Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=2)(O)[C:9]2[C:17]3[NH:16][C:15](=[O:18])[NH:14][C:13]=3[CH:12]=[C:11]([C:19]3[C:20]([CH3:25])=[N:21][O:22][C:23]=3[CH3:24])[CH:10]=2)=[N:6][CH:7]=1.C(N(S(F)(F)[F:40])CC)C.C([O-])(O)=O.[Na+]>ClCCl>[CH3:25][C:20]1[C:19]([C:11]2[CH:10]=[C:9]([C:8]([F:40])([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=3)[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)[C:17]3[NH:16][C:15](=[O:18])[NH:14][C:13]=3[CH:12]=2)=[C:23]([CH3:24])[O:22][N:21]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: Cc1noc(C)c1-c1cc(C(O)(c2ccc(F)cn2)c2ccc(F)cn2)c2[nH]c(=O)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1noc(C)c1-c1cc(C(F)(c2ccc(F)cn2)c2ccc(F)cn2)c2[nH]c(=O)[nH]c2c1
Reaction time: 1 h

Procedure:
To 4-(bis(5-fluoropyridin-2-yl)(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (10.4 mg, 0.02 mmol) in dichloromethane (2.3 mL) added (diethylamino)sulfur trifluoride (9.15 μl, 0.07 mmol) and stirred for 60 minutes before adding more (diethylamino)sulfur trifluoride (0.01 ml, 0.07 mmol). After 60 minutes from the second addition, the reaction was poured into saturated NaHCO3(aq) (5 mL), the layers were separated, and the aqueous was extracted with dichloromethane (2×5 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification by reverse-phase HPLC (25-75% acetonitrile/water with 0.01% trifluoroacetic acid, Gemini C18 5μ) afforded 6-(3,5-dimethylisoxazol-4-yl)-4-(fluorobis(5-fluoropyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one as an off-white solid.
Reaction SMILES: O[C:2]1([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:29])[CH3:28]>C(O)C>[CH3:28][C:3]1([CH3:29])[CH:2]([C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)[C:6]2[C:7]([CH3:27])=[C:8]([N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[CH2:17][CH2:18]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3cccc5ccccc35)C(C)(C)O4)CC2)cc1
Solvent: CCO
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(c3cccc5ccccc35)C(C)(C)O4)CC2)cc1
Yield: 63 %

Procedure:
Using 1-(3-hydroxy-2,2,4,6,7-pentamethyl-3-(1-naphthyl)-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine obtained in Example 38, the title compound was synthesized in the same manner as in Example 46. Yield 63%. mp. 165–166° C. (ethanol).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[H][H]>[Pd]>[CH3:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH2:28][CH2:29][C:30]4([OH:36])[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1cc(Nc2ncnc3ccc(C#CC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Agent: [Pd]
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(CCC4(O)CCCNC4)cc23)ccc1Oc1ccccc1
Yield: 103 %

Procedure:
A mixture of 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol dihydrochloride (100 mg, 0.19 mmol) and Pd/C (10%, 6 mg) was shaken in a Parr bottle with hydrogen at 50 psi overnight and filtered through a pad of Celite. The filtrate was concentrated to small volume and added dropwise into EtOAc with stirring. The solid was collected by suction filtration, rinsed with EtOAc, and further dried to yield 89 mg (89%) of yellow solid: 1H NMR (CO300) 5 1.69 (dt, 1H), 1.81(br d, 1H), 1.95 (t, 3H), 2.15 (m, 1H), 2.28 (t, 3H), 2.93 (t, 1H), 3.02 (m, 3H), 3.18 (d, 1H), 3.31(br, 1H), 6.94 (m, 3H), 7.08 (t, 1H), 7.34 (t, 2H), 7.55 (d, 1H), 7.66 (d, 1H), 7.78 (d, 1H), 8.02 (d, 1H), 8.58 (s, 1H), 8.73 (s, 1H); MS m/z (MH+) 455.2.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:23])[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:16]([N:4]1[C:3](=[O:23])[C:2]([N:1]([S:32]([CH3:31])(=[O:34])=[O:33])[S:32]([CH3:31])(=[O:34])=[O:33])=[CH:7][C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[N:5]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(-c2cc(N)c(=O)n(Cc3ccccc3)n2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(N(S(C)(=O)=O)S(C)(=O)=O)c(=O)n(Cc3ccccc3)n2)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of 4-amino-2-benzyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one (60 mg, 0.20 mmol) and triethylamine (80 mg, 0.79 mmol) in toluene (1 ml), methanesulfonyl chloride (70 mg, 0.61 mmol) was added, followed by heating under stirring at 40° C. for 1 hour. Chloroform was added to the reaction mixture. The organic layer was washed with water and brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was separated and purified by silica gel preparative chromatography [developer: hexane/ethyl acetate (1/1)], whereby the title compound (76 mg, 90.4%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2].I[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]#[C:19][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[CH:10][C:9]=1[CH3:20])[CH3:6])[CH3:2]
Reactant: C#CCCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Reactant: FC(F)(F)c1ccc(I)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(C(F)(F)F)cc2)cc1C

