Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2](=C)[CH2:3][CH2:4][CH:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[OH:6].[OH-].[Na+].Cl.[CH3:21]N(C)C=O>>[CH3:21][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)([CH2:4][C:3]#[CH:2])[OH:6]
Reactant: C=C(I)CCC(O)c1cccc2ccccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C#CCC(C)(O)c1cccc2ccccc12

Procedure:
5.00 Grams of 2-iodoallylmethyl-α-naphthylcarbinol were dissolved in 50 g of dimethylformamide, and 1.18 g of sodium hydroxide in a flake form were added. The resultant mixture was stirred at room temperature for 8 hours. After the reaction was completed, the reaction mixture was neutralized with concentrated hydrochloric acid, insolubles were filtered off, and the remaining filtrate was concentrated under reduced pressure. The concentration residue was subjected to extraction with toluene, and washed with a 7% sodium carbonate aqueous solution. Then, the toluene was distilled off under reduced pressure to give 2.77 g of methyl-α-naphthylpropargylcarbinol; nD25 =1.5141, FI-MS m/e 210 (M) (Propargyl compound/allene compound 100.0/0.0).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[CH3:28][NH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8](=[O:27])[N:29]([C@H:30]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]3)[CH3:28])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CN[C@H]1CC[C@H](O)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N(C)[C@H]3CC[C@H](O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with trans-4-methylamino-cyclohexanol and pyridine in chloroform. [α]D20=+20.5° (c=1.02, CHCl3), ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: C([O:3][C:4](=O)[NH:5][N:6]=[CH:7][C:8]1[N:9]=[C:10]([CH2:13][O:14][CH3:15])[NH:11][CH:12]=1)C.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:15][O:14][CH2:13][C:10]1[N:9]2[C:4](=[O:3])[NH:5][N:6]=[CH:7][C:8]2=[CH:12][N:11]=1
Reactant: CCOC(=O)NN=Cc1c[nH]c(COC)n1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COCc1ncc2cn[nH]c(=O)n12

Procedure:
A mixture of 25.9 gm. of 3-{[2-(methoxymethyl)-4-imidazolyl]methylene}carbazic acid ethyl ester and 125 ml. of diphenyl ether is reacted as described in Example 70 giving the desired product, m.p. 200°-205° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:38])[CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:36][CH3:37])[C:32]([O:34][CH3:35])=[CH:33][C:7]=2[N:6]=1
Reactant: COc1cc2nc(CCC(C)C)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(CCC(C)C)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1OC

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(3-methylbutyl)-5,6-dimethoxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[CH:4][CH:3]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.O>N1C=CC=CC=1>[S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[CH:3][CH:4]=1)[C:9]#[N:10]
Reactant: N#CSc1ccc(N)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SC#N)cc2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 4-Aminophenyl thiocyanate (10.0 g (66.6 mmol)) in pyridine (70 ml), p-toluenesulfonyl chloride (12.7 g (66.6 mmol)) was added with stirring at room temperature, and the mixture was stirred at room temperature for 16 hours. Then, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 19.4 g (98%) of 4′-thiocyano-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:3]2[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1C
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(F)cc2)c1C
Yield: 32 %

Procedure:
Using ethyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate (500 mg), sodium hydride (60% in oil, 175 mg) and 4-fluorobenzenesulfonyl chloride (848 mg), a procedure as in Reference Example 4 was performed to give the title compound as a brown oil (yield 270 mg, 32%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:25])(=O)C.[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][N:30]([S:38]([CH3:41])(=[O:40])=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[CH3:26][N:27]([CH3:42])[CH2:28][CH2:29][N:30]([C:31]1[CH:32]=[CH:33][C:34]([NH:37]/[C:17](=[C:6]2\[C:5](=[O:25])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:35][CH:36]=1)[S:38]([CH3:41])(=[O:40])=[O:39]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccc(C(F)(F)F)cc21
Product: CN(C)CCN(c1ccc(N/C(=C2\C(=O)Nc3cc(C(F)(F)F)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([N+:20]([O-])=O)=[CH:13][CH:12]=3)=[O:5])[CH3:2].O1CCCC1>C(O)C.[C].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc([N+](=O)[O-])cc3c2c1C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Reaction time: 3.5 h
Yield: 88.9 %

