ethyl]-thiophene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH:17]([C:19]1[NH:20][C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=2[C:27]=1[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=O>>[O:16]=[C:10]1[C:9](=[CH:17][C:19]2[NH:20][C:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=3[C:27]=2[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11]1
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: O=C(O)CCc1c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]c2c1CCCC2

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:9])=[CH:4][C:3]=1[N+:15]([O-:17])=O.O.[NH2:19][NH2:20].Cl>C(O)CCC>[ClH:1].[N:10]1([CH:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:20]=[N:19][N:15]([OH:17])[C:3]=3[CH:4]=2)[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: NN
Reactant: CC(c1ccc(Cl)c([N+](=O)[O-])c1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(c1ccc2nnn(O)c2c1)n1ccnc1
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 4.3 parts of 1-[1-(4-chloro-3-nitrophenyl)ethyl]-1H-imidazole, 3.42 parts of hydrazine monohydrate and 40 parts of 1-butanol was stirred for 12 hours at reflux temperature. After cooling, 3.4 parts of a hydrochloric acid solution 10N were added. The separated organic layer was evaporated. The residue was stirred in ethyl acetate. The product was filtered off and dried, yielding 4.5 parts (99.0%) of 6-[1-(1H-imidazol-1-yl)ethyl]-1H-benzotriazol-1-ol monohydrochloride (compound 149).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH2:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1.C(N(C(C)C)CC)(C)C.[Cl:24][C:25]1[N:30]=[CH:29][N:28]2[N:31]=[CH:32][C:33]([C:34](Cl)=[O:35])=[C:27]2[CH:26]=1>ClCCl>[CH3:1][C:2]1[S:3][C:4]([NH:14][C:34]([C:33]2[CH:32]=[N:31][N:28]3[CH:27]=[CH:26][C:25]([Cl:24])=[N:30][C:29]=23)=[O:35])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1
Reactant: Cc1nc(-c2ccccc2C)c(N)s1
Reactant: O=C(Cl)c1cnn2cnc(Cl)cc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(Cl)nc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
To an ice-cooled solution of 2-methyl-4-o-tolyl-thiazol-5-ylamine (55.0 mg, 0.27 mmol, 1.0 equiv) and diisopropylethylamine (52.0 mg, 0.41 mmol, 1.5 equiv) in dichloromethane (10 mL) was added a solution of 5-chloropyrazolo[1,5-c]pyrimidine-3-carbonyl chloride (58.0 mg, 0.27 mmol, 1.0 equiv) in dichloromethane (5 mL). The reaction mixture was warmed to ambient temperature and stirred overnight. The mixture was washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under vacuum. Purification by flash column chromatography on silica gel (gradient: 0 to 3% methanol in dichloromethane) afforded 74.0 mg (73%) of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide as a solid. LCMS (ESI) m+H=384.0 (mono chlorinated isotope pattern); 1H NMR (400 MHz, CDCl3) δ: 9.73 (s, 1H), 8.70 (s, 1H), 8.63 (d, 1H), 7.44-7.30 (m, 4H), 6.93 (d, 1H), 2.72 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.Cl.[CH:16]1([CH2:19][O:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([NH2:25])=[NH:24])[CH2:18][CH2:17]1.C(N(CC)CC)C>C(#N)C>[CH3:14][S:13][C:4]1[N:3]=[C:2]2[N:24]=[C:23]([C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[O:20][CH2:19][CH:16]3[CH2:18][CH2:17]3)[NH:25][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: N=C(N)c1ccccc1OCC1CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CSc1ncc2c(=O)[nH]c(-c3ccccc3OCC3CC3)nc2n1
Yield: 54.2 %

Procedure:
In a similar manner to Example 4 reaction of ethyl 4-chloro-2-methylthio-5-pyrimidine carboxylate (1.50 g) with 2-cyclopropylmethoxybenzamidine hydrochloride (1.45 g) and triethylamine (1.30 g) in acetonitrile (50 ml) yielded a white solid (1.18 g) which was collected, dissolved in chloroform and the chloroform solution was extracted twice with 2 Normal hydrochloric acid. The chloroform solution was evaporated under reduced pressure and the residue was recrystallised from ethanol to yield the title compound, 0.52 g, m.p. 186°-187° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.[CH2:14](OC(=N)C(Cl)(Cl)Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.C(Cl)Cl>[CH2:14]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of cis-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (3.556 g, 0.0190 mol) and benzyl-2,2,2-trichloroacetimidate (4.0 mL, 0.021 mol, 1.1 eq) in cyclohexane/DCM (20 mL/10 mL) at 0° C. was added trifluoromethanesulfonic acid dropwise with stirring under nitrogen atmosphere over 30 min. There was an immediate precipitate. The mixture was stirred at room temperature for 15 h, filtered, and the filtrate washed with sodium bicarbonate solution and brine. The organic layer was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (5/1) as eluent to give product as a colorless oil (5.079 g, 77%). 1H NMR (400 MHz, CDCl3) δ 7.38-7.23 (m, 5H), 4.50 (s, 2H), 3.71 (s, 3H), 3.70-3.66 (m, 1H), 3.18 (s, 3H), 2.78-2.62 (m, 1H), 2.07-1.89 (m, 4H), 1.59-1.25 (m, 4H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.N1C=CC=CC=1.[C:19](Cl)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29].Cl>O.C1(C)C=CC=CC=1>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:9]=[CH:10][CH:11]=[CH:12]1)(=[O:30])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH2:29]
Reactant: OCCCCCCn1cccc1
Reactant: C=CCCCCCCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCCCCCCCCC(=O)OCCCCCCn1cccc1
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
62.0 g (0.371 mol) of N-(6-hydroxyhexyl)-pyrrole, 33.2 g (0.420 mol) of dry pyridine, and 1850 ml of dry toluene were put in a 2-liter reactor, and 300 ml of a dry toluene solution of 75.7 g (0.373 mol) of 10-undecenoylchloride was dropped thereto at 20° C. or below. The dropping time was 30 minutes. Thereafter, the mixture was stirred at the same temperature for one hour. The reaction mixture was poured into 1.5 liter of iced water, and was made acidic with use of 1N hydrochloric acid. It was subjected to ethyl acetate extraction, an organic layer was washed with water and concentrated brine and was dried using anhydrous magnesium sulfate, and the solvent was removed. As a result, 128.2 g of crude substance was obtained. This was subjected to purification by silicagel column with use of n-hexane/acetone=20/1, whereby 99.6 g of N-[6-(10-undecenoyloxy)hexyl]-pyrrole was obtained. The yield was 80.1%. The reaction of the step 4 is expressed by a reaction formula (15) shown below:
Reaction SMILES: C([O-])([O-])=O.[K+:5].[K+].[CH3:7][N:8]1[C:15]2[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9]1>O.CO>[K+:5].[CH3:7][N:8]1[C:15]2[CH:14]=[C:13]([C:16]([O-:18])=[O:17])[NH:12][C:11]=2[CH:10]=[CH:9]1
Reactant: Cn1ccc2[nH]c(C(=O)O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cn1ccc2[nH]c(C(=O)[O-])cc21
Reaction time: 0.33 h
Yield: 182.2 %

Procedure:
To a suspension of K2CO3 (0.110 g, 0.798 mmol) in H2O (0.4 mL) and MeOH (2 mL) was added a solution of 4-methyl-1,4-dihydropyrrolo[3,2-b]pyrrole-2-carboxylic acid 12 (262 mg, 1.60 mmol) in MeOH (2 mL). The solution was stirred for 20 min and was then concentrated in vacuo to give potassium-4-methyl-1,4-dihydro-pyrrolo[3,2-b]pyrrole-2-carboxylate 12a as a grey solid (294 mg, 91%). 1H NMR (400 MHz, (CD3)2SO) δ (ppm) 9.80 (s, 1H) 6.58 (d, J=2.8 Hz, 1H) 6.10 (s, 1H) 5.70 (dd, J=2.8, 0.8 Hz, 1H) 3.55-3.57 (m, 3H).
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21]OS(C)(=O)=O)[N:19]=2)=[CH:11][CH:10]=1.ClCCl>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:16][C:17]([CH3:27])=[C:18]([CH2:20][CH2:21][N:3]3[CH2:2][CH2:7][CH2:6][CH2:5][CH2:4]3)[N:19]=2)=[CH:13][CH:14]=1
Reactant: CC1CCCCN1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Temperature: 60 °C
Yield: 70.2 %

Procedure:
Add 2-methyl piperidine (0.871 g, 8.77 mmol) to a solution of methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (0.316 g, 0.877 mmol) in tetrahydrofuran (5 mL) in a sealed tube, and heat at 60° C. overnight. Cool to room temperature and add dichloromethane. Wash the crude organic material with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate. Purify on silica gel eluting with 10% ammoniated methanol in dichloromethane to give (+/−)-1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.215 g, 67%): MS (m/e): 363 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][CH2:25][C:26](=O)[CH2:27][CH3:28].C(O)(=O)C>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[C:22]([NH:23][CH:26]([CH2:27][CH3:28])[CH2:25][CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCC(=O)CC
Solvent: CO
Solvent: CC(=O)O
Product: CCC(CC)Nc1cccnc1N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
Following the general procedure of PREPARATION 8 and making non-critical variations but starting with 1-[benzyloxycarbonyl]-4-[(3-amino)-2-pyridinyl]piperazine (PREPARATION 100 10.5 g), 3-pentanone (0.15 g) sodium cyanoborohydride (0.11 g), acetic acid (52.3 ml) and methanol (3.2), the title compound is obtained, NMR (300 MHz, CDCl3) 7.66, 7.38-7.33, 6.90, 6.79, 5.17, 4.21, 3.65, 3.15, 3.04, 1.66-1.46 and 0.93 δ.
Reaction SMILES: [ClH:1].C[O:3][C:4]1[C:9]([C:10]2[C:15]([O:16]C)=[CH:14][CH:13]=[C:12]([C:18](=[NH:26])[NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:11]=2)=[CH:8][C:7]([C:27](=[NH:35])[NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:6][CH:5]=1.Cl.N1C=CC=CC=1>O.Cl>[ClH:1].[OH:16][C:15]1[C:10]([C:9]2[C:4]([OH:3])=[CH:5][CH:6]=[C:7]([C:27](=[NH:35])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:8]=2)=[CH:11][C:12]([C:18](=[NH:26])[NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(C(=N)Nc2ccccc2)cc1-c1cc(C(=N)Nc2ccccc2)ccc1OC
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(Nc1ccccc1)c1ccc(O)c(-c2cc(C(=N)Nc3ccccc3)ccc2O)c1
Temperature: 180 °C
Reaction time: 16 h
Yield: 38.2 %