Procedure:
In analogy to the procedure described in example 13B], 2-methyl-2-(2-methyl-4-pent-4-ynyloxy-phenoxy)-propionic acid ethyl ester (example 13A]) and 1-iodo-4-trifluoromethyl-benzene gave the title compound as a light yellow viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)cnc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and benzenesulphonyl chloride
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+]>Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[NH2:12]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(NN)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93853.6 %

Procedure:
To a cold solution of methyl 4-aminobenzoate (15.0 g, 0.099 mol) in conc. HCl was added aq. solution of sodium nitrite (7.5 g, 0.109 mmol) at 0-5° C. The reaction mass was stirred at RT for 1-2 h. The reaction mass was cooled to 0° C. and stannous chloride (0.049 g, 0.210 mmol) was added and further stirred at RT for 2-3 h. The reaction mass was filtered to afford 17.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (s, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 10.69 (br s, 2H); MS (m/z): 167.28 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:38])[N:35]([OH:37])[CH3:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.Cl.[NH2:42][O:43][C:44]([CH3:60])([CH3:59])[C:45]([NH:47][NH:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=1)=[O:46]>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:42]/[O:43][C:44]([C:45](=[O:46])[NH:47][NH:48][C:49](=[O:58])[C:50]2[CH:55]=[CH:54][C:53]([OH:56])=[C:52]([OH:57])[CH:51]=2)([CH3:59])[CH3:60])/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:38])[N:35]([OH:37])[CH3:36])[N:33]=[C:29]4[N:28]=[C:27]([CH3:39])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CC(C)(ON)C(=O)NNC(=O)c1ccc(O)c(O)c1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OC(C)(C)C(=O)NNC(=O)c4ccc(O)c(O)c4)c4csc(N)n4)[C@H]3SC2)n2nc(C(=O)N(C)O)nc2n1
Reaction time: 20 h
Yield: 28.3 %

Procedure:
(6R,7R)-7-(2-Amino-4-thiazoleglyoxylamido)-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (40 mg) (0.066 mmol) and 29 mg (0.086 mmol) of 1-[2-(aminooxy)-2-methylpropionyl]-2-(3,4-dihydroxybenzoyl)hydrazine hydrochloride are dissolved in 1 ml of absolute dimethylacetamide. After stirring for 20 hours the solution is concentrated at room temperature in a high vacuum. The residue is crystallized from ethanol. There are obtained 16 mg of (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-[3-(3,4-dihydroxybenzoyl)carbazoyl]-1-methylethoxy]imino]acetamido]-3-[[[2-(N-hydroxy-N-methylcarbamoyl)-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a brown powder.
Reaction SMILES: [CH2:1]([CH:5]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:35]2([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH:30]=[C:31]([O:33][CH3:34])[CH:32]=1>C1COCC1>[CH3:34][O:33][C:31]1[CH:30]=[C:29]([C:35]2([CH:40]=[CH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH2:36][CH2:37][CH2:38][CH2:39]2)[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=1
Reactant: CCCCC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(OC)cc(C2(C=O)CCCC2)c1
Solvent: C1CCOC1
Product: CCCCC=CC1(c2cc(OC)cc(OC)c2)CCCC1
Reaction time: 0.75 h
Yield: 96 %

