Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl.[OH:27][C:28]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C:13]2[N:22]=[C:21]([C:23]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:28]=4[OH:27])[CH2:33]3)=[O:25])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2nc(C(=O)O)c3ccccc3n2)cc(OC)c1OC
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3cc(OC)c(OC)c(OC)c3)nc3ccccc13)C2
Yield: 18.9 %

Procedure:
Reaction of 2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 89 (18.9% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.77 and 2.90 (2t, 2H), 3.52 and 4.05 (2t, 2H), 3.74-3.80 (m, 6H), 3.87 and 3.92 (2s, 6H), 4.40 and 4.92 (2s, 2H), 6.31-6.92 (m, 2H), 7.67-8.17 (m, 6H), 8.70 and 8.73 (2s, 1H); MS (ESI) m/z 502 ([M+H]+).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:17][CH2:16][CH2:15][CH2:14][C:11]21[CH2:13][CH2:12]2)C1C=CC=CC=1.[H][H]>CO.CCOC(C)=O>[CH2:12]1[C:11]2([CH2:14][CH2:15][CH2:16][CH2:17][CH:10]2[CH2:9][OH:8])[CH2:13]1
Reactant: c1ccc(COCC2CCCCC23CC3)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCC1CCCCC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((benzyloxy)methyl)spiro[2,5]-octane (0.42 g, 1.8 mmol) in a 5:1 MeOH-EtOAc (12 mL) Pd/C (0.05 g, 5 wt %, 50% wet Degussa type) was added. The flask was fitted with a balloon of hydrogen, and the heterogeneous reaction mixture was stirred for 2 hours under a hydrogen atmosphere at rt. The catalyst solids were filtered off and the filtrate was concentrated under vacuum to give the desired product spyri[2.5]octan-4-ylmethanol as clear oil. 1H NMR (400 MHz, CDCl3) δ 3.74-3.62 (m, 2H), 3.48 (d, J=5.2 Hz, 2H), 1.65-1.59 (m, 2H), 1.51-1.43 (m, 3H), 1.27-1.24 (m, 1H), 1.12-1.11 (m, 1H), 0.96-0.95 (m, 1H), 0.41-0.37 (m, 1H), 0.29-0.17 (m, 3H). MS m/z 123.1 (M−17+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[NH:38][N:37]=[N:36][N:35]=2)=[CH:30][CH:29]=1.N1CCCCC1.O>CN(C=O)C>[NH:38]1[C:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:29][CH:30]=2)=[N:35][N:36]=[N:37]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Solvent: O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
Prepared by reacting 1-acetyl-3-{1-ethoxy-1-phenylmethylidene}-5-nitro-2-indolinone with 1.3 equivalents of 5-(4-amino-phenyl)-1H-tetrazole in DMF (125° C., for 2 hours), subsequent treatment with 6.7 equivalents of piperidine (20° C., 1 hour) and precipitation with water.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
2-Phenoxybenzoic acid (324 mg) was added gently to a suspension of lithium aluminum hydride (172 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. Water (1 mL) was added gently to the reaction mixture, and the resulting mixture was stirred for 30 minutes. The reaction mixture was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (256 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:23])([F:22])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C(O)(=O)C.[Na]>O1CCCC1.C(OCC)(=O)C>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccnc(NCc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.2 %

Procedure:
A solution of methyl 2-aminoisonicotinate (1.52 g, 10.00 mmol), 3-(trifluoromethyl)benzaldehyde (2.09 g, 12.00 mmol) and acetic acid (0.572 mL, 10.00 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 30 min. To this reaction mixture was added sodium triacetoxyhydroborate (4.46 g, 20.00 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-9/1) to give the title compound (1.06 g, yield 34%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=[CH:16][C:4]=2[NH:3]1.O=C1C2C=CC(C(O)=O)=CC=2SC2C=CC=CC=2[NH:22]1>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[C:14]([C:17]([NH2:22])=[O:19])[CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1C(=O)N2
Reactant: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1C(=O)N2

