Azzindani/Open_Reaction_Data huggingface dataset:
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]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2[C:27]([OH:29])=O.Cl.[F:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][CH:41]=1)[CH2:38][NH:37][CH2:36][CH2:35]2>>[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]([C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1)[N:7]=[C:6]2[C:27]([N:37]1[CH2:36][CH2:35][C:34]2[C:39](=[CH:40][CH:41]=[C:32]([F:31])[CH:33]=2)[CH2:38]1)=[O:29]
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)O)c2cc1OC
Reactant: Fc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(C(=O)N3CCc4cc(F)ccc4C3)c2cc1OC
Yield: 56.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline-4-carboxylic acid with 6-fluoro-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 120 (56.2% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.93 and 3.09 (2t, 2H), 3.51-4.05 (m, 17H), 4.47 and 4.98 (2s, 2H), 6.91-7.42 (m, 4H), 7.48 and 7.51 (2s, 1H), 7.78 and 7.83 (2s, 2H); MS (ESI) m/z 534 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]#[C:4][C:5]([F:8])([F:7])[F:6].[CH3:11][C:12]1[O:13][CH:14]=[CH:15][CH:16]=1>>[CH3:11][C:12]12[O:13][CH:14]([CH:15]=[CH:16]1)[C:3]([C:2]([F:10])([F:9])[F:1])=[C:4]2[C:5]([F:8])([F:7])[F:6]
Reactant: Cc1ccco1
Reactant: FC(F)(F)C#CC(F)(F)F
Product: CC12C=CC(O1)C(C(F)(F)F)=C2C(F)(F)F
Yield: 91.4 %

Procedure:
Hexafluoro-2-butyne (21.0 g, 0.13 mol) was transferred into a reaction bottle and 2-methylfuran (12.86 g, 0.157 mol) was added. This resulting mixture bottle was sealed and heated for 15 hr. at 120° C. After cooling, the excess 2-methylfuran was rotoevaporated in vacuo at rt, to give crude title product (29 g, 92%), which was used directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:26][C:25]3[C:16](=[CH:17][C:18]4[CH2:19][CH:20]([C:36](O)=[O:37])[N:21]([C@H:27]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH2:28][CH3:29])[CH2:22][C:23]=4[CH:24]=3)[N:15]([CH3:39])[C:14]2=[O:40])=[CH:9][CH:8]=1.[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH2:65])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:66])[C@:48]([NH:65][C:36]([CH:20]1[CH2:19][C:18]2[CH:17]=[C:16]3[C:25]([O:26][C@@H:13]([C:10]4[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]5[CH:41]=[CH:42][C:43]([Cl:44])=[C:2]([Cl:1])[CH:3]=5)=[CH:12][CH:11]=4)[C:14](=[O:40])[N:15]3[CH3:39])=[CH:24][C:23]=2[CH2:22][N:21]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:37])([CH3:64])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][C:59]([C:62]#[N:63])=[CH:58][CH:57]=2)=[CH:52][CH:51]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)O)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@](C)(N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2CC1C(=O)N[C@@](C)(Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carboxylic acid (31.6 mg) was coupled with (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-2-methyl-propionic acid methyl ester (14.7 mg) following general procedure 0 to provide (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (LC-MS (m/z): 909). Title compound was prepared from (S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-2-methyl-propionic acid methyl ester (25 mg) following general procedure B. LC-MS (m/z): 893.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([OH:35])=O)(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:50][NH:51][CH3:52]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:19]=3[CH2:20][CH2:21][CH2:22][C@H:23]4[NH:28][S:29]([CH2:32][C:33]([N:51]([CH3:52])[CH3:50])=[O:35])(=[O:31])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CNC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(=O)(=O)CC(=O)N(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Prepared using General Procedure 9: To a stirring solution of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl) acetic acid 34 (15 mg, 0.05 mmol) in DMF (0.5 mL) was added N-hydroxybenzotriazole (6.1 mg, 0.05 mmol) and EDC (8.7 mg, 0.05 mmol). After 5 min, dimethylamine (40 wt % solution in THF, 50 μL, 0.09 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The crude reaction was diluted with sat NaHCO3 and extracted with EA. The combined organic layers were dried over Na2SO4 and purified by preparative HPLC to give 4.41 mg (28%) of (R)-2-(N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)sulfamoyl)-N,N-dimethylacetamide 40. LCMS-ESI (m/z) calculated for C26H29N5O5S: 523.6; found 546.2 [M+Na]+, tR=3.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.2 Hz, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.36 (t, J=17.3 Hz, 1H), 4.88-4.73 (m, 2H), 4.27 (d, J=14.6 Hz, 1H), 4.07 (d, J=14.6 Hz, 1H), 3.24-3.09 (m, 4H), 3.09-2.97 (m, 4H), 2.23-2.08 (m, 2H), 2.10-1.84 (m, 2H), 1.47 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.75, 169.37, 163.15, 162.77, 137.79, 136.92, 134.13, 133.90, 132.50, 130.18, 126.36, 126.17, 116.79, 115.25, 113.55, 103.96, 72.74, 55.46, 53.05, 38.22, 35.98, 29.84, 28.10, 21.73, 19.10.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH:14]([F:19])[C:15]([F:18])([F:17])[F:16])([O-])=O.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>[Fe].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH:14]([F:19])[C:15]([F:17])([F:18])[F:16]
Reactant: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CCO
Product: Nc1ccc(OC(F)C(F)(F)F)c(N)c1
Reaction time: 2 h

Procedure:
89 g (0.31 moles) 2,4-dinitrotetrafluoroethoxybenzene, according to Step 1, 125 ml of a 50% aqueous solution of ethanol and 106.5 g iron powder (1.91 moles) are heated to 60°-70° C. in a water bath in a three-necked flask, which is equipped with a reflux condensor, drop addition funnel, stirrer and internal thermometer. Next, a solution of 6.5 ml concentrated hydrochloric acid in 30 ml 50% aqueous solution of ethanol is added dropwise so that the reduction takes place accompanied by reflux and gentle boiling. When the addition is terminated it is then stirred for 2 hours accompanied by reflux, allowed to cool and neutralized with alcoholic potassium hydroxide. Unconverted iron and iron oxides are vacuum filtrated, accompanied by rewashing with ethanol. The solution is concentrated and the residue is distilled in the vacuum. 40 g (57% of the theoretical yield) of the free base is obtained which has a boiling range of 114°-117° C. at 106 Pascal. This product can be transformed into dihyrochloride with hydrochloric acid.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][CH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=1>ClCCl>[N:26]([C:22]1[CH:21]=[C:20]([CH2:19][O:18][CH3:17])[N:25]=[CH:24][N:23]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COCc1cc(N)ncn1
Solvent: ClCCl
Product: COCc1cc(N=C=S)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.84 g, 3.59 mmol) was in dichloromethane at ambient temperature was added 6-(methoxymethyl)pyrimidin-4-amine (0.5 g, 3.59 mmol). The orange solution was stirred at ambient temperature for 18 h. The solution was purified by column chromatography (0-40% ethyl acetate/hexanes) to afford 4-isothiocyanato-6-(methoxymethyl)pyrimidine (0.32 g, 1.77 mmol, 49% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1 H, d, J=1.26 Hz), 7.19 (1 H, d, J=1.01 Hz), 4.52 (2 H, s), 3.49 (3 H, s). MS (LC/MS) R.T.=1.39; [M+H]+=182.10.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:17]1(C(OC(C)(C)C)=O)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N1CCNCC1)[C@](O)(c1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.7 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (10.0 g, 45.4 mmol) in DCM (200 mL) was added t-butyl 1-piperazinecarboxylate (8.5 g, 45.4 mmol). Into the reaction was added DIPEA (23.7 mL, 13.6 mmol), HOBt (10.4 g, 68.1 mmol), and then EDCI (10.4 g, 54.5 mmol). The mixture was stirred at room temperature for 12 hours. The mixture was then washed with 1N NaOH (300 mL), 1N HCl (300 mL) then saturated aqueous NaCl (300 mL). The organic layer was then removed, dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. A solution of 20% TFA/DCM was added to the crude material, and the resulting mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. DCM (300 mL) was added and the mixture was washed with saturated sodium bicarbonate (300 mL). The organic layer was then removed, dried over MgSO4 and filtered. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford the title compound as a white powder (9.0 g, 31.2 mmol).