Procedure:
To the above slurry of (butylmethylene)triphenylphosphorane at 10° C. under an argon atmosphere was added dropwise a solution of (3,5-dimethoxyphenyl)cyclopentane carboxaldehyde (1 equiv.) in dry THF (0.21M). The reaction was stirred for 45 min and upon completion was quenched by the addition of saturated aqueous ammonium chloride. The organic layer was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic layer was washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure to give an oil. The crude product was purified through a short column of silica gel using 5% diethyl ether-petroleum ether as eluent to afford the title compound in 96% yield.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:19])C1C=CC=CC=1>[Pd].CO>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Nc1ccncc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccncc1)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 5 h

Procedure:
Palladium on carbon (13.2 mg; 10% Pd/C) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-N-pyridin-4-yl-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (52.7 mg, 0.15 mmol; combined product of two runs) in methanol (1.5 mL) and the resulting mixture was stirred under hydrogen (balloon) for 5 hours. TLC and HPLC analysis showed a small amount of starting material remaining. Additional catalyst (5.6 mg) was added and the resulting mixture was stirred under hydrogen (balloon) for an additional 1 hour. The reaction mixture was filtered through a microfilter and the filtrate was concentrated under vacuum to afford the title compound as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[OH:17])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:18]Br>C(=S)=S>[Br:18][CH:7]1[C:6]2[C:15](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=2)[C:14](=[O:16])[C:13]2[C:12]([OH:17])=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: BrBr
Reactant: O=C1c2c(O)cccc2Cc2cccc(O)c21
Solvent: S=C=S
Product: O=C1c2c(O)cccc2C(Br)c2cccc(O)c21
Temperature: 50 °C
Yield: 77.6 %

Procedure:
1,8-Dihydroxy-9-anthrone (17.3 g) was dissolved in carbon disulphide (1.25 liter) by heating, and the solution was treated dropwise with 18.5 g of bromine with stirring at 50° C. The solution was left stirring at that temperature overnight, then cooled to room temperature and concentrated to one tenth of its volume by removal of the solvent under reduced pressure. The yellow precipitate was filtered off, dried and recrystallised from a petroleum ether (boiling point 40°-60° C.)/chloroform mixture (1:1) to give 10-bromo-1,8-dihydroxy-9-anthrone (18.1 g, 77.5%), melting point 149°-15° C. (with decomposition). [Literature reference, O. E. Schultz and H.-H. Schultze-Mosgau, Arch. Pharm. (Weinheim, Ger.), 1965, 298, 273, gives melting point 148°-150° C. (with decomposition)].
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[Cl:11][C:12]1[CH:17]=[C:16](Cl)[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1>C1COCC1.[H-].[Na+]>[Cl:11][C:12]1[CH:17]=[C:16]([O:9][C@@H:7]([C@@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:15]=[C:14]([S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])[N:13]=1
Reactant: C[C@@H](O)[C@@H]1COC(C)(C)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@@H]1COC(C)(C)O1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step (iii) using (1R)-1-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (prepared according to Liebigs Ann. Chem. 1987, 7-14) (0.25 g) and 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.53 g) in THF (20 mL) and 60% sodium hydride (80 mg). Crude material was purified by column chromatography on silica gel using EtOAc/isohexane (1:3) as eluent to give the subtitle compound as a clear, colourless oil. Yield: 0.37 g.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[C:1]([NH:5][C:6]([O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:21][CH:22]=2)=[CH:12][CH:13]=1)=[O:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NC(=O)Oc1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 44.5 %