Procedure:
A mixture of 2.5 g of 6,6'-dimethoxy-N,N"-diphenyl-[1,1'-biphenyl]-3,3'-dicarboximidamide, monohydrochloride (see Example 1) and 25 g of dry pyridine hydrochloride is heated at 180° C for 75 minutes. The mixture is then cooled, diluted with 10 ml of water and acidified with 10 ml of concentrated hydrochloric acid. The mixture is further diluted with 100 ml of 10% hydrochloric acid and allowed to stand at 0° C for about 16 hours. The crystalline material so obtained is recrystallized from dilute HCl (10% hydrochloric acid and water until solution occurs at 100° C) to yield 900 mg of the title compound, melting point 306-307° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]=1[C:34](OC)=[O:35]>O1CCCC1>[OH:35][CH2:34][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][C:13]=1[CH3:12]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C
Yield: 72.5 %

Procedure:
To a suspension of lithium aluminum hydride (12.24 g) in a mixture of dry tetrahydrofuran (180 ml) and diethyl ether (360 ml) was dropwise added a solution of methyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (45 g) in dry tetrahydrofuran (180 ml) under cooling at -50°~-40° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. The separated organic layer was washed with 15% sulfuric acid (400 ml) and extracted with ethyl acetate (1 l). The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was recrystallized from diethyl ether to give 5-hydroxymethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)pyrimidine (30 g).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:7](F)=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10]>CC(N(C)C)=O.O.CCOCC>[N:1]([C:11]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][C:8]=1[C:9]#[N:10])=[N+:2]=[N-:3]
Reactant: N#Cc1cccc(F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: O
Product: N#Cc1cc(F)ccc1N=[N+]=[N-]
Temperature: 100 °C
Yield: 102.8 %

Procedure:
A mixture of NaN3 (1.17 g, 1.8 mmol) and difluorobenzonitrile (0.5 g, 3.6 mmol) in DMA (60 mL) was heated at 100° C. for 30 minutes. The mixture was next diluted with water (300 mL) and ether (300 mL). The organic layer was washed three times with water and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography using ether:hexane (1:5) as eluent to give the desired product (1q) as white crystals (0.3 g, 53% isolated yield). 1H NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.27-7.18 (m, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1.[CH2:13](N(CC)CC)[CH3:14].C(#N)C.C([Si](C)(C)C)#C>C(OCC)C.[Cu]I.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>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH2:10][O:11][CH3:12])[CH:3]=1)#[CH:14]
Reactant: COCOc1cc(I)ccc1C
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: CC#N
Product: C#Cc1ccc(C)c(OCOC)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Argon was bubbled into a mixture of the 4-iodo-2-methoxymethoxy-1-methyl-benzene (7.63 g, 27.5 mmol) (from example 18 supra), triethylamine (55 mL) (Aldrich) and acetonitrile (100 mL) in a pressure reactor for 20 minutes at room temperature. Ethynyltrimethylsilane (9.2 mL, 64.5 mmol) (Aldrich), copper(I) iodide (245 mg, 1.28 mmol) (Aldrich) and dichlorobis(triphenylphosphine)palladium(II) (911 mg, 1.29 mmol) (Aldrich) were added. Reactor was capped and mixture heated at 100° C. for 5 hours with magnetic stirring. After cooling to room temperature, mixture was suspended in diethyl ether (250 mL) and water (250 mL) and filtered through Celite®. Layers were separated. Organic layer washed with water (250 mL) and brine (250 mL). Aqueous layers were back washed with ether (250 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was dissolved in methanol (50 mL) and potassium carbonate (500 mg) was added. Mixture was stirred at room temperature overnight. After concentrating, residue was partitioned between diethyl ether (2×250 mL) and water (2×250 mL). Organic layers were washed with brine (200 mL), combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (Biotage 40 L, hexanes, then hexanes-dichloromethane 9:1 and 3:1 as solvent) to give 4-ethynyl-2-methoxymethoxy-1-methyl-benzene as a brown oil. (Yield 4.65 g, 96.2%).