Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:16]=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8](O)=[O:9].Cl.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[CH2:25]([NH:32][C:8](=[O:9])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=[CH:15][CH:14]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Nc2ccnn2-c2ccccc2)c(C(=O)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 5-methoxy-2-[(1-phenyl-1H-pyrazol-5-yl)amino]benzoic acid (made by Ullmann reaction as described in Example 1, 42.0 mg, 0.14 mmol), benzylamine hydrochloride (23.4 mg, 0.16 mmol), EDCI (31.2 mg, 0.16 mmol), HOBT (22.0 mg, 0.16 mmol), and triethylamine (0.066 mL, 0.48 mmol) in DMF (3 mL) was stirred at rt for 16 h. The reaction was quenched with water (20 mL) and extracted with ethyl acetate (10 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Flash chromatography of the residue over silica gel, using 20% ethyl acetate/hexane, gave the title compound (16.1 mg, 30%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.14 (t, 1H), 7.57 (d, 1H), 7.38-7.51 (m, 4H), 7.16-7.36 (m, 7H), 6.96-7.06 (m, 2H), 6.15 (s, 1H), 4.37 (d, 2H), 3.70 (s, 3H); ES-MS m/z 399.1 (MH+), HPLC RT (min) 3.72.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[C:33](OC(=O)C)(=[O:35])[CH3:34]>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[C:33]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])=[CH:2]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)n1cc(/C=C/C(=O)N(NC(=O)c2ccccc2)C(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (27 mg, 0.07 mmol, 1.0 equivalent), K2CO3 (32.2 mg, 0.23 mmol, 3.0 equivalent), DMAP (cat, 0.12 equivalent) were introduced and dissolved in DMF, after which acetic anhydride (0.015 ml, 0.15 mmol, 2.0 equivalent) was introduced. After stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=7:3:1) and dried so that solid form of (E)-N-(3-(1-acetyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (2.6 mg, 8.9%).
Reaction SMILES: [NH3:1].[OH:2][CH:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[N:24]=[C:23]([NH:28][CH:29]([CH3:31])[CH3:30])[N:22]=3)[O:18][N:17]=2)=[CH:12][CH:11]=1)[CH2:4]OS(C)(=O)=O>CO>[NH2:1][CH2:4][CH:3]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[N:20]=[C:19]([C:21]3[CH:31]=[C:29]([CH3:30])[N:28]=[C:23]([NH:24][CH:25]([CH3:26])[CH3:27])[N:22]=3)[O:18][N:17]=2)=[CH:14][CH:15]=1)[OH:2]
Reactant: N
Reactant: Cc1cc(-c2nc(-c3ccc(C(O)COS(C)(=O)=O)cc3)no2)nc(NC(C)C)n1
Solvent: CO
Product: Cc1cc(-c2nc(-c3ccc(C(O)CN)cc3)no2)nc(NC(C)C)n1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A solution of 7M NH3 in methanol (35 mL) is added to methanesulfonic acid 2-hydroxy-2-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl ester (606 mg, 1.40 mmol, synthesis described for Example 143). The reaction mixture is stirred at 65° C. for 18 h and is then evaporated to give 293 mg of rac-2-amino-1-{4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethanol as a yellow oil; LC-MS: tR=0.73 min; [M+H]+=355.06.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: OB(O)c1cccnc1F
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3F)cc1-2

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-fluoropyridin-3-ylboronic acid were reacted to give 306. MS (ESI(+)): m/z 408.1 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[C:25]1[CH:34]=[CH:33][C:32]2[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=2[CH:26]=1.[CH:39]1([NH2:42])[CH2:41][CH2:40]1>C(O)C>[CH:39]1([NH:42][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[C:25]2[CH:34]=[CH:33][C:32]3[C:31]([CH3:36])([CH3:35])[CH2:30][CH2:29][C:28]([CH3:38])([CH3:37])[C:27]=3[CH:26]=2)[CH2:41][CH2:40]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCBr)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCCCCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Yield: 75.8 %

Procedure:
In a manner similar to that of Example 1b, by reaction of 600 mg (1 mmol) of ethyl 4′-(5-bromopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 720 μl (11.5 mmol) of cyclopropylamine in 50 ml of ethanol. 420 mg of ethyl 4′-(5-cyclopropylaminopentyloxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate are obtained in the form of a white paste (yield=73%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH3:34])[CH:8]=[CH:9][C:10]([CH:12]=CC1C=CC(OCCC)=C(OCCC)C=1)=[O:11])[CH2:2][CH3:3]>CO.[Pd]>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][CH3:34])[CH2:8][CH:9]([CH2:8][C:7]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH3:34])=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1)[C:10](=[O:11])[CH3:12])[CH2:2][CH3:3]
Reactant: CCCOc1ccc(C=CC(=O)C=Cc2ccc(OCCC)c(OCCC)c2)cc1OCCC
Agent: [Pd]
Solvent: CO
Product: CCCOc1ccc(CC(Cc2ccc(OCCC)c(OCCC)c2)C(C)=O)cc1OCCC
Yield: 153.6 %

Procedure:
20.5 g (0.044 mol) of bis-(3,4-dipropyloxybenzal)acetone were dissolved in 100 ml of methanol, 1 g of palladium/carbon was added thereto, and the mixture was hydrogenated in an autoclave at 25° to 30° C. under a hydrogen gas pressure. After the palladium/carbon was filtered off, the filtrate was condensed to deposit crystals followed by filtering to obtain 15.9 g of white crystals (yield: 77%).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([N:5]1[CH2:11][CH2:10][C:9]2[C:12](OS(C(F)(F)F)(=O)=O)=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1)=[O:4].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:35][C:12]1[C:9]2[CH2:10][CH2:11][N:5]([C:3](=[O:4])[C:2]([F:1])([F:28])[F:29])[CH2:6][CH2:7][C:8]=2[CH:15]=[CH:14][C:13]=1[C:16]([F:17])([F:18])[F:19]
Reactant: O=C(N1CCc2ccc(C(F)(F)F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1cccc(F)c1
Product: O=C(N1CCc2ccc(C(F)(F)F)c(NCc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 52.8 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (110 mg, 0.24 mmol) and 3-fluorobenzyl amine (90 μL, 0.7 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX chromatography to give 6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-7-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (55 mg, 53%). MS (ES+) m/z: 435 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>[Pd].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])=[CH:18][CH:19]=1
Reactant: O=C(O)CN(CC(=O)O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(CN(CC(=O)O)CC(=O)O)cc1
Reaction time: 6 h

Procedure:
Para-nitrobenzyliminodiacetic acid (1.g, 3.08 nmoles) and Milli-Q® water (55 ml) were combined. The pH of the resultant solution was adjusted to 11.5 by the addition of 10 N NaOH solution. Palladium catalyst (5% palladium on carbon, 700 mg) was added under a hydrogen atmosphere. The reaction mixture was stirred for approximately 6 hours and then filtered through glass sinters and a 0.45 micron Millex filter. The pH of the filtrate was adjusted to below 2 with 1 N HCl and then taken to dryness in vacuo. The residue was dissolved in Milli-Q® water (10 ml) and stored at -70° C. in 1 ml aliquots until further use. Nuclear magnetic resonance confirmed the structure (300 mHz, CDCl3) δ3.268(4H), 3.591(2H); 4.321(2H), 4.741(solvent); 6.822-6.850 (2H); 7.142-7.170 (2H). 13Carbon confirms the structure, δ45.09(1C); 61.05(1 C); 61.153(2C); 119.389 (2C); 131.295 (2C); 131.568 (1C); 148.104 (1C), 176.7 (1C); 181.843 (2C).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:36])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:23]4[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]5[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=5[F:32])[C:18]=4[N:17]=[C:16](S(C)=O)[N:15]=3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:37][NH:38][CH2:39][CH2:40][NH2:41]>C1COCC1>[NH2:41][CH2:40][CH2:39][N:38]([CH3:37])[C:16]1[N:15]=[C:14]([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=2[CH3:13])[C:6]([NH:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)=[O:36])[C:23]2[CH2:22][NH:21][C:20](=[O:24])[N:19]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:18]=2[N:17]=1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CNCCN
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N(C)CCN)nc2c1CNC(=O)N2c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of N-(Cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzamide (90 mg) in THF (10 mL) was added N-methyl ethylene diamine (70 uL) at r.t. The reaction mixture was stirred at r.t. overnight. The solution was then evaporated in vacuo and the residue was purified by column chromatography to provide the title compound as a white solid (in addition to compound 4c). LC-MS m/z 522 (M+H)+, 1.47 min (ret. time).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:40][CH:39]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (82 mg, 65%), MS (ISP) m/z=503.3 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[C:16]1[N:25]=[CH:24][C:23]2[CH2:22][CH2:21][C:20]3[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=3[C:18]=2[N:17]=1.C(N(CC)CC)C.[CH:40]([N:43]=[C:44]=[O:45])([CH3:42])[CH3:41]>C(#N)C>[CH:40]([NH:43][C:44]([N:13]1[CH2:12][CH2:11][CH:10]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:16]3[N:25]=[CH:24][C:23]4[CH2:22][CH2:21][C:20]5[N:26]=[C:27]([NH:29][C:30](=[O:32])[CH3:31])[S:28][C:19]=5[C:18]=4[N:17]=3)[CH:4]=2)[CH2:15][CH2:14]1)=[O:45])([CH3:42])[CH3:41]
Reactant: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCNCC4)ccc3Cl)ncc1CC2
Reactant: CC(C)N=C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc2c(s1)-c1nc(-c3cc(C#CC4CCN(C(=O)NC(C)C)CC4)ccc3Cl)ncc1CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
50 mg (0.11 mmol) N-[8-(2-chloro-5-piperidin-4-ylethynyl-phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-2-yl]-acetamide are suspended in 1 mL acetonitrile and combined successively with 17 μL triethylamine and 22 μM isopropyl isocyanate. The yellow suspension is stirred for three hours at ambient temperature and then washed with aqueous potassium carbonate solution. The organic phase is evaporated down and the residue is purified by RP-HPLC. Yield: 30 mg yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=O.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:19]([C:18]1[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=1)=[CH:12][C:11]2=[O:13])([O-:10])=[O:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1O
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1cc(-c2cccc(C(F)(F)F)c2)oc2c([N+](=O)[O-])cccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 13.5 %

