Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[I:28]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][C:2]1[C:7]([I:28])=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1
Reactant: II
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of the title compound from Example 5 Step B (4.0 g, 10.6 mmol) and silver sulfate (3.31 g, 10.6 mmol) in ethanol (20 mL) was added iodine (2.69 g, 10.6 mmol), and the resulting mixture was vigorously stirred at room temperature. After 2 h, the reaction mixture was quenched with water and sodium bisulfite solution, extracted with ethyl acetate and concentrated in vacuo. Purification by chromatography on silica gel (0 to 15% EtOAc in hexanes, then 15 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 503.7 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 13.08 (s, 1 H),8.17 (s, 1 H),8.10 (t, J=8.0 Hz, 1 H),8.06 (d, J=8.0 Hz, 1 H),7.86 (dd, J=7.5, 1.5 Hz, 1 H),7.82 (dd, J=8.0, 1.5 Hz, 1 H),7.52 (d, J=7.5 Hz, 1 H),6.75 (t, J=8.0 Hz, 1 H),4.33 (q, J=7.0 Hz, 2 H),1.43 (t, J=7.0 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH-:8].[O:9]=[C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:23](O)=O)[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2>C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:23]1[C:18]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:9])[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: [NH-]c1ccccc1N
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
In a 50-ml three-necked flask under an argon atmosphere, heat, at 80° C. for 2 hours, a solution of 3 g of the (2-amino-phenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid obtained in the preceding stage, in 150 ml of acetic acid. After cooling, the precipitate that formed is drained. After purification by silica gel flash chromatography, eluting with mixtures of dichloromethane and ethyl acetate (90-10 then 80-20 and finally 70-30 by volume), we obtain 1.73 g of 4-(1H-benzimidazol-2-yl)-fluoren-9-one in the form of a yellow powder, which is used as it is in the next stage, with the following characteristics:
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[NH:22][CH:21]=1>>[N:20]1([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[CH:21]1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Reactant: c1ccc2[nH]cnc2c1
Product: O=c1[nH]c2cc([N+](=O)[O-])c(-n3cnc4ccccc43)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and benzimidazole by a method analogous to the method described in example 11. M.p.>300° C. decomp.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:18]=[CH:17][C:7]2[N:8]=[C:9]([NH:11][C:12]3[NH:13][CH2:14][CH2:15][N:16]=3)[NH:10][C:6]=2[CH:5]=1.OO>Cl>[ClH:3].[Cl:3][C:4]1[C:18]([Cl:1])=[CH:17][C:7]2[N:8]=[C:9]([NH:11][C:12]3[NH:13][CH2:14][CH2:15][N:16]=3)[NH:10][C:6]=2[CH:5]=1
Reactant: Clc1ccc2nc(NC3=NCCN3)[nH]c2c1
Agent: Cl
Agent: OO
Product: Clc1cc2nc(NC3=NCCN3)[nH]c2cc1Cl
Temperature: 80 °C
Yield: 30 %

Procedure:
2-(5-Choro-2-benzimidazolyl) amino-2-imidazoline dihydrochloride (3.1g, 0.01 mol) in concentrated hydrochloric acid (25 ml) was treated with hydrogen peroxide (10%, 3.4ml) then heated to 80°C, maintained at this temperature for 15 minutes and then allowed to cool to room temperature. Recrystalisation of the resulting precipitate from water gave 2-(5,6-dichlorobenzimidazolyl) amino-2-imidazoline hydrochloride (0.46g, 15%) m.p. 279°-281°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OC1CCNCC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 4-hydroxypiperidine (49.1 mg; 0.48 mmol) to give Example 141 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.6 Hz), 7.52 (4H, t, J=8.4 Hz), 4.57 (1H, d, J=4.1 Hz), 3.56-3.43 (3H, m), 2.70 (2H, d, J=10.5 Hz), 2.13-2.04 (2H, m), 1.74 (2H, d, J=12.0 Hz), 1.48-1.37 (2H, m). LC/MS (Method C): 498 (M+H)+. HPLC (Method E) Rt 2.13 min (Purity: 99.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][CH:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])[CH:5]=[CH:4][C:3]=1[C:29]1[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=1.[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:3]1[CH:4]=[CH:5][C:6]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][CH:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[CH:7][C:2]=1[F:1])#[N:36]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(F)c2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 2′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) was added dropwise ethyl diazoacetate (0.52 mL) at 100° C., and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.33 g, 58%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][Si](C(C)(C)C)(C)C)[CH:10]=[CH:9][C:8]=1[C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[F:29])(=O)=O.[CH3:32][C:33]1([CH3:50])[CH2:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][C:35]([CH3:49])([CH3:48])[O:34]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[F-].[K+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.CO>[F:29][C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[C:8]1[CH:9]=[CH:10][C:11]([OH:13])=[CH:12][C:7]=1[C:37]1[CH2:36][C:35]([CH3:49])([CH3:48])[O:34][C:33]([CH3:50])([CH3:32])[CH:38]=1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)O1
Reactant: COc1ccc(F)c(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(O)cc2C2=CC(C)(C)OC(C)(C)C2)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 41.6 %

Procedure:
To a mixture of 4-((tert-butyl(dimethyl)silyl)oxy)-2′-fluoro-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (405 mg), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (452 mg), palladium acetate (20 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (83 mg), methanol (3 mL) and toluene (3 mL) was added potassium fluoride (151 mg) and, under microwave irradiation, the mixture was stirred at 100° C. for 20 min. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (125 mg) as white crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[NH:19][CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2].[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[CH2:1]([NH:3][C:4]([CH:6]1[N:19]([C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]=[C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1
Product: CCNC(=O)C1Cc2c([nH]c3ccccc23)C(C(=O)OCC)=CN1C(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-ethylcarbamoyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.21 (1H, br s), 8.27 (1H, s), 7.71-7.79 (3H, m), 7.53 (1H, m), 7.36 (1H, d), 7.20 (1H, m), 7.11 (2H, m), 6.11 (1H, d), 5.32 (1H, t), 4.21 (2H, m), 3.87 (1H, dd), 3.20 (1H, dd), 2.86-3.06 (2H, m), 1.18 (3H, t), 0.57 (3H, t); MS (ES): 450 (MH+).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH2:12][OH:13])[C:9]2[CH:14]=[C:15]([Br:20])[C:16]([O:18][CH3:19])=[CH:17][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.[Cl-].[Na+].O>[Br:20][C:15]1[C:16]([O:18][CH3:19])=[CH:17][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH:10]([CH2:12][OH:13])[C:9]=2[CH:14]=1
Reactant: COc1cc2c(cc1Br)C(CO)CN(C(=O)C(F)(F)F)CC2
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1Br)C(CO)CNCC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-hydroxymethyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.009 g, 0.024 mmol) in methanol (1 mL) was treated with 15% aqueous NaOH (1 mL), and stirred for 1 hour at 50° C. The product mixture was diluted with brine (5 mL), extracted twice with EtOAc (5 mL), dried with MgSO4, and concentrated to give 0.006 g clear oil. 1H NMR (400 MHz, CD3OD) δ 7.28 (s, 1H), 6.79 (s, 1H), 3.84 (m, 2H), 3.0-2.8 (m, 7H). MS calculated for C12H16BrNO2+H: 286, observed: 286.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:34])([F:33])[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH2:23][C:22]([F:21])([F:33])[F:34])[CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OCC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2,2,2-trifluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 424.43 g/mol.
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2>C1([C@@H](N)C)C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:4][C@H:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:2])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Agent: C[C@H](N)c1ccccc1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N[C@@H](C)c3ccccc3)nc2c1
Yield: 87.4 %

Procedure:
The solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (180 mg, 0.57 mmol) in (S)-1-phenylethanamine (2 mL) was stirred overnight at 95° C., and then purified via silica gel column chromatography (1%-2% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(4-fluorophenyl)-3-(1-phenylethylamino)quinoxaline-6-carboxylate as yellow oil (100 mg, 44%).
Reaction SMILES: [Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][O:16]CC2C=CC=CC=2)=[C:5](Cl)[N:4]=1.O.[CH2:26]([OH:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Na:1].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH2:12][O:13][CH2:14][CH2:15][OH:16])=[C:5]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:4]=1
Reactant: OCc1ccccc1
Reactant: Nc1nc(Cl)c2ncn(COCCOCc3ccccc3)c2n1
Agent: [Na]
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2ncn(COCCO)c2n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A solution of sodium benzylate in benzyl alcohol was prepared from sodium (2.58 g) and benzyl alcohol (28 ml). The solution was heated to 120° C. and 2-amino-6-chloro-9-(2-benzyloxyethoxymethyl)purine (3.47 g) was added over a 10 minute period. The reaction mixture was headed overnight with stirring at 120°-130° C. and then poured into a mixture of ice and water. The resulting mixture was extracted thoroughly with chloroform. The aqueous phase was neutralized with acetic acid, giving a white precipitate which was recrystallized from methanol and then from water to give analytically pure 2-amino-6-benzyloxy-9-(2-hydroxyethoxymethyl) purine, m.p. 291°-292° C. (dec.) in 50% yield.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:19])[CH2:16][CH2:17][CH3:18].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]>CO>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:19])[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:11]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CCCC#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CCCC(=N)Nc1ccccc1N1CCOCC1
Temperature: 170 °C

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (7.5 g) and n-butyronitrile (20 ml) was heated at 170° C. in a sealed stainless steel pressure vessel for 60 hours. Excess n-butyronitrile was removed and the residue dissolved in water, basified with 10% aqueous sodium hydroxide solution to pH 12 and extracted with dichloromethane. The extract was washed with water and then brine, dried and the solvent removed. The residue was purified by chromatography on a neutral alumina column. Elution with a 1:1 mixture of dichloromethane and hexane removed unreacted starting material and then elution with a 1:99 mixture of methanol and dichloromethane yielded a solid which was dissolved in methanol (10 ml) and treated with fumaric acid (0.4 g) to give N-(2-morpholinophenyl)butyramidine monofumarate (m.p. 168°-170° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1.[CH3:18][C:19]1([CH3:30])[C@H:24]2[CH2:25][C@@H:20]1[CH2:21][CH2:22][C@H:23]2[CH2:26][C:27](O)=[O:28]>>[CH3:18][C:19]1([CH3:30])[C@H:24]2[CH2:25][C@@H:20]1[CH2:21][CH2:22][C@H:23]2[CH2:26][C:27]([NH:1][N:2]1[C:7](=[O:8])[C:6]2[S:9][CH:10]=[CH:11][C:5]=2[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3]1)=[O:28]
Reactant: Nn1nc(-c2ccccc2)c2ccsc2c1=O
Reactant: CC1(C)[C@H]2CC[C@@H](CC(=O)O)[C@@H]1C2
Product: CC1(C)[C@H]2CC[C@@H](CC(=O)Nn3nc(-c4ccccc4)c4ccsc4c3=O)[C@@H]1C2

Procedure:
The product from Example 29B and 2-[(1S,2S,55)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]acetic acid (Eigenmann, G. W.; Arnold, R. T. JACS 1959, 81, 3440-2) were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.91 (d, J=9.76 Hz, 1H) 1.08 (s, 3H) 1.20 (s, 3H) 1.39-1.66 (m, 1H) 1.76-2.05 (m, 5H) 2.20-2.46 (m, 4H) 7.45-7.65 (m, 4H) 7.71 (dd, J=7.63, 1.83 Hz, 2H) 8.35 (d, J=5.19 Hz, 1H) 11.46 (s, 1H); MS (ESI) m/z 408 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](Cl)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].[Cl:17]CC(=O)CC1C=CC=CC=1Cl.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)Cc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1ccccc1Cl
Yield: 43 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(2-chlorophenyl)propan-2-one (0.556 g, 2.74 mmol) with acetic acid (0.31 mL, 0.33 g, 5.5 mmol) and triethylamine (0.76 mL, 0.56 g, 5.5 mmol). Flash chromatography over silica gel (5-40% ethyl acetate in hexanes) gave pure product (0.251 g, 43% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.88 (s, 2H) 4.75 (s, 2H) 7.24-7.27 (m, 3H) 7.38-7.42 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[N:12][C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=2)[NH:8][N:7]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][C@@H:32]1[CH2:36][OH:37]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:31]4[CH2:35][CH2:34][CH2:33][C@@H:32]4[CH2:36][OH:37])[C:14]=23)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OC[C@H]1CCCN1
Reactant: ClCCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: OC[C@H]1CCCN1CCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 14 %

Procedure:
The procedure described in Example 23 was repeated using 3-(3-chloropropoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and (R)-2-pyrrolidinemethanol to give the title compound in 14% yield; NMR Spectrum (DMSO+TFA): 1.77-1.81 (m, 1H), 1.89-1.93 (m, 1H), 1.99-2.04 (m, 1H), 2.09-2.14 (m, 1H), 2.25 (br s, 2H), 3.14-3.19 (m, 1H), 3.26 (br s, 1H), 3.58-3.65 (m, 4H), 3.76-3.79 (m, 1H), 4.48 (br s, 2H), 5.62 (s, 2H), 7.45 (d, 1H), 7.56 (d, 1H), 7.80 (s, 1H), 7.98 (t, 1H), 8.12 (d, 1H), 8.40 (s, 1H), 8.55 (t, 1H), 8.98 (d, 1H); Mass Spectrum: 510 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([NH:27][CH2:28][C:29](O)=[O:30])[CH:22]=[N:21]1>>[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([NH:27][CH2:28][C:29](=[O:30])[N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[C:3]([F:2])([F:17])[F:18])[CH2:8][CH2:9]2)[CH:22]=[N:21]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Cn1ncc(NCC(=O)O)cc1=O
Agent: Cl
Product: Cn1ncc(NCC(=O)N2CCC(Oc3ccccc3C(F)(F)F)CC2)cc1=O
Yield: 40 %

Procedure:
Compound 19 is prepared from intermediate 1a in base form and intermediate 4h following synthesis method 2 (yield: 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[NH:21])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][N:4]=1.C(=O)(O)[O-].[Na+].Br[CH2:28][C:29](=[O:34])[C:30]([F:33])([F:32])[F:31]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH2:28][C:29]([OH:34])([C:30]([F:33])([F:32])[F:31])[N:21]=2)=[CH:5][N:4]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: COc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cn1
Yield: 42.5 %

Procedure:
To a mixture of the amidine of step 1 (1.9 g, 6.23 mmol) and sodium bicarbonate (1.05 g, 12.46 mmol) in isopropanol (150 ml), 3-bromo-1,1,1-trifluoroacetone (0.97 ml, 9.34 mmol) was added. After heating at 85–90° C for 48 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (4.25 g) was purified by chromatography (silica gel, methylene chloride/methanol/ammonium hydroxide, 95/5/0.5) to give the 4,5-dihydro-imidazole (1.1 g, 42%) as a white solid: Anal. Calcld. for C17H16N3SO4F3.0.5 EtOAc: C, 49.67, H, 4.39, N, 9.15. Found: C, 49.80, H, 4.06, N. 9.33.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3].C[Sn](C)(C)[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=1.[Cl-].[Li+]>O1CCOCC1.[Cu]I>[CH2:1]([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=2)=[N:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:2]=[CH2:3]
Reactant: CC(=O)Nc1cc([Sn](C)(C)C)ccn1
Reactant: C=CCn1ccnc1-c1sc(Br)nc1-c1ccc(Cl)cc1Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccc(Cl)cc1Cl
Temperature: 115 °C
Yield: 43.2 %

Procedure:
To a solution of 5-(1-Allyl-1H-imidazol-2-yl)-2-bromo-4-(2,4-dichlorophenyl)-1,3-thiazole (0.133 g, 0.320 mmol) in 1,4-dioxane (8 mL) was added N-[4-(trimethylstannyl)pyridine-2-yl]acetamide (0.115 g, 0.384 mmol), lithium chloride (0.0407 g, 0.961 mmol), copper (I) iodide (0.0183 g, 0.0961 mmol) and tetrakis (triphenylphosphine)palladium(0) (0.0185 g, 0.0160 mmol). The flask was purged with argon and then the mixture was heated at 115° C. for 3 hours. The reaction was allowed to cool to room temperature, and then the solvent was evaporated in vacuo. Column chromatography was performed to yield the title compound (0.0650 g, 43%). LCMS: (FA) ES+, 472. 1H NMR (400 MHz, d4-Methanol) δ: 8.75-8.72 (m, 1H), 8.45-8.41 (m, 1H), 7.71-7.68 (m, 1H), 7.58-7.55 (m, 1H), 7.43-7.35 (m, 2H), 7.20 (d, 1H, J=1.51 Hz), 7.14 (d, J=1.51 Hz, 1H), 5.69-5.58 (m, 1H), 5.13-5.08 (m, 1H), 4.94-4.88 (m, 1H), 4.38-4.33 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[OH:12].[Na+].[I-].C([O-])([O-])=O.[K+].[K+].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(#N)C>[CH3:28][C:27]1[CH:29]=[CH:30][C:24]([S:21]([O:12][C:4]2[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][CH3:11])=[CH:8][C:3]=2[O:2][CH3:1])(=[O:23])=[O:22])=[CH:25][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCc1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(OC)c1
Temperature: 70 °C
Reaction time: 36 h
Yield: 66 %

Procedure:
To a solution of 2-methoxy-4-propylphenol (10.0 mmol; 1.6 mL), NaI (1.0 mmol; 150 mg), and K2CO3 (11.0 mmol; 1.52 g), under argon, in acetonitrile (20 mL) was added tosyl chloride (10.5 mmol; 2.0 g). The reaction mixture was stirred at 70° C. for 36 hr, then quenched with NaOH (0.1N; 3 mL), and extracted with ethyl acetate (2*10 mL). Combined organic phases were washed with saturated NaHCO3 sat. (5 mL), dried over MgSO4, concentrated in vacuo. The crude was chromatographed on silica gel (gradient cyclohexane/dichloromethane) to yield the desired compound as a clear oil (2.13 g; 6.6 mmol; 66%).