Procedure:
In a similar manner, substituting 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-7-carboxylic acid for the 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-3-carboxylic acid in Step A, there is obtained 10,11-dihydro-11-oxodibenzo[b,f][1,4]thiazepin-7-carboxamide. Carboxamides of 10,11-dihydrodibenzo[b,f][1,4]thiazepin-3(or 7)-carboxylic acid or dibenzo[b,f][1,4]thiazepin-3(or 7)-carboxylic acid are prepared by the process of Example 33, by substituting the desired 3(or 7) carboxylic acid for the starting material of Step A.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH3:21][C:22]1[C:23]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1>>[O:20]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:35]2[CH2:36][CH2:37][N:32]([C:23]3[C:22]([CH3:21])=[CH:27][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:25][N:24]=3)[CH2:33][CH2:34]2)=[O:13])=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 82.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazine (245 mg) described in Preparation Example 84 and by the reaction and treatment in the same manner as in Example 87, the title compound (449 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([O:16]C)=[O:15])[N:4]=1.[OH-].[Na+].O>C(O)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:13]=2[C:14]([OH:16])=[O:15])[N:6]=1
Reactant: COC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1

Procedure:
To a solution in ethanol (10 ml) of methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (3.0 g), an equimolar amount of an aqueous sodium hydroxide solution (30 ml) was added, and the mixture was reacted at room temperature for 12 hours under stirring. The reaction mixture was poured into water, and extracted with ethyl ether, and non-reacted starting materials were removed. Then, the aqueous phase was acidified with a 10% hydrochloric acid aqueous solution. The aqueous solution was then extracted with ethyl ether. The extract was washed with water and dried, and then the solvent was distilled off under reduced pressure to obtain the above identified compound as a white crystal (1.5 g). (Melting point: 133°-134° C.)
Reaction SMILES: [B:1]([Cl:4])(Cl)Cl.[OH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]>CCCCC>[Cl:4][B:1]1[O:12][C:9]([CH3:11])([CH3:10])[C:6]([CH3:8])([CH3:7])[O:5]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: ClB(Cl)Cl
Solvent: CCCCC
Product: CC1(C)OB(Cl)OC1(C)C
Temperature: 20 °C
Reaction time: 1 h

Procedure:
About 82 mL of BCl3 is added dropwise over 30 minutes to a stirred solution of dry pinacol in pentane (1.3 L) at −30° C. The reaction mixture is stirred at 20° C. for 1 hour. A solid byproduct, B2[(OCMe2)2]3 is removed by filtration. The remaining solution is distilled to give about 90 grams of 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([Br:1])[C:11]([CH2:12][Br:14])=[C:10]([Br:13])[CH:9]=1
Reactant: COC(=O)c1cc(Br)c(C)c(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(Br)c(CBr)c(Br)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 3,5-dibromo-4-methylbenzoate (150.0 g, 0.487 mol) in 2 L anhydrous CCl4 under a nitrogen atmosphere was added N-bromosuccinimide (125.7 g, 0.706 mol) and benzoyl peroxide (12.98 g, 0.054 mol). The solution was then heated to reflux. Once the solution reached reflux it was irradiated with a 250 W sun lamp. After 6 h the solution was cooled to RT and filtered. The precipitate (succinimde) was washed with DCM and the filtrate concentrated. The residue (ca. 246 g) was purified by silica gel chromatography (3 Kg SiO2) using 5 to 25% DCM/hexanes as the eluent to give methyl-4-bromomethyl-3,5-dibromo-benzoate. 1H NMR(CDCl3, 500 MHz): δ 3.93 (s, 3H), 4.84 (s, 2H), 8.21 (s, 2H). MS(ES) 385 (M+1); LC 1: 3.93 min.
Reaction SMILES: NCCN(CC)CCOC1C(F)=NC=CC=1.IC1C=CC2N(C=C(C(OCC)=O)N=2)C=1.[CH2:32]([N:34]([CH2:45][CH2:46][NH:47][C:48]([C:50]1[CH:59]=[N:58][C:57]2[C:52](=[CH:53][CH:54]=[C:55]([I:60])C=2)[N:51]=1)=[O:49])[CH2:35][CH2:36][O:37][C:38]1[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=1)[CH3:33]>>[CH2:32]([N:34]([CH2:45][CH2:46][NH:47][C:48]([C:50]1[N:51]=[C:52]2[CH:53]=[CH:54][C:55]([I:60])=[CH:57][N:58]2[CH:59]=1)=[O:49])[CH2:35][CH2:36][O:37][C:38]1[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=1)[CH3:33]
Reactant: CCN(CCNC(=O)c1cnc2cc(I)ccc2n1)CCOc1cccnc1F
Agent: CCN(CCN)CCOc1cccnc1F
Agent: CCOC(=O)c1cn2cc(I)ccc2n1
Product: CCN(CCNC(=O)c1cn2cc(I)ccc2n1)CCOc1cccnc1F
Yield: 58 %