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][C:15]=1[CH:24]=O.[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[NH:28]1>CO.CCOC(C)=O>[CH3:26][C@@H:27]1[CH2:31][CH2:30][C@@H:29]([CH3:32])[N:28]1[CH2:24][C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[CH:18]=[CH:19][C:14]=1[C:7]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=1[F:5]
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C=O)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CN2[C@H](C)CC[C@H]2C)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Sodium cyanoborohydride (0.071 g, 1.1 mmol) was added to a solution of 66.60C (0.180 g, 0.62 mmol) and (2R,5R)-2,5-dimethylpyrrolidine (available from Aldrich) (0.073 g, 0.74 mmol) in MeOH (3 mL). The reaction was stirred at 110° C. for 30 minutes and then was diluted with EtOAc (100 mL). The mixture was washed with an aqueous Na2CO3 solution and brine, and dried over anhydrous sodium sulfate. After filtration, solvent was removed, and the residue was purified by flash chromatography (silica gel, 1:6 EtOAc/hexane) and gave 66.71A (32 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C2C=CC=CC=2)=O)=[CH:10][C:9]2[C:4](=[C:5]([OH:21])[CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:1][C:2]1[C:11]([C:12]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:10][C:9]2[C:4](=[C:5]([OH:21])[CH:6]=[CH:7][CH:8]=2)[CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Oc1ccccc1)c1cc2cccc(O)c2cc1O
Product: O=C(Nc1ccccc1)c1cc2cccc(O)c2cc1O
Temperature: 25 °C

Procedure:
The aromatic ester is reacted with an aniline in a solvent and heating to form the anilide product. The reaction temperature can be varied to from about 140° C. to about 280° C. or above. Specifically, phenyl 2,8-dihydroxy-3-naphthoate can be reacted with aniline in methyl N-pyrrolidinone at about 250° C. The ratio of the phenyl ester to the aniline can vary, for example, from about 1:1 equivalent and up to about 20 equivalents. After the reaction is completed, the product mixture is cooled to room temperature, about 25° C., and discharged into an acidic aqueous solution, such as a 5 percent HCl ice cold solution. The precipitated anilide product, 2,8-dihydroxy-3-naphthanilide, is isolated by filtration and washed with water. Purification can be accomplished by first dissolving the crude product in a hot solvent, such as DMF, and then precipitating the product by adding water or methanol, or a mixture of methanol and water. The purified product is then characterized by m.p., IR, mass spectrometry, NMR spectroscopy and elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[NH:12][N:11]=[CH:10]2)[CH3:2].[CH2:32](I)[CH3:33]>>[CH2:1]([O:3][C:4](=[O:31])[CH2:5][N:6]([CH2:17][C:18]([N:20]([N:22]1[CH2:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30]1)[CH3:21])=[O:19])[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[CH3:16])[N:12]([CH2:32][CH3:33])[N:11]=[CH:10]2)[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Reactant: CCI
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cnn(CC)c2cc1C
Yield: 69 %

Procedure:
Using the compound (746 mg, 1.77 mmol) of Example 241, step B and ethyl iodide (0.26 n2, 3.23 mmol), and according to the method of Example 241, step C, the title compound (549 mg, yield 69%) was obtained as a colorless amorphous solid.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18][N:19]([CH2:21][CH2:22][Cl:23])[CH3:20]>>[ClH:23].[CH3:18][N:19]([CH3:20])[CH:21]([C:14]1[C:13]([CH3:16])=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:8][NH:9]2)[CH3:22]
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CN(C)CCCl
Agent: Cl
Product: Cc1ccc2[nH]nc(-c3ccccc3)c2c1C(C)N(C)C
Yield: 63.2 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenyl-5-methylindazole (4.17 g) and dimethylaminoethyl chloride hydrochloride (4.32 g) were treated to obtain 4.0 g of 1-dimethylaminoethyl-3-phenyl-5-methylindazole hydrochloride (m.p. 191°-192° C).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: c1nc[nH]n1
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: C[C@H](N)c1cccc(-n2cncn2)c1
Temperature: 195 °C
Yield: 35.7 %

Procedure:
To a solution of (S)-1-(3-bromo-phenyl)-ethylamine (1.5 g, 7.5 mmol) and 1,2,4-triazole (1.04 g, 15 mmol) in N-methylpyrrolidinone (10 mL) in a quartz tube were added potassium carbonate (2.1 g, 15 mmol) and copper (1) iodide (143 mg, 0.75 mmol). The reaction mixture was heated at 195° C. for 5 h in a Mars 5 microwave oven (600 W), cooled down to room temperature and filtered. The crude product was purified by flash chromatography (10% MeOH/89% EtOAC/1% triethylamine) to provide the title compound (504 mg, 36% yield) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: ClCCCOc1ccccc1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccccc4)CC3)noc2c1
Yield: 47 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (100 mg), 3chloropropoxybenzene (3.4 g, 20.0 mmol), and acetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to afford 6.2 g of a damp, beige solid. The compound was recrystallized twice from ethanol to yield (47%) of 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as a light beige solid, m.p.=78-80° C.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([N:24]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].[OH-].[K+]>CO>[CH2:25]([N:24]([CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]3=[N:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCN(CCCC)CCCCl
Reactant: Cc1cccn2c(C(=O)c3ccc(O)cc3)cnc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)c2cnc3c(C)cccn23)cc1

Procedure:
A mixture of 3-(4-hydroxybenzoyl)-8-methylimidazo[1,2-a]-pyridine (2.3 g, 9.6 mmol), dibutylaminopropyl chloride (6.8 g, 33 mmol) and potassium hydroxide (1.3 g, 23 mmol) in methanol (60 ml) was stirred at reflux for 96 hours. The mixture was concentrated and the resulting oil was flash chromatographed (silica gel, 2.5% methanol in diethyl ether) to give 1.3 g (31% yield) of the free base of the title compound. The HCl salt was prepared by dropwise addition of concentrated hydrochloric acid to a solution of the free base in methanol, concentrated and recrystallized from acetone-ether to give the HCl salt of the title compound as an off-white solid, mp 105° C. to 107° C. lR(KBr): 3440, 2640, 1645, 1605 cm-1. MS: 421 (M+). 1H NMR (CD3OD): δ9.66 (d, J=8 Hz, 1H), 8.74 (s, 1H), 8.00-7.61 (m, 4H), 7.20 (d, J=7.2 Hz, 2H), 4.29 (t, J=5 Hz, 2H), 3.41-3.15 (m, 6H), 2.75 (s, 3H), 2.31 (m, 2H), 1.80-1.42 (m, 8H), 1.02 (m, 6H).
Reaction SMILES: C(=O)([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[C:22]([F:25])[CH:23]=3)[N:18]3[CH:27]=[CH:28][CH:29]=[C:17]3[CH:16]2[CH2:30][CH3:31])(=[O:14])=[O:13])=[CH:8][CH:7]=1)OCC.[OH-].[Na+]>CO>[CH2:30]([CH:16]1[N:15]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([OH:5])=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:24]2[C:19](=[CH:20][C:21]([F:26])=[C:22]([F:25])[CH:23]=2)[N:18]2[CH:27]=[CH:28][CH:29]=[C:17]12)[CH3:31]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)c(F)cc3-n3cccc3C2CC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC1c2cccn2-c2cc(F)c(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To 50 ml round bottom flask charged with 30 ml of methanol was added 0.67 g (1.4 mmol) of the product from Example 6, then 2 ml of 2N NaOH. The solution was stirred for 0.5 hr to completion then concentrated. The residue was neutralized with 2N HCl and extracted with ethyl acetate (2×10 ml), dried (MgSO4) and concentrated. The solid was passed through a plug of silica gel eluting with 40% ethyl acetate:hexane. The product so obtained was triturated with hexane to induce solidification, then crystallized from ethyl acetate:hexane to afford 0.47 g (86%) of product as colorless crystals, mp 177-179° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11][O:12][C:13](=[O:20])[CH2:14][C:15](=[O:19])[CH:16](Br)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:11][O:12][C:13]([CH2:14][C:15](=[O:19])[CH:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[N:3][CH:4]=1)[CH3:17])=[O:20]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COC(=O)CC(=O)C(C)Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(=O)C(C)OC(=O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-Chloro-nicotinic acid (10 g, 63.5 mmol) and 4-Bromo-3-oxo-pentanoic acid methyl ester (1.51 g, 7.2 mmol) (14.6 g, 70 mmol) in acetone (100 mL) is added triethyl amine (9.76 mL, 70 mmol) at 0-5° C. After addition, the reaction mixture is warmed to room temperature and stirred overnight, solid is filtered off, the filtrate is concentrated and taken into methylene chloride, washed with water and brine, dried. The residue is purified by column giving 6-chloro-nicotinic acid 3-methoxycarbonyl-1-methyl-2-oxo-propyl ester (16.3 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C(O)(C)C.Cl>[ClH:1].[OH:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCn1ccnc1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3cccc(O)c3)ncnc2cc1OCCn1ccnc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of 4-chloro-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline (49 mg, 0.16 mmol) and 3-hydroxyaniline (21 mg, 0.19 mmol) in isopropanol (3 ml) and isopropanolic hydrogen chloride (0.2 ml of a 5M solution) was stirred at 80° C. for 1 hour. The precipitated solid was collected by filtration, washed with isopropanol and ether and dried under vacuum to give 4-(3-hydroxyanilino)-7-(2-(imidazol-1-yl)ethoxy)-6-methoxyquinazoline hydrochloride (56 mg, 93%).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: CCOC(=O)CCBr
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Product: CCOC(=O)CCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 66.3 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (100 mg, 0.47 mmol) and ethyl 3-bromopropanoate (0.01 mL, 0.57 mmol) to provide 459 (97 mg, 66% yield) as a white powder. LC-MS (M+H=312, obsd.=312). 1H NMR (400 MHz, DMSO-D6) δ 8.54 (dd, J=6.3, 14.0, 1H), 8.03 (d, J=8.7, 1H), 7.29 (m, 2H), 6.88 (d, J=6.8, 1H), 6.17 (s, 1H), 4.68 (t, J=7.5, 2H), 4.01 (q, J=7.1, 2H), 2.63 (dd, J=21.6, 29.0, 4H), 1.10 (t, J=7.1, 3H).