Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[C:14](=[O:15])[C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1.[I-].[K+]>CN(C=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][CH:5]3[C:14](=[O:15])[C:9]4[C:10]([CH3:13])=[N:11][O:12][C:8]=4[CH2:7][CH2:6]3)[CH2:31][CH2:30]2)=[O:28])=[CH:35][CH:36]=1
Reactant: Cc1noc2c1C(=O)C(CCCCl)CC2
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc2c1C(=O)C(CCCN1CCC(C(=O)c3ccc(F)cc3)CC1)CC2
Temperature: 80 °C
Yield: 47.1 %

Procedure:
To a solution consisting of 5-(3-chloropropyl)-6,7-dihydro-3-methyl-1,2-benzisoxazol-4(5H)-one (0.85 g) and DMF (20 ml) was added anhydrous potassium carbonate (0.52 g) diisopropylethyl amine (0.33 ml), 4-(4-fluorobenzoyl)piperidine (0.92 g) and potassium iodide (62 mg) at room temperature with stirring. The flask was flushed with nitrogen and warmed to 80° C. for 24 hours. Upon cooling to room temperature, water and ethyl acetate were added to the reaction mixture. The layers were separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were washed with water twice, then brine. The organic phase was then dried (MgSO4), filtered, and concentrated to give the crude product. Purification via flash column chromatography (silica gel, 2% triethylamine/ether) afforded 0.70 g of 6,7-dihydro-5-[3-(4-(4-fluorobenzoyl)-1-piperidinyl)-propyl]-3-methyl-1,2-benzisoxazol-4(5H)-one as an oil which solidified on standing. The product was dissolved and flushed through alumina with dichloromethane. Recrystallization with ether/hexane gave the product as a solid, m.p. 81°-83° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)(=[O:7])=[O:6].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccc(B(O)O)cc1
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(=O)(=O)NCCO)cc3)cc2)CC1
Yield: 26.2 %

Procedure:
The title compound (25 mg, 26%) was prepared as a white solid from (4-{[(2-hydroxyethyl)amino]sulfonyl}phenyl)boronic acid (49 mg, 0.2 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol), Pd(PPh3)2Cl2 (50 mg, 0.07 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.90 (d, 2H, J=8.6 Hz), 7.68 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.98 (d, 2H, J=8.9 Hz), 4.98-4.86 (m, 2H), 4.21 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.75-3.69 (m, 2H), 3.19-3.12 (m, 2H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 3H), 1.37-1.27 (m, 2H), 1.25 (d, 6H, J=6.4 Hz); LRMS (ESI), m/z 477 (M+H).
Reaction SMILES: C([O:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[N:17][C:16]=12)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.CN(C=O)C.[Pd]>[OH:8][NH:9][C:10]([C:12]1[N:13]=[CH:14][N:15]2[C:20](=[O:21])[N:19]([CH3:22])[N:18]=[N:17][C:16]=12)=[O:11]
Reactant: Cn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnc2c(C(=O)NO)ncn2c1=O
Yield: 24.9 %

Procedure:
A solution of N-(benzyloxy)-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (200 mg, 0.67 mmol) and 10% Pd/C (20 mg) in ethyl acetate:DMF (5:1) (36 mL) was put under an atmosphere of hydrogen for 3 days. The mixture was filtered through a pad of Celite™ and the filtrate was concentrated under vacuum. The residue was suspended in ethyl acetate and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give the pure title compound as a pale orange solid (35 mg, 25% yield). δH (DMSO-d6): 11.2 (1H, s), 9.18 (1H, s), 8.82 (1H, s), 3.86 (3H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:28]=[CH:29][C:30]2[CH2:35][O:34][CH2:33][O:32][C:31]=2[CH:36]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl.O>[O:32]1[C:31]2[CH:36]=[C:27]([C@@H:3]([O:4][C:5]3[CH:6]=[C:7]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]4)[C@@H:2]([NH:1][C:40](=[O:41])[C:39]([F:44])([F:38])[CH3:43])[CH3:37])[CH:28]=[CH:29][C:30]=2[CH2:35][O:34][CH2:33]1
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)N)ccc32)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of isobutyl 3-(5-((1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propoxy)-1H-indazol-1-yl)benzoate (420 mg, 0.84 mmol) (I5b), 2,2-difluoropropanoic acid (213 mg, 1.94 mmol) and HBTU (420 mg, 1.11 mmol) were suspended in dichloromethane (10 mL). N-ethyl-N-isopropylpropan-2-amine (0.85 mL, 5.13 mmol) was added and the mixture was stirred at room temperature overnight. Water (ca 10 mL) was added to the solution. After stirring for some minutes the mixture was added to a phase separator. The water phase was stirred with dichloromethane (5 mL) and added to the phase separator. The combined organic phases were concentrated to a brown oil. Purification by flash chromatography on silica (dichloromethane/ethyl acetate 10/1) gave the title compound as a white foam (400 mg, 80%).
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13]1[C:14]([N+:19]([O-:21])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[N+:19]([C:14]1[C:13]([S:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:18][CH:17]=[CH:16][N:15]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ncccc1Cl
Reactant: COC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Sc2cccnc2[N+](=O)[O-])cc1
Yield: 84.2 %

Procedure:
Stirred a mixture of methyl 4-mercaptobenzoate (4.46 g, 26.5 mmol), 3-chloro-2-nitropyridine (4.00 g, 25.2 mmol) and cesium carbonate (9.04 g, 27.8 mmol) in DMSO (60 mL) at ambient temperature for 90 minutes. The solution was diluted with water, extracted with EtOAc, dried, and concentrated. The crude solid was suspended in MeOH (80 mL) and triturated for 0.5 hours. The solid was filtered and dried to provide the title compound (6.16 g, 84.1% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[S:39]2)[S:34][CH2+:33]1SC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N:11]=[C:33]2[N:32]([CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:36](=[O:37])[C:35](=[C:38]3[N:42]([CH3:43])[C:41]4[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=4[S:39]3)[S:34]2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CS[CH2+]1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(=O)c1ccc(O)c(N=C2SC(=C3Sc4ccccc4N3C)C(=O)N2Cc2ccccc2)c1

Procedure:
In a manner similar to Example 30, 4′-hydroxy-3′-nitroacetophenone was hydrogenated and then condensed with 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazolium p-toluenesulfonate to afford the title compound. MS(ESI): 488 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:24][N:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>CN1CCCC1=O.O>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=5)=[O:31])[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)Nc2cccc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
To a solution of N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (195 mg, 0.6 mmol) in N-methylpyrrolidone (3.0 mL) was added 1,3-dimethylpyrazole-5-carbonyl chloride (159 mg, 1.0 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→70/30) and precipitated from methanol to give the title compound (245 mg, 91%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH3:18]O>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: COc1ccc(C(=O)O)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(OC)c(O)c1
Yield: 91 %

Procedure:
To a suspension of 3-hydroxy-4-methoxy benzoic acid (33.63 g, 0.2 mol) in MeOH (500 ml) was added concentrated sulphuric acid (25 ml) and the reaction mixture was heated to reflux for 2 h. On cooling the reaction mixture was concentrated under reduced pressure to 100 ml and the residue was extracted with EtOAc. The organic layer was washed sequentially with H2O (×2), saturated aqueous sodium bicarbonate and saturated brine, dried over MgSO4 and evaporated under reduced pressure, to afford the subtitle compound as colourless crystals (33.0 g, 91%). Rf 0.59 (EtOAc). MS m/z 183 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29]Cl)[CH2:24][CH2:23]3)=[O:21])[C:10]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][C:33]=3[O:42][CH2:43][CH3:44])=[N:9]2)=[CH:4][CH:3]=1.[CH:45]([N:48](C(C)C)[CH2:49]C)(C)C.CNC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][N:48]([CH3:49])[CH3:45])[CH2:24][CH2:23]3)=[O:21])[C:10]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:40])([F:39])[F:41])=[CH:34][C:33]=3[O:42][CH2:43][CH3:44])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CCl)CC1
Agent: CNC
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)CN(C)C)CC1
Temperature: 60 °C
Yield: 92 %

Procedure:
To a solution of 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-chloro-ethanone (9.65 mg) and diisopropylethylamine (5 uL) was added dimethylamine (50 uL, 2.0M solution in tetrahydrofuran). The reaction mixture was capped and heated at 60° C. overnight. It was diluted with methylene chloride and washed with water. The organic layer was concentrated to dryness to give 1-{4-[4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-2-dimethylamino-ethanone (9.17 mg, 92% yield). LR-MS: 677.3 [(M+H)+].
Reaction SMILES: NC1C=CC=CC=1.O=[S:9](Cl)Cl.[NH2:12][C:13]1[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=1[NH2:19]>C1(C)C=CC=CC=1>[N:19]1[S:9][N:12]=[C:13]2[CH:14]=[C:15]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:17][C:18]=12
Reactant: CCC(=O)c1ccc(N)c(N)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: CCC(=O)c1ccc2nsnc2c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
To a solution of aniline (1.86 g, 20 mmol) in 50 mL of toluene was added SOCl2 (2.6 g, 22 mmol) dropwise at 0° C. and the mixture was then refluxed for 2 h. After cooling to rt, 1-(3,4-diaminophenyl)propan-1-one (1.65 g, 10 mmol) was added. The mixture was refluxed for 2 h, cooled, concentrated, and purified by flash chromatography to give the desired product (960 mg, 50%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.21 (d, J=9.2 Hz, 1H), 8.06 (d, J=9.2 Hz, 1H), 3.15 (q, J=7.2 Hz, 2H), 1.30 (t, J=7.2 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[CH2:4][CH2:5][C:6]2([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]=1[C:13]1[C:8](=[CH:9][C:10]([O:15][CH3:16])=[CH:11][CH:12]=1)[CH2:7]2.C([Sn](CCCC)(CCCC)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=1)CCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([C:6]12[CH2:5][CH2:4][C:3](=[O:21])[C:2]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][O:35][CH3:36])=[CH:29][CH:28]=3)=[C:14]1[C:13]1[C:12](=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH2:7]2)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC12CCC(=O)C(Br)=C1c1ccc(OC)cc1C2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OCOC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCCC12CCC(=O)C(c3ccc(OCOC)cc3)=C1c1ccc(OC)cc1C2
Temperature: 100 °C
Reaction time: 22 h
Yield: 84.5 %

Procedure:
A mixture of 4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (800 mg, 2.29 mmol), Pd(PPh3)4 (132 mg, 0.114 mmol), and tributyl-(4-methoxymethoxy-phenyl)-stannane (1.174 g, 2.75 mmol) in anhydrous toluene (11.5 mL) was placed under a nitrogen atmosphere and heated with stirring in an oil bath at 100° C. After 22 hours, the mixture was cooled to room temperature and evaporated under vacuum to a dark oil (2.208 g). This material was purified by chromatography on EM silica gel 60 (230-400 mesh, 115 mL dry), using 4:1 hexanes-EtOAc as eluting solvent, to afford 9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg) as a yellow gum.
Reaction SMILES: [C:1]([C:3](=[N:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([NH:6][C:7](OCC)=[O:8])=[O:5])#[N:2].C([O-])(=O)C.[Na+].C(O)(=O)C>O>[C:14]1([N:13]2[C:7](=[O:8])[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[N:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)NC(=O)C(C#N)=NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1nn(-c2ccccc2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Intermediate b (21 g, 0.08 mol) and anhydrous sodium acetate (29 g, 0.35 mol) were added to glacial acetic acid (20 v/w, 420 mL). The mixture was warmed up to react under reflux for 2 h. After completion of the reaction, the reaction solution was cooled to 0° C. and poured into water (1200 mL). The mixture was stirred for 30 min and filtered by suction. The filtered cake was washed with water and petroleum ether, and dried to produce an orange red solid (12 g) in a yield of 67.8%.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C@@H:15]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:16](=[O:23])[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:11]([NH:13][OH:14])=[O:12])C1C=CC=CC=1>CO.[Pd]>[OH:14][NH:13][C:11](=[O:12])[C@@H:10]([CH2:9][OH:8])[C@@H:15]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[C:16](=[O:23])[N:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1ccc([C@@H](C(=O)N2CCCCC2)[C@H](COCc2ccccc2)C(=O)NO)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc([C@@H](C(=O)N2CCCCC2)[C@H](CO)C(=O)NO)cc1

Procedure:
A solution of hydroxamic acid 3 (330 mg, 0.64 mmol) in 20 ml of methanol was hydrogenated under normal pressure with 70 mg of palladium on barium sulfate for about 5 hours. After filtration of the catalyst the solvent was evaporated and the crude product was purified by preparative HPLC to give a white solid. Yield: 133 mg (62%).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH:14]([OH:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:16][CH2:15][CH:14]([O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: OCC(O)COc1ccccc1
Reactant: NS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NS(=O)(=O)OCC(COc1ccccc1)OS(N)(=O)=O
Reaction time: 0.75 h

Procedure:
To the above sulfamoyl chloride solution in acetonitrile was added dropwise with stirring a solution of 8.4 g (0.05 mole) of 3-phenoxy-1,2-propanediol (95% purity obtained from Aldrich Chem. Co., Inc.) and 20.2 g (0.2 mole) of triethylamine in 50 ml of acetonitrile at such a rate that the temperature did not exceed 12° C. over a 45 min period. The cooling bath was removed and the mixture was stirred for 2 hr and treated with 100 ml of ethyl acetate and 50 ml of water. The mixture was vigorously stirred for 5 min and the layers were separated. The organic layer was washed with 50 ml of water and 100 ml of salt brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was purified by column chromatography on 350 g of silica gel. Fractions eluted with 15% acetone in methylene chloride were combined and concentrated to give a clear gum as residue. The gum was triturated with petroleum ether (b.p. 30°-60° C.) to give crystalline solid. The solid was collected by filtration and recrystallized from benzene-acetonitrile to yield 4.2 g (26% yield) of white solid title compound, mp 116°-118° C.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([CH2:9][C:10]2[N:11]=[C:12](O)[C:13]3[CH:19]=[N:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][C:14]=3[N:15]=2)[CH2:3]1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:41]>C(Cl)(Cl)Cl>[Cl:41][C:12]1[C:13]2[CH:19]=[N:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:27])[F:29])=[CH:16][C:14]=2[N:15]=[C:10]([CH2:9][N:4]2[CH2:5][CH:6]([CH3:8])[O:7][CH:2]([CH3:1])[CH2:3]2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CN(Cc2nc(O)c3cnc(-c4ccccc4C(F)(F)F)cc3n2)CC(C)O1
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CC1CN(Cc2nc(Cl)c3cnc(-c4ccccc4C(F)(F)F)cc3n2)CC(C)O1

Procedure:
Reflux a mixture of 2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]-pyrimidin-4-ol (0.6 g), 2,6-lutidine (0.62 g), and POCl3 (1.1 g) in CHCl3 (15 mL) for 20 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-(2,6-dimethyl-morpholin-4-ylmethyl)-7-(2-trifluoromethyl-phenyl)-pyrido[4,3-d]pyrimidine.
Reaction SMILES: [N:1]1([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[K+].[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[C:18]3=[C:19]4[N:14]([CH2:15][CH2:16][CH2:17]3)[CH:13]=[C:12]([C:20]([OH:22])=[O:21])[C:11](=[O:23])[C:10]4=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:29])=[O:28]
Reactant: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCN(c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)CC1
Reaction time: 8 h
Yield: 40 %

Procedure:
2.0 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid was dissolved in 20 ml of water having dissolved therein 0.8 g of potassium hydroxide and 0.8 g of methanesulfonyl chloride was added dropwise to the solution. The resulting mixture was allowed to stand overnight at the same temperature as above while stirring. The crystals precipitated were separated by filtration and washed with water. The crystals thus-treated were dissolved in 1 N aqueous sodium hydroxide solution and the solution was treated with activated carbon and rendered neutral with a 10% aqueous hydrochloric acid solution to precipitate crystals, which were separated by filtration and washed with water. Recrystallization of the crystals thus-obtained from dimethylformamide gave 1.0 g of 8-(4-methanesulfonyl-1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of not lower than 300° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([CH2:25][CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:27][CH2:26][CH2:25][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCc1ccccc1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2NCCc2ccccc2)C1
Temperature: 180 °C
Yield: 57.7 %

Procedure:
A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.025 g, 0.09 mmol) and 2-phenylethanamine (0.065 mL, 0.51 mmol)) in acetonitrile (1 mL) was heated in a sealed tube via microwave (Emrys Optimizer model, Personal Chemistry) to 180° C. for 10 min. The reaction mixture was cooled to r.t. and concentrated to dryness. The residue was purified by silica gel chromatography using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as a white solid (19 mg).