Procedure:
3.5 g (10.2 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl N-(tert-butyl)carbamate, 3 g (25.5 mmole) 2,4-thiazolidindione, 0.1 g piperidine and 0.07 g acetic acid in toluene was refluxed with water separation in a Dean-Stark apparatus. The solvent was evaporated in vacuo, acetone and water was added and the formed precipitate was filtered off to give 2 g (yield 45%) of 5-(4-[2-(4-tert-butylaminocarbonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [Br:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].[Sn](Cl)(Cl)(Cl)Cl.CCOCC>C1C=CC=CC=1>[C:11]([C:10]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[C:7]=2[S:8][CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Brc1cccc2ccsc12
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(=O)c1csc2c(Br)cccc12
Temperature: 0 °C
Yield: 64 %

Procedure:
7-Bromo-benzo[b]thiophene (See Amin et al., J. Chem Soc. Perkin Trans., vol. 2, pp.1489-1492 (1982), incorporated herein by reference), (2.49 g, 11.7 mmol) was stirred in benzene (25 mL) with acetic anhydride (3.31 mL, 35.1 mmol) under argon. Tin (IV) chloride (4.1 mL, 35.1 mmol) in benzene (15 mL) was added slowly, and the reaction stirred at reflux under argon for 2 h. The red solution was allowed to cool, and was poured over ice water (60 mL). Ether (100 mL) was added, and organics were separated, washed with water (50 mL), sat NaHCO3 (50 mL), brine (50 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (10% EtOAc/hexanes) gave 1.92 g (64%) of 3-acetyl-7-bromo-benzo[b]thiophene as a white solid. 1H NMR (300 MHz, CDCl3) δ8.74 (d, 1H, J=7.8 Hz), 8.33 (s, 1H), 7.58 (d, 1H, J=7.8 Hz), 7.38 (t, 1H, J=7.8 Hz),2.65 (s, 3H). Anal. (C10H7BrOS) C, H. Calculated C=47.08, H=2.77; found C=47.03; H=2.78. In addition, 490 mg (16%) of the more polar 2-acetyl-7-bromo-benzo[b]thiophene was isolated. 1H NMR (300 MHz, CDCl3) □ 8.02 (s, 1H), 7.85 (d, 1H, J=7.8 Hz), 7.62 (d, 1H, J=7.8 Hz), 7.30 (t, 1H, J=7.8 Hz), 2.67 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: COCCOc1cc(Cl)ccc1CO
Product: COCCOc1cc(Cl)ccc1COc1ccnn1-c1cc(C#N)ccn1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (4-chloro-2-(2-methoxyethoxy)phenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 3.39 (3H, s), 3.74 (2H, t, J=4.8 Hz), 4.18 (2H, t, J=4.8 Hz), 5.26 (2H, s), 5.81 (1H, s), 6.92 (1H, d, J=1.6 Hz), 6.98 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.39 (1H, d, J=5.2 Hz), 7.57 (1H, d, J=1.2 Hz), 8.06 (1H, s), 8.70 (1H, d, J=5.2 Hz). [M+H] Calc'd for C19H17ClN4O3, 385; Found, 385.
Reaction SMILES: C([O:6][C:7]1[C:13]([Cl:14])=[C:12]([Cl:15])[C:10]([OH:11])=[C:9]([Cl:16])[C:8]=1[Cl:17])CCCC.Cl[C:19]1[C:20](=O)[C:21](C#N)=C(C#N)[C:23](=O)[C:24]=1Cl>CO>[CH2:23]([C:13]1([Cl:14])[CH:12]([Cl:15])[C:10](=[O:11])[C:9]([Cl:16])=[C:8]([Cl:17])[C:7]1=[O:6])[CH2:24][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCOc1c(Cl)c(Cl)c(O)c(Cl)c1Cl
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Product: CCCCCC1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C1Cl
Reaction time: 2 h

Procedure:
To a solution of 110 mg (0.388 mmol) of 3 in methanol, 880 mg (10 eq) of 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was added. The reaction mixture was stirred for 2 hr, and then the solvent was removed. Silicagel chromatography (hexane:EA=20:1) gave 4 as an orange solid with quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH2:18][C:17]#[CH:16]
Reactant: Oc1cc(Cl)ccc1Cl
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,5-Dichlorophenol (8 g, 49 mmol) was mixed with potassium carbonate (13.6 g, 98 mmol) and 80% solution of propargyl bromide in toluene (11 ml, 98 mmol) in acetone (100 ml) and stirred overnight at room temperature. The precipitate was removed by filtration and washed with acetone. The acetone solution obtained was concentrated by rotary evaporation and kept under vacuum for 5 h. The product was obtained as yellow oil with quantitative yield. It was used for further transformations without additional purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:18])[N:3]=1.O.[NH2:20][NH2:21]>O1CCCC1>[Cl:18][C:4]1[CH:5]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:7]=[C:2]([NH:20][NH2:21])[N:3]=1
Reactant: COc1ccc(CNc2cc(Cl)nc(Cl)n2)cc1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(Cl)nc(NN)n2)cc1

Procedure:
A 5.57 g portion of 2,6-dichloro-4-(4-methoxybenzyl)aminopyrimidine was suspended in 20 ml of tetrahydrofuran, mixed with 3.0 ml of hydrazine monohydrate and heated under reflux for 24 hours. After evaporation of the solvent under a reduced pressure, water was added to the residue and the resulting precipitate was collected by filtration to obtain 5.06 g of 4-chloro-2-hydrazino-6-(4-methoxybenzyl)aminopyrimidine as a white solid. This was suspended in 150 ml of ethanol and mixed with 3.37 g of ethoxymethyleneacetoacetic acid ethyl ester at room temperature, and the mixture was stirred for 1 hour and then heated under reflux for 15 hours. By concentrating the reaction solution to dryness under a reduced pressure, 7.22 g of the title compound was obtained as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3C=C4[C:24](=[C:25]([C:31](OC)=[O:32])[C:26]=3[CH2:27][CH2:28][C:29]#[N:30])C35OCOC3C=CC=C5C=C4)=[CH:9][C:4]=2[O:3][CH2:2]1.CN([CH:38]=[O:39])C>[Ni]>[NH2:30][CH2:29][CH2:28][CH2:27][C:26]1[C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[C:6]2[C:7]([CH:8]=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=32)=[CH:24][C:25]=1[C:31]([O:39][CH3:38])=[O:32]
Reactant: CN(C)C=O
Reactant: COC(=O)c1c(CCC#N)c(-c2ccc3c(c2)OCO3)cc2c1C13OCOC1C=CC=C3C=C2
Agent: [Ni]
Product: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1CCCN)OCO3
Reaction time: 6 h

Procedure:
To a DMF (1 ml) solution of methyl 9-(1,3-benzodioxol-5-yl)-8-(2-cyanoethyl)-naphtho[1,2-d]-1,3-benzodioxole-7-carboxylate (21 mg) was added Raney nickel (about 200 mg) and stirred for 6 hours under hydrogen atmosphere. The catalist was filtered off and the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified with column chromatography (silica gel 1 g, eluent:dichloromethane-methanol concentrated NH4OH=15:1:0.1) to give the entitled compound (11 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:7][CH2:8][N:9](CC2C=CC=CC=2)[CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][CH2:8][NH:9][CH2:10][CH:11]1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccc(F)c(F)c2)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CCNCC1c1ccc(F)c(F)c1
Yield: 97.7 %

Procedure:
A solution of 2.73 g (7.6 mmol) 1-benzyl-5-(3,4-difluoro-phenyl)-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid ethyl ester in 150 mL ethanol was hydrogenated over 600 mg Pd/C (10%). The catalyst was filtered off and the filtrate was evaporated to dryness to yield 2 g (87%) of the title compound which was used without further purification in the subsequent step. MS (m/e): 270.3 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C)[CH:17]=[O:18]>C(N(CC)CC)C>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:6][CH:7]=1)=[C:17]=[O:18]
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reaction time: 0.5 h

Procedure:
5-(4-Aminophenyl)pyrazin-2(1H)-one (1 g) was dissolved in dimethylformamide (20 ml) and triethylamine (1.0 ml). The dark solution was filtered through diatomaceous earth, and then added dropwise to an ice-cooled solution of N,N'-carbonyldiimidazole (3.0 g) in dimethylformamide (20 ml) over 11/2 hours The mixture was stirred for a further 30 minutes, to form 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone.