Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:24]1[O:28][CH:27]=[N:26][CH:25]=1)=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3cnco3)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC(C)C)c(=O)c2ccc(-c3cnco3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a solution of tert-butyl[4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 0.6 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 ml) and the obtained solution was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give 3-(aminomethyl)-4-butoxy-2-isobutyl-6-(1,3-oxazol-5-yl)-1(2H)-isoquinolinone hydrochloride (0.22 g, 91.7%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7](Br)([F:9])[F:8])[CH:6]=1.[F-:11].[K+]>C(OC(C)C)(C)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:7]([F:9])([F:11])[F:8])[CH:6]=1
Reactant: [F-]
Reactant: FC(F)(Br)n1cc(Br)cn1
Agent: *CC(*)C
Agent: [K+]
Solvent: CC(C)OC(C)C
Product: FC(F)(F)n1cc(Br)cn1
Yield: 55 %

Procedure:
HF-pyridine complex (129 mL) was added to a stirred and cooled (ice bath) solution of bromide 5 (72.68 g, 0.263 mol) in diisopropyl ether (196 mL) in a polypropylene reaction vessel. Mercuric oxide red (48.4 g, 0.222 mol) was then added in small portions over a period of 3 h at RT. The mixture was stirred for additional 4 h at RT and was poured onto a 25% aqueous KF (650 mL). The solid was filtered off and washed with ether (100 mL). The filtrate was extracted with ether (3×100 mL). Combined extracts were dried (MgSO4), concentrated under reduced pressure and distilled to afford 6 (31.05 g, 55%) as colourless liquid b.p. 35-37° C./25 mm Hg, which crystallized on standing in a refrigerator, m.p. 4° C. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.86 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([F:28])([CH3:27])[CH3:26])[CH2:4][CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1)O)[CH3:2].FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([F:28])([CH3:27])[CH3:26])[CH2:4][CH2:5]/[CH:6]=[CH:7]/[C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCN(CCCCCC(C)(C)F)CCCC(O)c1ccc(NS(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC/C=C/c1ccc(NS(C)(=O)=O)cc1)CCCCCC(C)(C)F

Procedure:
In the process as described in Example 2 the product from Example 17 is treated with trifluoroacetic acid to give the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:26])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22](OC)=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8].[BH4-].[Li+].C1COCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:26])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[CH2:22][OH:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1ccc(N(C)c2c(CO)n(C)c(=O)c3ccccc23)cc1C
Temperature: 70 °C
Reaction time: 6 h
Yield: 48.4 %

Procedure:
To a stirred solution of methyl 4-[(3,4-dimethylphenyl)(methyl)amino]-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.11 g, 6.02 mmol) in toluene (12 mL) was added dropwise 2 M lithium borohydride/THF (3.06 mL, 6.11 mmol). The mixture was stirred at 70° C. for 6 hours, quenched with 1M HCl/water and partitioned between EtOAc and aq. NaHCO3. The organic phase was dried over sodium sulfate, evaporated in vacuo and purified on silica using EtOAc/hexanes 20-50% to provide the title compound as an off-white solid (0.94 g, 48%). 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (br. s., 1 H), 7.57 (br. s., 2 H), 6.96 (br. s., 1 H), 6.44 (br. s., 2 H), 4.80-4.48 (m, 2 H), 3.80 (br. s., 3 H), 3.27 (br. s., 3 H), 2.16 (d, 11 H), 2.29-2.06 (m, 6 H); ES-LCMS: 323.4 (M+1); ES-LCMS: 323.4 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:17][C:18]#N)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.S([O-])([O-])(=O)=[O:46].[Na+].[Na+].[BH4-].[Na+]>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:17][CH2:18][OH:46])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: CN(C(=O)OC(C)(C)C)C(CCC#N)c1ccc(OCc2ccccc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C(CCCO)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
t-Butyl N-[1-(4-benzyloxyphenyl)-3-cyanopropyl]-N-methylcarbamate (1.00 g, 2.6 mmol) obtained from Example 115c was dissolved in dichloromethane (20 ml) under an atmosphere of nitrogen. To the solution was added 0.95 M solution of diisobutylaluminum hydride in hexane (5.5 ml, 5.3 mmol) at −78° C. and the temperature was slowly raised to room temperature and then the mixture was stirred at room temperature for 2 hours. To the resulting mixture was added sodium sulfate (2.6 g) and this mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (10 ml) and to the solution was slowly added sodium borohydride (98 mg, 2.6 mmol). The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the methanol was evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate=70:30 to 50:50 as the eluent to afford the desired compound (830 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH:5]=[N:4][C:3]1=2.[CH3:25][CH2:26][N:27]([CH2:30][CH2:31][NH:32][C:33]([C:35]1[CH:36]=[CH:37][C:38]([NH2:41])=[CH:39][CH:40]=1)=[O:34])[CH2:28][CH3:29].[ClH:42].CS(C)=O>CC(C)=O>[ClH:42].[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:41][C:38]3[CH:37]=[CH:36][C:35]([C:33]([NH:32][CH2:31][CH2:30][N:27]([CH2:28][CH3:29])[CH2:26][CH3:25])=[O:34])=[CH:40][CH:39]=3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
0.300 g (0.9111 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester (AIT-0081) was placed into a 10 ml round bottom flask with 0.250 g (0.9198 mmol) of procainamide hydrochloride. 2 ml of dimethylsulfoxide was added and the solution was heated to 40° C. for four days. The solution was then poured into 40 ml acetone and was stirred vigorously for 20 minutes. The solid was collected by vacuum filtration and washed with acetone. The solid was placed into a 25 ml round bottom flask with 5 ml ethanol and was stirred for 15 minutes. The solid was collected by vacuum filtration and washed with ethanol and then with ether. This yielded 133 mg of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]-N-[2-(diethylamino)ethyl]-benzamide monohydrochloride (AIT-0095) as a slightly yellow non-hygroscopic solid. m.p. 210°-213° C. (no decomposition).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:38]=[C:24]4[CH:25]=[CH:26][CH:27]=[C:28]([C:29]5[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=5)[C:32](O)=[O:33])[N:23]4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:39]([NH:47][NH2:48])(=O)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(=O)([O-])O.[Na+]>>[C:40]1([C:39]2[O:33][C:32]([C:31]3[CH:30]=[C:29]([C:28]4[N:23]5[N:22]=[C:21]([NH:20][C:17]6[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][N:6]7[CH2:10][CH2:9][CH2:8][CH2:7]7)=[CH:19][CH:18]=6)[N:38]=[C:24]5[CH:25]=[CH:26][CH:27]=4)[CH:37]=[CH:36][CH:35]=3)=[N:48][N:47]=2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-c2nnc(-c3cccc(-c4cccc5nc(Nc6ccc(OCCN7CCCC7)cc6)nn45)c3)o2)cc1
Temperature: 0 °C

Procedure:
Phosphorus oxychloride (5 ml) was added dropwise to 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-benzoic acid (50 mg, 0.113 mmol) and benzhydrazide (15 mg, 0.113 mmol). The solution was heated to reflux overnight. Once cooled the reaction mixture was added gradually to ice/water. The solution was basified with saturated aqueous sodium hydrogencarbonate and subsequently extracted twice with dichloromethane. The organics were combined, washed several times with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The product was purified by preparatory HPLC. LCMS RT: 2.80 min, MI: 544, Method: 2.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2OC)(=[O:23])=[O:22])=[CH:17][CH:16]=1.Cl[C:34]1C=C(S(N=C2C3C(=CC=CC=3)C(=O)C(Cl)=C2)(=O)=O)SC=1Cl>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:34])=[CH:29][CH:30]=2)(=[O:22])=[O:23])=[CH:17][CH:16]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(NC2=C(Cl)C(=O)c3ccccc3C2=O)cc1
Reactant: O=C1C(Cl)=CC(=NS(=O)(=O)c2cc(Cl)c(Cl)s2)c2ccccc21
Product: Cc1ccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)cc1

Procedure:
5.2.42 (N-methyl-3-(1-oxo-4-(thiophen-2-ylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)propanamide (13g) was prepared according to the procedure for 13d except using 4, 5-dichloro-N-(3-chloro-4-oxonaphthalen-1(4H)-ylidene)thiophenesulfonamide (12c) and 3-mercapto-N-methylpropanamide( ) which afforded the title compound 21 mg (32%) as a yellow solid, m.p.: ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1>CO.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:17]4[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:27])([F:28])[F:13])[CH:16]=4)[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CO
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1

Procedure:
Following the general procedure of Example 39, Step 2, and making non-critical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-α]pyridine (Example 4, Step 1; 0.2982 g) and 1-[3-(trifluoromethyl)phenyl]piperazine (Aldrich; 0.34 mL) are converted to product, followed by chromatography on silica gel using methanol/dichlormethane (2/98). Crystallization from ethyl acetate and then from ethyl acetate/dichloromethane gives 0.053 g of the title compound; mp 145-145.5° C.; MS m/z 394; IR (mineral oil) 1117, 1163, 1451, 1073, 1339 cm-1 ; 1H NMR (CDCl3) δ2.75, 3.28, 3.78, 7.12, 7.34, 7.52, 7.54, 8.14.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[CH:13]=[N:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27](O)[CH3:28]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]([CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=3[CH:26]=2)[CH:13]=[N:14][CH:15]=1)[CH2:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)oc2ccc(-c3cncc(CNCc4ccccc4)c3)cc21
Reactant: CCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCN(Cc1ccccc1)Cc1cncc(-c2ccc3oc(=O)n(C)c3c2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-(5-(Benzylamino-methyl)-pyridin-3-yl)-3-methyl-3H-benzooxazol-2-one (crude from step 2, ˜0.39 mmol) and Pd(OH)2 (20 mg, 10%) in ethanol (10 mL) and acetic acid (0.5 mL) was stirred under 1 atmosphere of H2 at room temperature for 48 h. After filteration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-5%) and yielded yellow solid (3 mg), ESI-MS m/z: 387.9 [M+1]+, Retention time 1.45 min; 1HNMR (CDCl3, 400.342 MHz) δ 1.48 (t, J=7.2 Hz, 3H), 3.05 (s, 2H), 3.48 (s, 3H), 4.23 (s, 2H), 4.05-4.27 (m, 2H), 7.21 (s, 1H), 7.23 (5, 1H), 7.40-7.43 (m, 3H), 7.62-7.64 (m, 2H), 7.83 (s, 1H), 8.52 (5, 1H), 8.85 (d. J=1.84 Hz, 1H), 9.21 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.CC1(C)C(C)(C)OB([C:15]2[CH:16]=[N:17][NH:18][CH:19]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[NH:17]1[CH:16]=[C:15]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:19]=[N:18]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1csc(-c2cn[nH]c2)n1
Temperature: 70 °C
Yield: 57.3 %

Procedure:
To a solution of 2-bromothiazole (1 g, 6 mmol) in toluene (20 mL) and ethanol (10 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-Pyrazole (1.41 g, 7.3 mmol), 2 M sodium carbonate solution (17.3 mL) and Pd(PPh3)4 (7 mg, 0.06 mmol). The reaction mixture was purged with argon for 15 min. The resulting mixture was heated at 70° C. for 4 h. The reaction mixture was concentrated and diluted with water (100 mL), extracted with ethyl acetate (2×200 mL). The combined extracts were washed with brine solution (20 mL), the organic solvent was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by flash chromatography (60-120μ; 50% ethyl acetate in hexane) to afford racemic 2-(1H-pyrazol-4-yl)thiazole as brown liquid (520 mg, 56% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.22 (br s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.55 (d, 1H); LC-MS m/z calculated for [M+H]+ 152.02. found 152.1.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[K+].Br[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.C1COCC1>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cccc(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1ccccc1
Yield: 79 %

Procedure:
An oven dried resealable Schlenk tube was evacuated and backfilled with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 1.0 mol %), 2-(di-tert-butylphosphino)biphenyl (6.0 mg, 0.020 mmol, 2.0 mol %), phenylboronic acid (183 mg, 1.5 mmol), and potassium fluoride (174 mg, 3.0 mmol). The tube was evacuated and backfilled with argon, and THF (1 mL) and 2-bromo-m-xylene (0.144 mL, 1.0 mmol) were added through a rubber septum. The tube was sealed with a teflon screwcap, and the reaction mixture was stirred at 65° C. until the starting aryl bromide had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (30 mL), filtered through celite, and concentrated. The crude material was purified by flash chromatography on silica gel to afford 144 mg (79%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]4[CH2:20][C:21]5[S:22][CH:23]=[CH:24][C:25]=5[C:18]=4[N:17](COCC[Si](C)(C)C)[N:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Cl>CO>[S:22]1[CH:23]=[CH:24][C:25]2[C:18]3[NH:17][N:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([NH:8][C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)=[CH:14][CH:13]=4)[C:19]=3[CH2:20][C:21]1=2
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Nc3ccc(F)cc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: Fc1ccc(Nc2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 84 %

