Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24](O)=O>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][C:24]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: O=C(O)CCc1ccc(F)cc1F
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Product: Fc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)c(F)c1

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3-(2,4-difluorophenyl)propionic acid (186 mg, 1 mmol) as described in method 2;
Reaction SMILES: CN(C)S(N1C(S[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=CN=C1[Si](C(C)(C)C)(C)C)(=O)=O.[Li]CCCC.[CH3:31][N:32]([CH3:50])[S:33]([N:36]1[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]1[Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])(=[O:35])=[O:34].C(OCC)(=O)C.CCCCCC>C1COCC1>[CH:12]1([CH2:41][C:40]2[N:36]([S:33](=[O:35])(=[O:34])[N:32]([CH3:50])[CH3:31])[C:37]([Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])=[N:38][CH:39]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CN(C)S(=O)(=O)n1c(C=O)cnc1[Si](C)(C)C(C)(C)C
Reactant: CN(C)S(=O)(=O)n1c(Sc2ccccc2)cnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)n1c(CC2CCCCC2)cnc1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
2-Tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (1) (4.1 g, 14.2 mmol) is taken up in 47 mL of anhydrous THF and cooled to −200° C. n-BuLi (8.9 mL, 14.2 mmol) is added dropwise to the solution of (1). The resultant solution is stirred at −20° C. for 45 min. Cyclohexylmethyl iodide (2) (3.14 g, 14 mmol) is then added dropwise to the reaction mixture. Then reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with saturated ammonium chloride and diluted with water. The mixture is extracted with ethyl acetate (3×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (4:1 ethyl acetate/hexane) affords 2.26 g (5.6 mmol) of 5-cyclohexylmethyl-2-tert-butyldimethylsilyl-1-dimethylsulfamoyl imidazole (3). (3) (2.26 g, 5.6 mmol) is taken up in 56 mL of THF and cooled to 0° C. A 1M solution of TBAF in THF (5.6 mL, 5.6 mmol) is added dropwise to the solution of (3). The reaction is warmed to rt and stirred overnight. The next day the reaction is quenched with water and then extracted with ethyl acetate. The organic layer is washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (1:1 ethyl acetate/hexane) affords 1.2 g (4.42 mmol) of 5-cyclohexylmethyl-1-dimethylsulfamoyl imidazole (4). (4) (1.2 g, 4.42 mmol) is taken up in 25 mL of a 1.5N HCl solution and heated at reflux for 2 h. The reaction is cool to rt and diluted with ethyl acetate. The mixture is brought to pH 13 with 2N NaOH and then extracted with chloroform (4×100 mL). The organic layers are combined and washed with water followed by brine. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure. Flash chromatography (9:1 chloroform/methanol) affords 700 mg (4.27 mmol) of 4(5)-cyclohexylmethyl-1H-imidazole (5) (J-1).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=2)/[C:10]#[N:11])=[CH:5][CH:4]=1>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](=[CH:12]/[C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)/[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(/C=C(\C#N)c2ccc(OC)cc2)cc1
Solvent: ClCCCl
Product: N#C/C(=C\c1ccc(O)cc1)c1ccc(O)cc1
Yield: 64.9 %

Procedure:
The procedure of Preparation Example 2 was repeated, except that 224 mg of (2Z)-2,3-bis(4-methoxyphenyl)prop-2-enenitrile was used in place of 4′-methoxy-2-biphenylacetonitrile, and 1,2-dichloroethane was used in place of methylene chloride. The resulting crude product was purified by TLC (using a 3:1 mixture of chloroform and acetone as the developing solvent) to obtain 130 mg of (2Z)-2,3-bis(4-hydroxyphenyl)-prop-2-enenitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:15]([C:12]1[CH:13]=[N:14][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:10][CH:11]=1)=[O:17])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2cc(F)ccc2F)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cc(F)ccc3F)nc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A mixture of 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid (118 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), and 0-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mmol) in dry DMF (5 mL) is treated with 0.09 mL of diisopropylethylamine and stirred at room temperature for 30 minutes. A solution of 3-methylsulfamoylbenzylamine (150 mg, 0.75 mmol) in dry DMF (1 mL) is added and the mixture stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated and washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 20% EtOAc in DCM to afford 2-(2,5-difluoro-phenyl)-pyrimidine-5-carboxylic acid 3-methylsulfamoyl-benzylamide (135 mg, 65%) as a solid. MS: 419 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.41 (d, 3H), 4.64 (d, 2H), 7.43-7.78 (m, 5H), 7.89 (s, 1H) 7.90 (t, 1H), 9.37 (s, 2H), 9.60 (t, 1H).