Procedure:
1.02 g of 4-methyl-6-nitro-β-carbolin-3-carboxylic acid ethyl ester is dissolved or suspended in 30 ml of ethanol and 6 ml of tetrahydrofuran and, after the addition of 150 ml of palladium-carbon (10%), is hydrogenated at 24° C. and normal pressure. Within 3.5 hours, 210 ml of hydrogen is absorbed. The solution is filtered off and the catalyst and the solvent is distilled off in vacuo. The crude product is recrystallized from methanol-chloroform. 816 mg of 6-amino-4-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 225°-238° C. (decomposition) is obtained.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.[NH2:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.N>>[Br:19][C:17]1[CH:18]=[C:13]([NH:12][C@@H:4]2[CH:5]3[CH2:10][N:1]4[CH2:8][CH:7]([CH2:9][CH:3]2[CH2:2]4)[CH2:6]3)[CH:14]=[N:15][CH:16]=1
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: Nc1cncc(Br)c1
Agent: N
Product: Brc1cncc(NC2C3CC4CC2CN(C4)C3)c1

Procedure:
Prepared from 1-azatricyclo[3.3.1.13,7]decan-4-one (1.51 g, 10 mmol; see Becker, D. P.; Flynn, D. L. Synthesis 1992, 1080) and 3-amino-5-bromopyridine (2.06 g, 12 mmol; Aldrich) according to the procedure described in Example 65A: 1H NMR (300 MHz, methanol-D4) δ ppm 1.81-1.99 (m, 2H), 2.02-2.15 (m, 1H), 2.17-2.40 (m, 4H), 3.44-3.51 (m, 2H), 3.53-3.66 (m, 4H), 3.91 (s, 1H), 7.26-7.41 (m, 1H), 7.84 (d, J=1.7 Hz, 1H), 8.01 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/z=308/310 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:12][CH2:11][C:10](=[O:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>C1COCC1>[F:18][C:19]([F:29])([F:30])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH2:6][CH2:5][C:4]3([CH2:12][CH2:11][C:10](=[O:13])[C:9]4[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=4[NH:7]3)[CH2:3][CH2:2]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: O=C1CCC2(CCNCC2)Nc2ccccc21
Solvent: C1CCOC1
Product: O=C1CCC2(CCN(Cc3ccc(OC(F)(F)F)cc3)CC2)Nc2ccccc21
Reaction time: 12 h
Yield: 68.2 %

Procedure:
A solution of diamine 11 (5 mg, 0.022 mmol) in anhydrous THF (0.2 mL), KF-Celite (12.6 mg, 0.109 mmol), and 4-trifluoromethoxybenzyl bromide (5.22 μL, 0.033 mmol) was agitated at RT for 16 h. The reaction was filtered and piperidinomethyl polystyrene N-2-(mercaptoethyl) aminoethyl polystyrene (26 mg, 0.033 mmol) was added to the filtrate. The reaction was agitated for another 12 h and then filtered. The filtrate was concentrated to yield 18 (6 mg, 0.015 mmol, 68%) as an oil. LRMS: M+=403.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:16])[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[CH2:9]([C:5]1[C:6]([Cl:19])=[N:7][C:2]([NH2:1])=[N:3][C:4]=1[CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(N)nc(O)c1Cc1ccccc1
Product: Cc1nc(N)nc(Cl)c1Cc1ccccc1
Temperature: 90 °C
Yield: 53.7 %

Procedure:
A mixture of 2-amino-5-benzyl-6-methylpyrimidine-4-ol (1.2 g, 5.57 mmol) and phosphorous oxychloride (9 ml) was kept to warm at 90° C. for 6 hours. The reaction mixture was concentrated in vacuo. Ice-water was added to the residue and an aqueous ammonia was cautiously added thereto. The solution was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (chloroform: ethyl acetate=8:2) to give the object compound (700 mg, 53.7%).
Reaction SMILES: Br[CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1>O.C1COCC1>[CH2:2]=[C:3]1[O:4][CH2:5][CH:6]2[CH:10]([O:9][C:8]([CH3:14])([CH3:13])[O:7]2)[CH2:11][O:12]1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Solvent: C1CCOC1
Solvent: O
Product: C=C1OCC2OC(C)(C)OC2CO1
Yield: 69 %

Procedure:
0.943 mol (105.8 g) of potassium tert.butylate were dissolved in 800 ml of water-free THF. A solution of 865 mmol (231 g) of 4-bromomethyl-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane in 800 ml of THF were added dropwise within 90 minutes with stirring and the mixture was subsequently heated for 6 h under reflux. The resulting KBr was filtered and the THF was subsequently distilled under a filter pump vacuum. The dark brown residue underwent fractional distillation under vacuum. 111.2 g of colourless clear 4-methylene-9,9-dimethyl-3,5,8,10-tetraoxabicyclo[5.3.0]decane (yield 70%) go over at between 45° and 49° C. (0.2 mbar).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN1CCCC1.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:14][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)c2ccccc12
Reactant: COC(=O)CBr
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccc([N+](=O)[O-])c2ccccc12
Temperature: 70 °C
Reaction time: 5 h
Yield: 325.7 %

Procedure:
4-Nitronaphthalen-1-ol (0.70 g, 3.7 mmol) in N-methylpyrrolidine (6 ml) is treated with potassium carbonate (1.0 g) and methyl bromoacetate (0.169 g, 1.1 eq). The mixture is stirred at 70° C. for 5 h. The mixture is then diluted with water and extracted with ethyl acetate. The organic layer is repeatedly washed with water, dried over Na2SO4, and evaporated to dryness to provide (4-nitronaphthalen-1-yloxy)-acetic acid methyl ester (0.94 g). MS: 262 (M+1).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][N:11]=[N:10]1.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CS(C)=O.O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:9]1[CH:13]=[CH:12][N:11]=[N:10]1
Reactant: c1c[nH]nn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnn2)c(F)c1
Temperature: 90 °C
Yield: 50 %

Procedure:
A slurry of dibasic potassium phosphate, 38.0 g (0.218 mol), and 1H-1,2,3-triazol, 7.53 g (6.3 mL, 0.109 mol), in 325 mL dimethylsulfoxide was treated dropwise with 3,4-difluoronitrobenzene, 17.3 g (12.1 mL, 0.109 mol), with heating to 90° C. for 18 h. The mixture was cooled to room temperature, diluted with water (500 mL) and extracted with ethyl acetate (4×50 miL). Drying (Na2SO4) and concentrating in vacuo afforded a light yellow solid. This material was chromatographed over 600 g 230-400 mesh silica gel eluting with methylene chloride, 1% (v:v), 2% (v:v) and 5%(v:v) methanol-methylene chloride to afford 11.38 g (50%) of 3-Fluoro-1-nitro-4-(1H-1,2,3-triazol-1-yl)benzene as a light yellow solid, mp=123-124.5° C., along with 9.66 g (43%) of regioisomer 3-Fluoro-1-nitro-4-(2H-1,2,3-triazol-2-yl)benzene as a light yellow solid, mp 137-139° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][C:31](O)=[O:32]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:31](=[O:32])[CH2:30][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:20]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1ccc2ccccc2c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product from Example 86A and 2-(2-naphthyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.96-8.04 (m, 2H), 7.86-7.94 (m, 4H), 7.72-7.75 (m, 1H), 7.61-7.66 (m, 4H), 7.50-7.57 (m, 3H), 3.88 (s, 2H); MS (APCI+) M/Z 440 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[S:26][C:25]([C:27](O)=[O:28])=[N:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:25]3[S:26][C:22]([CH3:21])=[CH:23][N:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: Cc1cnc(C(=O)O)s1
Product: Cc1cnc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)s1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 5-methyl-2-thiazolecarboxylic acid, as starting materials, MS (LC/MS): 428.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]=CN(C)C)[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].C[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:19]([C:17]#[N:18])[C:20](=[O:21])[NH:22][C:9]=2[CH3:10])=[CH:4][CH:3]=1
Reactant: N#CCC(N)=O
Reactant: CC(=O)C(C=CN(C)C)c1ccc(F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 90.1 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-(dimethylamino)ethenyl-2-propanone (59.6 grams), cyanoacetamide (26.7 grams) and sodium methoxide (34.3 grams) in 830 ml of dimethylformamide is heated under reflux for two hours and then the reaction mixture is concentrated on a rotary evaporator. The residual solid is suspended in water (2 liters) and is stirred overnight. The aqueous mixture is acidified with 12 N HCl, diluted with water to a volume of 4 liters, and stirred for two hours. The solid product is collected, washed with water (500 ml) and then with ethanol to give 55.4 grams of 1,2-dihydro-5-(4-fluorophenyl)-6-methyl-2-oxo-3-pyridinecarbonitrile.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[N:5]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([N:8]1[CH2:7][CH2:6][N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][CH2:9]1)[C:2]#[CH:3]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: C#CCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Propargyl bromide (356.9 mg, 3 mmol) was slowly added to a mixture of tert-butyl 1-piperazinecarboxylate obtained in step 2(i) above (558.8 mg, 3 mmole) and diisopropylethylamine (407.1 mg, 3.15 mmol) in CHCl3 (25 ml) at 0° C. The mixture was stirred for 24 h at room temperature. 50 ml of CHCl3 was then added and the solution was washed with 5% NaHCO3 (3×50 ml), brine (2×50 ml), and then dried over Na2SO4. The solution was filtered and evaporated to dryness. The residue was crystallized from a mixture of benzene-hexane (1:1) to give tert-butyl 4-propargylpiperazine-1-carboxylate (D6) (crude 337 mg, 86%). H1 NMR (250 MHz, CDCl3): 1.42 (s, 9H), 2.22 (s, 1H), 2.46 (s, 4H), 3.26 (s, 2H), 3.41 (s, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cc(N)cc(OC)c1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 3,5-dimethoxyaniline (26 mg, 0.172 mmol) similar to Example 180 and was isolated as a light yellow solid (16 mg, 37% yield). 1H NMR (CDCl3): 8.85 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d, J=6.9 Hz, 1H), 7.89 (ddd, J=9.3, 7.5, 1.5 Hz, 1H), 7.65 (brs, 1H), 7.45 (dd, J=9.3, 4.5 Hz, 1H), 7.09 (s, 1H), 6.51 (d, J=1.8 Hz, 1H), 6.37 (t, J=1.8 Hz, 1H), 3.93 (s, 6H).
Reaction SMILES: Br[Mg][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C1COCC1.CCOCC>[O:9]1[C:5]2[CH:4]=[C:3]([C:12](=[O:14])[CH3:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: CC(=O)OC(C)=O
Reactant: Br[Mg]c1ccc2c(c1)OCC2
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of bromo(2,3-dihydro-1-benzofuran-6-yl)magnesium (prepared from 6-bromo-2,3-dihydro-benzofuran (2.50 g, 12.56 mmol) and Mg (0.336 g, 13.8 mmol)) in THF (10 mL) was dropwise added to a solution of acetic anhydride (2.40 mL, 25.4 mmol) in Et2O (10 mL) held at −78° C. The reaction mixture was stirred at −78° C. for 1 h before the temperature was allowed to reach −10° C. over a period of 1 h. The reaction mixture was quenched by the addition of NH4Cl (aq, saturated, 20 mL) and the resulting mixture was extracted twice with Et2O (2×10 mL). The organic extracts were pooled, washed with NaOH (aq, 5%, 10 mL) and brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[O:20][CH3:21])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:30].S.[OH-].[Na+]>C(O)C.C1(C)C(C)=CC=CC=1>[C:1]1([C:7]2[S:30][C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])=[CH:9][C:8]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)c(OC)c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1ccc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)c(OC)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 61.9 %

Procedure:
In a 1-l stainless steel autoclave were placed 56.2 g (0.150 mole) of 1,2-diphenyl-4-(2,4-dimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 33.3 g (0.075 mole) of phosphorus pentasulfide and 120 g of hydrogen sulfide. The contents of the autoclave were stirred at 160°-162° C. (1040-1080 psig) for three hours. The autoclave was then cooled, and the remaining hydrogen sulfide was vented into a trap of aqueous sodium hydroxide. The residue was stirred with 150 ml of absolute ethanol to destroy excess phosphorus pentasulfide. Chilling to -78° C. and filtration gave 27.6 g (49.4%) of crude product, m.p. 107°-110° C. Recrystallization from 30 ml of dioxane and 60 mll of ethanol gave 17.3 g (31%) of pure 2,3-diphenyl-5-(2,4-dimethoxyphenyl)thiophene, m.p. 112°-114° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1(C)C=CC=CC=1>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([N:21]2[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]3[N:7]=[C:6]([NH2:30])[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=3)[CH3:16])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:39])[CH:32]=1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: O=C=Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)Nc4cccnc4)CC3)nc(N)c2cc1OC

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (340 mg) in dichloromethane (5 mL) was slowly added dropwise with stirring a dilute solution of 3-pyridylisocyanate in toluene. The progress of the reaction was monitored by TLC. After completion of the reaction, aq. sodium carbonate was added and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid pyridin-3-ylamide 15, MS: 528 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 242 mg of the hydrochloride salt.
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1.O.Cl.[CH3:15][O:16][CH2:17][CH2:18][OH:19]>>[CH3:15][O:16][CH2:17][CH2:18][O:19][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([NH2:12])[N:4]=1
Reactant: COCCO
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1nc(N)c2[nH]cnc2n1
Yield: 73 %

Procedure:
After sodium (3.00 g, 130 mmol) was dissolved in 2-methoxyethanol (150 ml), thereto was added 2-chloroadenine (3.00 g, 17.69 mmol) and the mixture was refluxed for 8 hours. After the mixture was allowed to cool, water (400 ml) was added thereto and neutralized with concentrated hydrochloric acid. The resulting precipitate was filtered and washed with methanol to give the captioned compound (3.06 g, 14.48 mmol, yield 73%) as a white solid.