Procedure:
This compound was prepared, starting from compound 5 (100 mg, 0.44 mmol) and ethyl 6-iodoimidazo[1,2-a]pyridine-2-carboxylate (75) (197 mg, 0.62 mmol) (Sunberg, R. J.; Biswas, S.; Murthi, K. K.; Rowe D.; McCall, J. W.; Dzimianski, M. T. Bis-cationic heteroaromatics as macrofilaricides: synthesis of bis-amidine and bis-guanylhydrazone derivatives of substituted imidazo[1,2-a]pyridines. J. Med. Chem. 1998, 41, 4317-4328.), according to the procedure developed for compound 10. Reaction time under reflux: 12 h; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 98/2, v/v) to give compound 76 (180 mg, 0.36 mmol) as a yellow oil. Yield 58%; Rf (Al2O3, CH2Cl2/EtOH, 98/2, v/v) 0.61; IR (CCl4) ν 1249, 1283, 1466, 1564, 1669, 2800-3000, 3411 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.08 (t, 3H, J=7.1 Hz), 2.71 (q, 2H, J=7.1 Hz), 2.81 (t, 2H, J=6.0 Hz), 2.97 (t, 2H, J=5.9 Hz), 3.55 (q, 2H, J=6.0 Hz), 4.11 (t, 2H, J=5.9 Hz), 6.98 (dd, 1H, J=4.8, 7.8 Hz), 7.23 (d, 1H, J=9.6 Hz), 7.31 (m, 1H), 7.34 (dd, 1H, J=1.6, 9.6 Hz), 7.64 (td, 1H, 4JH-F=1.5 Hz, J=1.5, 4.8 Hz), 7.77 (m, 1H), 8.09 (s, 1H), 8.43 (se, 1H); ESI-MS m/z 497.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:32])[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)=[C:10]([CH:17]([CH3:19])[CH3:18])[NH:11]2.Cl[CH:35]([F:37])[F:36]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:32][CH:35]([F:37])[F:36])=[C:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[N:28]3)=[CH:23][CH:22]=1)[C:10]([CH:17]([CH3:19])[CH3:18])=[N:11]2
Reactant: FC(F)Cl
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(=O)c12
Product: COC(=O)COc1ccc(F)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(OC(F)F)c12

Procedure:
The title compound was prepared by the method of Preparation 10c using [8-fluoro-2-isopropyl-4-oxo-3-(4-pyrazol-1-ylbenzyl)-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester and chlorodifluoromethane.
Reaction SMILES: [F:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[C:4]([CH2:5][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(F)c1N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(F)c2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 121.4 %

Procedure:
A 50 mL round-bottom flask was charged with 3-fluoro-2-(morpholin-4-yl)benzaldehyde (0.500 g, 2.39 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (404 mg, 2.17 mmol, 0.91 equiv), dichloromethane (10 mL). The mixture was stirred at room temperature for 0.5 hour. Sodium triacetoxyborohydride (1.38 g, 6.51 mmol, 2.72 equiv) was added. The resulting solution was stirred overnight at room temperature and diluted with dichloromethane. The resulting mixture was washed with H2O (3×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/3) to yield 1.00 g (crude) of tert-butyl 4-[[3-fluoro-2-(morpholin-4-yl)phenyl]methyl]piperazine-1-carboxylate as colorless oil. LCMS (ESI, m/z): 380 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:11]2/[C:10](=[O:15])[CH2:14][CH2:13][CH2:12]/2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCCC1
Product: O=C1CCC/C1=C\c1ccc(O)cc1

Procedure:
The procedure was similar to that in Example 4 by reacting 4-hydroxybenzaldehyde with the morpholine enamine of cyclopentanone to give 2-(E)-[(4-hydroxy) benzylidene]cyclopentanone. The melting point of this intermediate compound was determined to be 188°-190° C. A subsequent Mannich reaction yielded the 2-Dimethylaminomethyl-5-(E)-[(4-hydroxy) benzylidene] cyclopentanone hydrochloride. The melting point of the product was determined to be 174°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]2=[C:11]([OH:13])[CH:12]=1.[N+](C1C=C(C=CC=1)O[CH2:21][C@@H:22]1[CH2:24][O:23]1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[O:23]1[CH2:24][C@H:22]1[CH2:21][O:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=12
Reactant: COc1cc(O)c2nc(C)oc2c1
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(OC[C@@H]2CO2)c2nc(C)oc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.6 %

Procedure:
A suspension of 6-methoxy-2-methyl-1,3-benzoxazol-4-ol (0.11 g, 0.60 mmol), (2S)-2-[(3-nitrophenoxy)methyl]oxirane (0.16 g, 0.79 mmol) and cesium carbonate (0.44 g, 1.37 mmol) in dry DMF (4 mL) was stirred at room temperature for 5 hours. After aqueous work-up the crude product was purified by flash chromatography (SiO2, toluene-ethyl acetate, 3:1) to afford the subtitle compound (0.118 g, 83.7%).
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]CC)=[O:10])[CH2:5][CH2:4]1.[CH2:16]=[C:17](N1CCOCC1)[CH2:18][CH3:19].C(N(CC)CC)C>ClCCl>[CH2:18]([C:17]1[O:15][N:14]=[C:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]2)[CH:16]=1)[CH3:19]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: C=C(CC)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc([C@H]2CC[C@H](C(=O)O)CC2)no1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (2.35 g, 10.1 mmol) and 4-(1-methylene-propyl)-morpholine (4.26 g, 30.2 mmol) in dichloromethane (100 ml) was added triethylamine (1.40 ml, 10.1 mmol at 0-5° C. The cooling bath was removed 30 minutes after completed addition. After stirring for 20 h the solvent was evaporated. The residue was redissolved in 6 M aqueous hydrochloric acid solution (100 ml), and the mixture was heated at reflux for 3 h. After cooling to room temperature the reaction mixture was partitioned between crushed ice (300 g) and ethyl acetate (100 ml). The layers were separated. The aqueous layer was extracted with two 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification with n-heptane/tert-butyl methyl ether as eluent gave the title compound (0.42 g, 19%) as white solid. MS m/e: 222 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:14])=[N:8][C:9](O)=[N:10]2)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:17]>O>[Cl:17][C:9]1[N:8]=[C:7]([CH3:14])[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: COc1ccc2c(C)nc(O)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc2c(C)nc(Cl)nc2c1
Temperature: 100 °C
Yield: 60 %

Procedure:
To 7-methoxy-4-methylquinazolin-2-ol was added POCl3 and the mixture was added heated to 100° C. for 16 h when the reaction went to completion. To the reaction mixture was added ice and water and the precipitated solid was filtered and dried on the high vacuum overnight to give 2-chloro-7-methoxy-4-methylquinazoline in 60% yield. ES/MS m/z 209 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].C([O-])([O-])=O.[K+].[K+].Br[CH:21]([CH3:23])[CH3:22].C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:5]=[CH:4][C:3]=1[O:13][CH:21]([CH3:23])[CH3:22]
Reactant: Oc1ccc(OC(F)(F)F)cc1Br
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 2-bromo-4-trifluoromethoxyphenol (Description 11; 1 g, 3.9 mmol) and K2CO3 (1.1 g, 7.8 mmol) in dimethylformamide (15 ml) was added 2-bromopropane (0.55 ml, 5.9 mmol). The solution was stirred for 14 h. at room temperature under an atmosphere of nitrogen. Waster (200 ml) and ethyl acetate (3×70 ml) was added to the solution and the organic phase washed with water (100 ml), brine (100 ml) and dried (MgSO4). The solvent was removed in vacuo and the residue purified by chromatography on silica gel (eluting with 5% ethyl acetate in hexane) to give the title compound. 1H NMR (250 MHz, CDCl3) δ1.38 (6H, d, J 6.1 Hz), 4.53 (1H, m), 6.88 (1H, d, J, 9 Hz), 7.12 (1H, dd, J 8.8, 2.6 Hz), and 7.43 (1H, d, J 2.8 Hz).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)=[N+]=[N-].[H][H]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1
Reactant: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nc(CN)n(C)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 68.4 %

Procedure:
In 8 ml of ethanol was dissolved 150 mg (0.44 mmol) of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60), and 50 mg of 10% palladium carbon was added at -20° C. The mixture was stirred at room temperature under a stream of hydrogen. After 4 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated to give 94 mg of Compound I-101 (yield 68%).
Reaction SMILES: [C:1]([C:3](=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:22]1([CH3:30])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Mg]Br.N#N>[Cu](I)I.C1COCC1>[C:1]([CH:3]([C:9]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:30])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)C(C#N)=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccccc1[Mg]Br
Agent: I[Cu]I
Agent: N#N
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C1(c2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (196 mg, 0.667 mmol), copper iodide (39 mg, 0.3 equiv) and dry THF (4 mL) was degassed and recharged with N2 gas (3×), and cooled to 0° C. A solution of o-tolylmagnesium bromide (2.0 M in ether, 600 μL, 1.8 equiv) was added dropwise. The mixture was stirred 1 h at 0° C. under protection of N2 gas before being warmed to rt slowly and stirred 2 h at rt. LC-MS found the reaction was complete. The mixture was cooled to 0° C. again, quenched with 2% aq HCl to pH=˜5, extracted with EtOAc (3×35 mL). The combined organic layers were washed with satd NH4Cl (10 mL) and brine (10 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge, eluted with a 0 to 30% EtOAc in hexanes gradient, to afford tert-butyl 4-(1-cyano-2-ethoxy-2-oxoethyl)-4-o-tolylpiperidine-1-carboxylate (226 mg, 88%) as a clear oil.
Reaction SMILES: C(S)CCC.[CH2:6]([N:8]([CH2:27][CH3:28])[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[C:22]([CH:23]=[C:14]2[C:13]([NH2:26])=[N:12]1)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=3)[CH3:7].[H-].[Na+].Cl.CN(C)C=[O:35]>>[NH2:26][C:13]1[NH:12][N:11]([CH2:10][CH2:9][N:8]([CH2:6][CH3:7])[CH2:27][CH3:28])[C:15]2[C:14]=1[CH:23]=[C:22]1[C:17](=[CH:18][C:19]([O:24][CH3:25])([OH:35])[CH:20]=[CH:21]1)[N:16]=2
Reactant: CCN(CC)CCn1nc(N)c2cc3ccc(OC)cc3nc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCS
Product: CCN(CC)CCN1NC(N)=c2cc3c(nc21)=CC(O)(OC)C=C3

Procedure:
Butanethiol (5.34 ml) was added to a mixture of 13.0 g 1-[2-(diethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine (Example 22) and 2.0 g sodium hydride in 150 ml dimethylformamide, and the reaction mixture was heated at reflux for about 16 hours. The resulting mixture was treated with 2N hydrochloric acid to pH 7-8, the volatile materials removed by distillation and evaporation, and the residue acidified with 2N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was made strongly basic, extracted to remove starting material, and finally adjusted to PH 8 to obtain the desired product. There was obtained 2.5 g of 3-amino-1-[2-(diethylamino)ethyl]-7-methoxy-1H-pyrazolo[3,4-b]quinolin-7-ol, orange solid, m.p. 232°-235° C.