Reaction SMILES: [Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4](O)=[O:5].C([Cl:18])(=O)C1C=CC=CC=1>>[Cl:1][CH:2]([F:9])[C:3]([F:8])([F:7])[C:4]([Cl:18])=[O:5]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)C(F)(F)C(F)Cl
Product: O=C(Cl)C(F)(F)C(F)Cl

Procedure:
In a three-necked 2 l flask provided with a Vigreux column, a condenser, and a collecting flask were brought 325 g (2 moles) of 3-chloro-2,2,3-trifluoro-propionic acid (Org.Synth.Coll. 5, 239) and 562 g (4 moles) of benzoyl chloride. The mixture was heated so that the acid chloride distilled over slowly. The collected product was refluxed for 20 min to eliminate any residual hydrochloric acid. Finally the product was distilled at normal pressure. Yield: 280 g. Boiling point: 72°-74° C.
Reaction SMILES: C([O:3][C:4]1[CH:5]=[C:6]2[CH:12]=[CH:11][S:10][C:7]2=[CH:8][N:9]=1)C.Cl.N1C=CC=CC=1>O>[S:10]1[C:7]2=[CH:8][N:9]=[C:4]([OH:3])[CH:5]=[C:6]2[CH:12]=[CH:11]1
Reactant: CCOc1cc2ccsc2cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1cc2ccsc2cn1
Temperature: 175 °C
Yield: 55.5 %

Procedure:
A mixture of 5-ethoxythieno[2,3-c]pyridine (127 mg, 0.700 mmol), pyridine hydrochloride (827 mg, 7.00 mmol) and H2O (1.2 mL) was heated in a microwave reactor at 175° C. for 2 h. The reaction mixture was concentrated in vacuo and purified by ISCO chromatography (0 to 15% MeOH:DCM) to afford 58.7 mg (55%) of the title compound as a brown solid. 1H NMR (400 MHz, CDCl3): δ 14.04 (br s, 1 H), 8.12 (s, 1 H), 7.66 (d, J=5.6 Hz, 1 H), 7.07 (dd, J=5.6, 0.4 Hz, 1 H), 6.95 (d, J=0.8 Hz, 1 H); MS (ESI): 152.02 [M+H]+; HPLC tR=0.74 min (TOF: polar—3 min).
Reaction SMILES: [CH3:1][N:2]([CH3:54])[C:3](=[O:53])[C:4]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][NH:14][C@:15]23[CH2:49][CH2:48][C@@H:47]([C:50]([CH3:52])=[CH2:51])[C@@H:16]2[C@@H:17]2[C@@:30]([CH3:33])([CH2:31][CH2:32]3)[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:46])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18]2)[CH2:8][CH2:7]1)=[O:5].O=C(N1CC[CH2:63][CH2:62][CH2:61]1)C(O)=O>>[CH3:33][C@:30]12[C@@:29]3([CH3:34])[C@@H:20]([C@:21]4([CH3:46])[C@@H:26]([CH2:27][CH2:28]3)[C:25]([CH3:36])([CH3:35])[C:24]([C:37]3[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=3)=[CH:23][CH2:22]4)[CH2:19][CH2:18][C@@H:17]1[C@H:16]1[C@H:47]([C:50]([CH3:52])=[CH2:51])[CH2:48][CH2:49][C@:15]1([NH:14][CH2:13][CH2:12][N:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[C:3](=[O:53])[N:2]3[CH2:1][CH2:63][CH2:62][CH2:61][CH2:54]3)[CH2:7][CH2:8]1)[CH2:32][CH2:31]2
Reactant: O=C(O)C(=O)N1CCCCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N4CCCCC4)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(4-(2-(dimethylamino)-2-oxoacetyl)piperazin-1-yl)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-oxo-2-(piperidin-1-yl)acetic acid as the acid in Step 1. The product was isolated as a white solid (1.1 mg, 18%). LCMS: m/e 781.7 (M+H)+, 1.72 min (method 11). 1H NMR (500 MHz, CHLOROFORM-d) δ 7.99 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 5.31 (d, J=4.6 Hz, 1H), 4.77 (s, 1H), 4.65 (s, 1H), 3.84 (dd, J=7.6, 2.7 Hz, 1H), 3.68-3.56 (m, 3H), 3.49 (t, J=4.9 Hz, 2H), 3.43-3.30 (m, 2H), 2.93-2.63 (m, 9H), 2.60-1.05 (m, 28H), 1.72 (s, 3H), 1.17 (s, 3H), 1.04 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.97 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]2[N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][CH:9](C(OCC)=O)[C:10](=[O:11])[C:4]=2[CH:3]=1.CC1C=C(C)C2N(C(OC(C)(C)C)=O)CCC(C(OC)=O)C(=O)C=2C=1.[ClH:52].N#N>CC(O)C>[ClH:52].[CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[C:5]2[NH:6][CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)c2c(C)cc(C)cc2C1=O
Agent: COC(=O)C1CCN(C(=O)OC(C)(C)C)c2c(C)cc(C)cc2C1=O
Agent: Cl
Agent: N#N
Solvent: CC(C)O
Product: Cc1cc(C)c2c(c1)C(=O)CCCN2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Charge a 5 L flask equipped, with an overhead stirrer, heating mantle, thermocouple, nitrogen purge and a teflon transfer line, with the mixture of tert-butyl 4-ethyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylate and tert-butyl 4-methyl 7,9-dimethyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-1,4-dicarboxylate (1286 g, 3.56 moles) dissolved in IPA (2 L) and heat the resulting mixture to 50° C. In a separate 12 L flask, equipped with an overhead stirrer, heating mantle, thermocouple, and nitrogen purge to a scrubber, add 5 N NaOH (1 L) and H2O (3 L). Thereafter add HCl (conc, 1.87 L, 21.8 moles) to the 12 L flask and heat to 50° C. Transfer the contents of the 5 L flask to the 12 L flask via the transfer line while flushing with N2 to remove the off gases from the reaction. After the addition, warm the resulting mixture to 80° C., and continue the N2 flush. After the reaction is complete allow the reaction mixture to cool to less than about 20° C. Add MTBE (4 L), and adjust the pH to neutral with aqueous NaOH. Transfer the resulting reaction mixture to a 22 L flask and separate the layers. Wash the aqueous layer with MTBE (2×2 L). Combine the organic washings and wash with brine (2 L), dry over MgSO4, filter and rinse with MTBE. Concentrate the filtrate to a dark oil. Dissolve in IPA (8 volumes) and transfer to a 12 L flask equipped with an overhead stirrer, thermocouple, 1 L addition funnel and N2 purge. Charge the addition funnel with HCl (conc. 765 mL) and add drop-wise over about 1 hr to the IPA solution. Stir the resulting slurry for about 1-2 hrs, filter, rinse the solids with cold IPA (3×500 mL), and dry the solid over night at about 50° C. to yield 561 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH:26]4[CH2:27][CH2:28][CH2:29][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCC1CCCO1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydrofuran-2-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.49-1.67 (m, 1 H) 1.75-1.89 (m, 2 H) 1.89-2.01 (m, 1 H) 2.44 (s, 3 H) 3.35-3.42 (m, 2 H) 3.65 (q, J=7.49 Hz, 1 H) 3.80 (q, J=6.82 Hz, 1 H) 4.00 (t, J=6.32 Hz, 1 H) 7.67 (d, J=7.83 Hz, 1 H) 7.74 (s, 1 H) 7.78 (br. s., 1H) 8.18 (br. s., 1 H) 8.43 (d, J=6.57 Hz, 2 H) 8.82 (t, J=5.31 Hz, 1 H) 8.93 (s, 1 H) 13.20 (br. s., 1 H). MS m/z [M+H]+ 404.2
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[OH:16][CH2:17][CH2:18][N:19]([CH2:32][CH2:33]O)[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21].N1C(C)=CC(C)=CC=1C>C(Cl)Cl.C(Cl)(Cl)Cl>[F:13][C:12]([F:15])([F:14])[S:9]([O:16][CH2:17][CH2:18][N:19]([CH2:32][CH2:33][O:8][S:9]([C:12]([F:13])([F:14])[F:15])(=[O:10])=[O:11])[S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])(=[O:22])=[O:21])(=[O:10])=[O:8]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCO)CCO
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCOS(=O)(=O)C(F)(F)F)CCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triflic anhydride (13.6 g, 48.3 mmol) was added dropwise with stirring to a 0° C. solution of N,N-bis-(2-hydroxyethyl)-2-nitrobenzenesulfonamide (7.00 g, 24.1 mmol) from Example 16A and 2,4,6-collidine (5.85 g, 48.3 mmol) in anhydrous methylene chloride (50 mL)(J. A. Kozlowski, et al., Bioorg. Med. Chem. Lett. 12: 791-794, 2002). Reaction stirred two hours at 0° C. and then overnight at room temperature. Reaction diluted with chloroform, washed with saturated NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal phase HPLC on a Biotage pre-packed silica gel column eluting with 3:1 hexane:ethyl acetate to afford the title compound. MS(ESI) m/z 555 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([OH:24])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:26][CH2:27][N:28]1[CH2:32][CH2:31][O:30][C:29]1=[O:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([O:24][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][O:30][C:29]4=[O:33])[CH:23]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21
Reactant: O=C1OCCN1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(OCCN4CCOC4=O)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-(5-Hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (100 mg, 0.305 mmol) is dissolved in 2 mL DMF and added to 3-(2-hydroxy-ethyl)-oxazolidin-2-one (48 mg, 0.37 mmol). Triphenylphosphine (192 mg, 0.733 mmol) in 1 mL DMF is added followed by di-t-butyl azodicarboxylate (168 mg, 0.733 mmol) in 1 mL DMF. The solution is shaken at room temperature for 16 hrs. The reaction mixture is evaporated to dryness to afford the crude product. Purification by HPLC chromatography affords 6-{5-[2-(2-oxo-oxazolidin-3-yl)-ethoxy]-pyridin-3-yl}-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:16]([CH2:22][NH2:23])=[N:17]2.C(N(CC)C(C)C)(C)C.C(O)CCC>C(Cl)Cl.CCCCCC>[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[N:14]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30])[C:16]([CH2:22][NH:23][C:2]1[N:10]=[CH:9][N:8]=[C:7]3[C:3]=1[N:4]=[CH:5][NH:6]3)=[N:17]2
Reactant: NCc1nc2cccc(Cl)c2nc1-c1ccccc1Cl
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: Clc1ccccc1-c1nc2c(Cl)cccc2nc1CNc1ncnc2[nH]cnc12
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
A mixture of 6-bromopurine (0.4553 g, 2.288 mmol), (5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methanamine (0.6959 g, 2.288 mmol), and N,N-diisopropylethylamine (0.7970 mL, 4.576 mmol) in 1-butanol (13.46 mL, 2.288 mmol) was stirred at 100° C. After 3.5 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give a light-yellow solid. The light-yellow solid was suspended in CH2Cl2-Hexane (1:1) and filtered to give N-((5-chloro-3-(2-chlorophenyl)quinoxalin-2-yl)methyl)-9H-purin-6-amine as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.93 (1 H, s), 8.02-8.16 (4 H, m), 7.95 (1 H, br. s.), 7.83-7.90 (1 H, m), 7.61-7.72 (2 H, m), 7.53-7.59 (1 H, m), 7.47-7.53 (1 H, m), 4.72-4.98 (2 H, m), 89676-20-1-1H-NMR; LC-MS (ESI) m/z 422.0 and 424.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[C:8]([O:28][CH3:29])[CH:7]=1>C1C=CC=CC=1>[CH3:1][NH:2][C:3](=[O:4])[NH:5][C:6]1[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[C:8]([O:28][CH3:29])[CH:7]=1
Reactant: COc1cc(N)ccc1OCCCN1CCN(c2ccccc2)CC1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(OCCCN2CCN(c3ccccc3)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 95 h
Yield: 95.1 %

Procedure:
260 mg of methyl isocyanate are added to a solution of 1.0 g of 1-[3-(4-amino-2-methoxyphenoxy)-n-propyl]-4-phenylpiperazine in 60 ml of anhydrous benzene, and the mixture is stirred at room temperature for 95 hours. The crystalline precipitates are collected by filtration, and then recrystallized from isopropyl alcohol. 1.11 g of 1-{3-[4-(3-methylureido)-2-methoxyphenoxy]-n-propyl}-4-phenyl-piperazine are thereby obtained as colorless needles. Yield: 93%
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[N:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH2:12])[CH:6]=1.[F:17][C:18]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[CH:20][C:19]=1[C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[N:37][CH:38]=1>>[NH2:12][C:7]1[N:8]=[C:9]([CH3:11])[N:10]=[C:5]([O:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[C:22]2[CH:21]=[CH:20][C:19]([C:33]3[CH:38]=[N:37][C:36]([NH2:39])=[N:35][CH:34]=3)=[C:18]([F:17])[CH:23]=2)[CH:6]=1
Reactant: Cc1nc(N)cc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Cc1nc(N)cc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)-2-methylpyrimidin-4-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H17FN6O, 388.14; m/z found, 389.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.45 (d, J=1.4, 2H), 7.54 (dd, J=7.6, 1.7, 1H), 7.50-7.42 (m, 2H), 7.42-7.29 (m, 3H), 7.20 (dd, J=8.0, 1.2, 1H), 5.43-5.31 (m, 1H), 2.25 (s, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][NH2:13].[CH3:14][N:15]1[CH:20]=[C:19]([CH2:21]Cl)[C:18]([C:23](OC)=[O:24])=[C:17]([Cl:27])[C:16]1=[O:28]>CCO>[Cl:27][C:17]1[C:16](=[O:28])[N:15]([CH3:14])[CH:20]=[C:19]2[CH2:21][N:13]([CH2:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[C:23](=[O:24])[C:18]=12
Reactant: NCCc1ccc2ccccc2n1
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Solvent: CCO
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 80 °C
Yield: 38.2 %

Procedure:
TEA (4.18 ml, 30.0 mmol) and 2-quinolin-2-yl-ethanamine (1.89 g, 11 mmol, see Example a1)) were each rapidly added in sequence to a suspension of 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (2.5 g, 10.00 mmol, see compound (6) of Example b1.5)) in EtOH (10 ml). The reaction was heated in a microwave at about 80° C. for about 20 min. The reaction was cooled to r.t. and the mixture was filtered and washed with a little EtOH to afford the title compound (1.35 g, 38.2% yield). MS (ESI+): m/e 418 (M+H)+, Rt:1.67 min; 1H-NMR (400 MHz, CDCl3): δ=3.28 (t, J=7.2 Hz, 2H); 3.53 (s, 3H); 3.97 (t, J=7.2 Hz, 2H); 4.31 (s, 2H); 7.49 (d, J=8.4 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.73 (t, J=7.6 Hz, 1H); 7.92-7.95 (m, 2H); 7.98 (s, 1H); 8.30 (d, J=8.4 Hz, 1H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.I[CH3:17]>CN(C=O)C>[CH3:17][N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[N:4]1
Reactant: COC(=O)c1ccc2[nH]ncc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(cnn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
To a stirred suspension of 60% NaH oil dispersion (87 mg, 2.2 mmol) in DMF (4 mL) was added methyl 1H-indazole-5-carboxylate (264 mg, 1.50 mmol). The mixture was stirred at room temperature for 1 hour before the dropwise addition of iodomethane (0.11 mL, 1.8 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and the residue was purified by Biotage chromatography (40S column, 15% acetone/heptane) to afford methyl 1-methyl-1H-indazole-5-carboxylate (107 mg, 38%).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1>[Ni].CO>[CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(C)(C)CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)CN1CCN(c2ccc(N)cc2)CC1
Yield: 84.2 %

Procedure:
1-(2,2-Dimethyl-propyl)-4-(4-nitro-phenyl)-piperazine (4 g, 14.4 mmol) was hydrogenated over Raney nickel (500 mg) in methanol (150 mL) at atmospheric pressure and room temperature for 3 hours. The mixture was filtered through Celite and the filtrate concentrated to dryness to afford 4-[4-(2,2-dimethyl-propyl)-piperazin-1-yl-]-phenylamine (3 g, 84%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:19][C:18](=O)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C=O)C.S(Cl)([Cl:28])=O>>[Cl:28][C:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:19]=1
Reactant: O=c1[nH]c(-c2cccc([N+](=O)[O-])c2)nc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2nc(Cl)c3ccccc3n2)c1

Procedure:
To a suspension of 2-(3-nitrophenyl)quinazolin-4(3H)-one (5.7 g, 21.32 mmole) in thionyl chloride (70 mL) was added of DMF (2 mL). The reaction mixture was refluxed for 4.5 h. The reaction was then concentrated in vacuo and residue suspended in a mixture of CH2Cl2 (400 mL) and CHCl3 (500 mL). The organic layer was washed with water, saturated NaHCO3, water, brine, dried with Na2SO4 and concentrated in vacuo. The residue was dried under high vacuum to afford 4-chloro-2-(3-nitrophenyl)quinazoline as an off-white solid. (6.0 g, mmol, 97%).