Procedure:
(4-Fluoro-phenyl)-{4-[4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl]-phenyl}-amine (0.25 g, 0.5 mmol) was dissolved in MeOH and treated with concentrated HCl (0.16 mL, 5 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding [4-(4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-phenyl]-(4-fluoro-phen yl)-amine (0.14 g, 0.42 mmol) as white solid in 85% yield.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([O:19]CC)=[O:18])=[CH:4]1)[CH3:2].[CH3:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1>N1C=CC=CC=1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:27]3[CH2:26][CH2:25][NH:24][CH:23]([CH3:22])[CH2:28]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(C)C3)c(F)c21
Yield: 56.8 %

Procedure:
A mixture of 1.50 g of ethyl 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 1.50 g of 2-methylpiperazine and 5 ml of pyridine was heated for 3 hours under reflux. The solvent of the reaction mixture was evaporated and the residue was dissolved in chloroform. The solution was washed with water, dried and evaporated. The residue was recrystallized from a mixture of benzene and isopropyl ether to give 1.00 g of the title compound as colorless needles, M.p. 126.5°-127.5° C.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][CH2:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][CH:23]([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:18]([C:14]1[S:13][C:12]([CH2:11][CH2:10][C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:26]
Reactant: CC(N)CO
Reactant: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)O)s1
Product: CCCCc1noc(C)c1CCc1nc(C)c(C(=O)NC(C)CO)s1
Yield: 58 %

Procedure:
As described for example 49, 2-[2-(3-butyl-5-methyl-isoxazol-4-yl)-ethyl]-4-methyl-thiazole-5-carboxylic acid (80 mg, 0.26 mmol) was converted, using rac-2-amino-1-propanol instead of 1-amino-2-methyl-propan-2-ol, to the title compound (55 mg, 58%) which was obtained as a light brown oil. MS: m/e=366.1 [M+H]+.
Reaction SMILES: [N+]([O-])([O-])=O.[NH4+].C[O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18]C)=[CH:10][C:9]=1[CH2:20][O:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:25][NH:24][CH2:23]1>O.C(#N)C>[CH2:38]([O:37][CH2:36][CH2:35][O:34][C:31]1[CH:30]=[CH:29][C:28]([CH:27]2[CH2:26][CH2:25][NH:24][CH2:23][CH:22]2[O:21][CH2:20][C:9]2[C:8](=[O:7])[C:17]3[C:12]([C:11](=[O:18])[CH:10]=2)=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:33][CH:32]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1cc(COC2CNCCC2c2ccc(OCCOCCc3ccccc3)cc2)c(OC)c2ccccc12
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=C(COC2CNCCC2c2ccc(OCCOCCc3ccccc3)cc2)C(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.2 %

Procedure:
A solution of 240 mg of Cer(IV) ammonium nitrate in 1 ml of water was added dropwise at room temperature to a solution of 118 mg of (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidine in 10 ml of acetonitrile. The reaction solution was stirred at room temperature for 15 minutes and subsequently evaporated under reduced pressure. The residue was partitioned between methylene chloride and water, the organic phase was dried and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 9:1 mixture of methylene chloride and methanol as the eluent. There were obtained 95 mg (85% of theory) of (3RS,4RS)-2-[4-[4-(2-phenethyloxy-ethoxy)-phenyl]-piperidin-3-yloxymethyl]-[1,4]naphthoquinone as a red solid; MS: 512 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:15])=[O:7].C[O:43][C:44](=[O:52])[CH2:45][NH:46][CH:47]([CH2:50][CH3:51])[CH2:48][CH3:49]>>[C:44]([CH2:45][N:46]([CH2:2][C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[CH2:38][CH2:37][CH2:36][CH2:35][C:12]=2[C:13]=1[C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:21][CH:22]=1)=[O:15])=[O:7])[CH:47]([CH2:50][CH3:51])[CH2:48][CH3:49])([OH:52])=[O:43]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Reactant: CCC(CC)NCC(=O)OC
Product: CCC(CC)N(CC(=O)O)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)O)cc4)cc2)CCCC3)c1
Yield: 25.1 %

Procedure:
By using 23 mg of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 19 mg of methyl[(1-ethylpropyl)amino]acetate as starting materials, alkylation was performed under the conditions similar to Preparation Example 30, and then hydrolysis was performed under the conditions similar to Example 6, thereby obtaining 6.7 mg of 4-(2-{4-[({2-[(3-{[(carboxymethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoic acid.