Procedure:
1-(2-Hydroxy-3-nitrophenyl)ethanone 1 (1.2 g, 6.61 mmol) was taken up in 20 mL of pyridine along with 3-trifluoromethylbenzoyl chloride 48 (1.2 mL, 7.9 mmol) and DBU (2.9 mL, 14.5 mmol). The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with EtOAc and washed with dilute 1 N HCl. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (1:1 pentane/EtOAc) afforded 300 mg of 2. MS (ESI) calcd for C16H8F3NO4: 335.04. found: 336 [M+H].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[C:22]([NH:26][C:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[CH:21]=[C:22]([NH:26][C:27]([CH:29]4[CH2:30][CH2:31]4)=[O:28])[CH:23]=[CH:24][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:9]=1
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Product: O=C(CCCN1CCC(c2cccc(NC(=O)C3CC3)c2)CC1)c1ccc(F)cc1

Procedure:
Prepared by Procedure K and Scheme B1 using 4-chloro-1-(4-fluorophenyl)-1-butanone and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 409.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[CH:9]N(C)C)[C:5]([Cl:13])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].C(O)(=O)C(O)=[O:19]>C(Cl)Cl.O>[Cl:13][C:5]1[CH:4]=[C:3]([N+:14]([O-:16])=[O:15])[C:2]([Cl:1])=[CH:7][C:6]=1[CH2:8][CH:9]=[O:19]
Reactant: CN(C)C=Cc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: O
Product: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl

Procedure:
2,5-Dichloro-4-(2-dimethylaminoethenyl)-nitrobenzene (10 g, 38.3 mmol) was dissolved in methylene chloride (200 ml) and stirred with a solution of oxalic acid (14.5 g, 115 mmol) in water (80 ml) at room temperature for 18 hours. The layers were separated and the aqueous layer extracted with methylene chloride (50 ml). The combined organic layers were washed with water and brine, dried over magnesium sulfate and filtered. The solution was evaporated to yield the title compound. NMR (CDCl3) δ 9.70 (s, 1), 8.01 (s, 1), 7.49 (s, 1), 3.98 (s, 2).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]=1>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:2]=[C:3]([C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:5])[N:13]=2)[CH:16]=1
Reactant: O=C(CBr)C(=O)c1ccccc1
Reactant: Cc1ccc(N)nc1
Solvent: CO
Product: Cc1ccc2nc(C(=O)c3ccccc3)cn2c1
Temperature: 4 °C
Reaction time: 15 h
Yield: 30.7 %

Procedure:
To a solution of 454 mg of 3-bromo-1-phenylpropane-1,2-dione in 1 mL of methanol is added dropwise at 4° C. a solution of 179 mg of 2-amino-5-methylpyridine in 4 mL of methanol. The reaction mixture is stirred for 15 hours at 4° C. and then refluxed for 2 hours. After evaporating off the solvent under reduced pressure, the residue is taken up in dichloromethane and basified with normal sodium hydroxide solution. The basic aqueous phase is extracted with dichloromethane and the combined organic phases are washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on a cartridge of 20 g of silica, eluting with an 85/15 and then 65/35 mixture of cyclohexane and ethyl acetate. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 120 mg of (6-methylimidazo[1,2-a]pyridin-2-yl)phenylmethanone in the form of a beige-colored solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[CH:40][CH:41]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 67.9 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (628 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (731 mg, yield 68%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](=[O:5])[CH3:4].[Cl:12][S:13](O)(=[O:15])=[O:14]>>[C:3]([N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][C:9]([S:13]([Cl:12])(=[O:15])=[O:14])=[CH:8][CH:7]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)N(C)c1ccccc1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C

Procedure:
(Based on the procedure of O. K. Stojanovic et al. Chem. Abstr. 1973, 78, 3902s.) N-Methyl-N-phenyl-acetamide (10.0 g, 67 mmol) is heated with 50 ml of ClSO3H at 70° C. for 90 min. The mixture is poured into 200 ml of ice, and the resulting product is filtered and washed with 2×25 ml of H2O to the give the title compound as an off-white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=[C:12]2[C:4]=1[C:5](=O)[CH2:6][C:7]1([O:11]2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].Cl.[CH3:21][O:22][NH2:23].C([O-])(=O)C.[Na+]>CO>[CH3:21][O:22]/[N:23]=[C:5]1\[CH2:6][C:7]2([O:11][C:12]3[C:4]\1=[C:3]([CH2:1][CH3:2])[C:15]([OH:16])=[C:14]([CH2:17][CH3:18])[CH:13]=3)[CH2:10][CH2:9][CH2:8]2
Reactant: CCc1cc2c(c(CC)c1O)C(=O)CC1(CCC1)O2
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCc1cc2c(c(CC)c1O)/C(=N/OC)CC1(CCC1)O2
Yield: 69.7 %

Procedure:
A mixture of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one (400 mg), methoxyamine hydrochloride (385 mg), and sodium acetate (379 mg) in methanol (10 mL) was refluxed for 16 hours. The methanol was removed by distillation and the residue was treated with sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water and brine. Evaporation and chromatography (silica gel, hexane-ethyl acetate, 3.5%) gave 310 mg of (E)-5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one O-methyl oxime. 1H-NMR (300 MHz, CDCl3) δ=6.62 (s, 1H), 4.61 (s, 1H), 4.01 (s, 3H), 3.08 (q, J=7.5 Hz, 2H), 3.01 (s, 2H), 2.61 (q, J=7.5 Hz, 2H), 2.30-1.65 (m, 6H), 1.30-1.20 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=150.5, 149.4, 146.2, 133.1, 128.0, 115.7, 115.4, 77.0, 62.0, 33.3, 33.0, 23.3, 21.2, 13.4, 12.2 ppm. MS (m/z)=290 (100, M+H+).
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:20]C(=O)C(OCC)=O)=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][C:9](=[O:28])[C:8]2=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O>C(O)C>[NH2:20][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:29])[C:9](=[O:28])[NH:10]2
Reactant: CCOC(=O)C(=O)Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Yield: 111.7 %

Procedure:
42 g (0.1 mol) of ethyl N-(1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedion-6-yl)oxamate were refluxed in a mixture of 11 of concentrated sulfuric acid and 500 ml of ethanol for 4 h. The precipitate was filtered off with suction to yield 34 g (100%) of the product. Melting point>250° C. (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:28]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:28]2)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: OCCCC1CNCCO1
Product: CCOC(=O)C1=C(CN2CCOC(CCCO)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 70.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.26 g, 2.5 mmol) was reacted with 3-(morpholin-2-yl)propan-1-ol (0.43 g, 3 mmol) according to the procedure as described in Example 25, Step B to give the title compound as a yellow solid (1.0 g, 70%). The compound was characterized by the following spectroscopic data: