Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=[CH:14][CH:13]=1.C(Cl)(=O)C>C1COCC1>[CH3:13][C:14]1[NH:6][C:4](=[O:5])[C:3]2[C:2](=[C:10]([CH3:11])[CH:9]=[CH:8][CH:7]=2)[N:1]=1
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: c1ccncc1
Solvent: CC(=O)Cl
Solvent: C1CCOC1
Product: Cc1nc2c(C)cccc2c(=O)[nH]1
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 2-amino-3-methylbenzamide (0.5 g, 3.3 mmol) (prepared by conventional methods) and pyridine (0.35 ml, 4.3 mmol) in dry THF (15 ml), was added a solution of acetyl chloride (0.36 ml, 5.0 mmol) in THF (2 ml) dropwise, and the mixture was stirred overnight under nitrogen. The solvent was removed under vacuum and the remaining white slurry was resuspended in 2% aqueous sodium hydroxide solution and neutralised with aqueous hydrochloric acid, whereupon a white precipitate formed. The solid was collected and recrystallised from methanol-water to furnish the required quinazolinone (0.47 g, 81%) m.p. 217°-220° C.;
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:13]=2)=[CH:5][CH:6]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].II>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[C:15]1([N:14]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)=[CH:9][CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: II
Agent: O=C([O-])[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 111.3 %

Procedure:
41.4 g of N,N′-diphenyl-p-phenylenediamine, 66 g of iodobenzene, 100 ml of nitrobenzene, 45 g of K2CO3, 10.8 g of copper powder, and I2 (trace) were put in a four-neck flask of 300-milliliter volume, and were refluxed gently over 24 hours by stirring the same while removing generated water by reflux. Subsequently, steam distillation was carried out, and when a distillate no longer came out, residues were filtered out after cooling, washed with water, and extracted using toluene. After removing toluene by distillation, ethanol was added to the residues, and the mixture was filtered. Recrystallization was carried out using a solvent of toluene and ethanol (toluene:ethanol=4:1 (by volume)), whereby 36.5 g of N,N,N′,N′-tetraphenyl-p-phenylenediamine was obtained. It had a melting point of 200° C. to 202° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]#[C:18][CH3:19])[C:11]=1[NH2:20].O.CCOC(C)=O>CN1C(=O)CCC1>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]2[C:11]=1[NH:20][C:18]([CH3:19])=[CH:17]2)=[O:21]
Reactant: CC#Cc1cc(Cl)cc(C(=O)OC)c1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(Cl)cc2cc(C)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a cold (−10° C.) solution of t-BuOK (30 mg, 0.27 mmol) in 4 ml NMP was added a solution of 2-amino-5-chloro-3-prop-1-ynylbenzoic acid methyl ester (46 mg, 0.21 mmol) in NMP (2 ml). The reaction mixture was slowly warmed to rt and stirring was continued for 1 h. Water and EtOAc were added and organic phase was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography (9:1 cyclohexane:EtOAc) to give 5-chloro-2-methyl-1H-indole-7-carboxylic acid methyl ester (25 mg, 54%) as a light yellow solid. MS (ISP) 222.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]([O-])(O)=O.[Na+].IC.C(Cl)(Cl)Cl.CO>CN(C=O)C.O.C(OCC)(=O)C>[CH3:29][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C=O)cc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
Dissolve (S)-2-tert-butoxycarbonylamino-3-(4-(4-formylphenoxy)phenyl)-propanoic acid (2.97 Kg, 7.7 moles) in dry DMF (14.84 L). Add NaHCO3 (1.29 Kg, 15.4 moles) and iodomethane (6.56 Kg, 46.19 moles) under inert atmosphere and stirred at room temperature for 14 h. Check completion of the reaction by TLC (SiO2 gel, CHCl3-MeOH, 9:1). Poured the reaction mixture in water and stirred for 15 min. Add ethyl acetate (40 L). Oraganic layer was washed with brine and evaporated under reduced pressure. Yield 3.06 Kg, 99.3%, HPLC purity 94.6% and chiral purity 100% ee. 1HNMR (300 MHz, CDCl3): 9.92 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.02 (overlapped d, 4H), 5.03 (brs, 1H), 4.59 (m, 1H), 3.74 (s, 3H), 3.13 (dd, J=5.7 and 13.8 Hz, 1H), 3.00 (dd, J=6.3 and 13.8 Hz, 1H), 1.43 (3, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH3:17])=[C:14]([OH:16])[CH:15]=1.C(N(CC)CC)C.[Si:25](OS(C(F)(F)F)(=O)=O)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].CCOC(C)=O>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:16][C:14]1[CH:15]=[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:11]=[CH:12][C:13]=1[CH3:17])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1O
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2nc3ccccc3o2)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 5-(1,3-benzoxazol-2-yl)-2-methylphenol (0.8 g, 3.5 mmol) and triethylamine (0.6 mL, 4.3 mmol) in CH2Cl2 (20 mL) was cooled to 0° C. and TBDMS-OTf (900 mL, 3.9 mmol) was added. The reaction was slowly warmed to rt and EtOAc (200 mL) was added. The mixture was washed with H2O (3×50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 2-(3-{[tert-butyl-(dimethyl)silyl]oxy}-4-methylphenyl)-1,3-benzoxazole as light yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[CH3:10]O>O>[O:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:6][CH3:10])=[O:9])[CH2:8][CH2:7]1
Reactant: O=C1OCCC1CCO
Reactant: CO
Solvent: O
Product: COC(=O)C1CCOCC1
Reaction time: 60 h

Procedure:
A solution consisting of 45 wt % of 3-(2'-hydroxyethyl)-dihydro-2(3H)furanone, 45 wt % of methanol, and 10 wt % of water, was evaporated at a rate of 25 g per hour and the vapors were passed over 90 g of aluminum oxide catalyst (diameter 1.5 ram) in a tubular reactor at a temperature of 250° C. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. The experiment was carried out for a period of 60 h and the total amount of starting material used was 1500 g. 57 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 32 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 4 mol % of 5-oxaspiro-[2.4 ]heptan-2-one, the conversion of 3-(2'-hydroxyethyl)-dihydro-2(3H)furanone being better than 97%.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[O:6][C:7]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:8]=2[C:9]=1[CH2:10][C:11](O)=[O:12])=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([NH:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH3:33].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH:35]1([N:34]([CH2:32][CH3:33])[C:11](=[O:12])[CH2:10][C:9]2[C:8]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:7]=3[O:6][C:5]=2[C:3](=[O:4])[C:2]([CH3:1])([CH3:20])[CH3:21])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COc1ccc2oc(C(=O)C(C)(C)C)c(CC(=O)O)c2c1
Reactant: CCNC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Cc1c(C(=O)C(C)(C)C)oc2ccc(OC)cc12)C1CCCCC1
Temperature: 40 °C

Procedure:
Dissolve a mixture of 17 mg [2-(2,2-dimethylpropanoyl)-5-methoxy-1-benzofuran-3-yl]acetic acid from the Step B Example 1 and 18.5 mg HOBt in 1 mL dry DMF. Add 13.2 μL N-ethylcyclohexylamine followed by 23.0 mg EDC and 35 μL DIEA. This solution was heated at 40° C. for 2 hours. It was purified directly on RP-HPLC using 65-100% MeCN gradient. The fractions containing pure product were pooled and lyophilized to give the title compound. LC-MS: 4.34 min. (m/Z=400.2, 422.1, 316.1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]([F:13])([F:12])[F:11])[N:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:10]([F:13])([F:11])[F:12])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9]
Reactant: OCc1ccc(C(F)(F)F)nc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)nc1Cl
Reaction time: 4 h
Yield: 88.3 %

Procedure:
To a stirred solution of [2-chloro-6-(trifluoromethyl)pyridin-3-yl]methanol (Int-16) (80.0 g, 1.0 eq.) in dichloromethane (700 ml) was added pyridinium chlorochromate (160.0 g, 2.0 eq), silicium dioxide (240 g) at room temperature and stirred for 4 h. The progress of the reaction was monitored by TLC. After completion of reaction, reaction mixture was filtered through silica gel bed and washed the bed with excess 90% ethyl acetate in pet ether and filtrate was concentrated under reduced pressure to get crude 2-chloro-6-(trifluoromethyl)nicotinaldehyde (Int-17) as yellow liquid (70.0 g, 88.3%). GC-MS: m/z 209 ([M]).
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:26]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][N:32]=[C:31]([F:35])[CH:30]=3)=[N:25][CH:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.C(N(CC)CC)C.[N:43]([C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([C:56]([F:59])([F:58])[F:57])[CH:47]=1)=C=O>ClCCl.CCOC(C)=O>[F:53][C:52]([F:54])([F:55])[C:50]1[CH:51]=[C:46]([NH:43][C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([F:35])[CH:30]=4)=[N:25][CH:24]=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:12])[CH:47]=[C:48]([C:56]([F:57])([F:59])[F:58])[CH:49]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCc2ccnc(F)c2)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nccnc2OCc2ccnc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A 20% solution of TFA in dichloromethane was added to 3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (113 mg, 0.290 mmol). The solution was stirred at room temperature for 1 h until complete de-protection was evident by LCMS, then concentrated in vacuo. The resulting solid was diluted with dichloromethane (3 mL). Triethylamine (193 mg, 1.91 mmol) was added and assured bacisity with pH paper. The solution was cooled to −5° C. and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (88.6 mg, 0.347 mmol) was added dropwise. After the addition was complete, the solution was stirred at −5° C. for 5 min, then allowed to warm up to room temperature and stirred for an additional 3 h. The solution was then diluted with EtOAc (20 mL), washed with satd. NaHCO3(aq) and brine, dried over MgSO4 and concentrated in vacuo. The crude solids were dissolved in MeOH and purified by preparative HPLC (50 mM NH4OAc(aq), acetonitrile solvent system). The product was isolated by lyophilization of pure fractions yielding N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide (50.5 mg, 32.0% yield). 1H NMR (CDCl3) 8.24 (d, 1H), 7.91 (s, 2H), 7.82 (d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.73 (d, 1H), 5.51 (s, 2H), 3.70-3.65 (m, 8H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH2:5])=[S:4].Cl[CH:7]([C:13]([CH3:15])=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9]>ClCCCl>[CH3:1][NH:2][C:3]1[S:4][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:13]([CH3:15])[N:5]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CNC(N)=S
Solvent: ClCCCl
Product: CCOC(=O)c1sc(NC)nc1C
Yield: 97.5 %

Procedure:
3.6g of methyl thiourea and 7.9g of ethyl 2-chloroacetoacetate were added to 100ml of 1,2-dichloroethane and the mixture was stirred under reflux for 10 hours. After removing the solvent under reduced pressure, 10% aqueous sodium hydroxide solution was added thereto to recrystallize the resulting product which was then filtered to obtain 7.8g (Yield 96%) of ethyl 2-methylamino-4-methyl-thiazole-5-carboxylate as a pale yellow solid. The obtained solid product was dissolved in 60ml of a mixed solvent of methanol-distilled water (v/v=3/1) containing 1.8g of sodium hydroxide. The reaction mixture was stirred under reflux for 8 hours, evaporated under reduced pressure to remove methanol and then adjusted to pH 2 to 3 by adding 10% aqueous hydrochloric acid solution to precipitate the white solid. The precipitated solid product was filtered, washed with water and diethylether and then dried to obtain 6.0g (Yield 90%) of the title compound as a white solid.
Reaction SMILES: [S:1]1[C:5]([C@H:6]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][C:14](=[O:17])[CH2:15]3)[CH2:11][C@H:10]2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[S:1]1[C:5]([C@H:6]([O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)/[CH:7]=[CH:8]/[C@@H:9]2[C@@H:16]3[C@@H:12]([O:13][CH:14]([OH:17])[CH2:15]3)[CH2:11][C@H:10]2[O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][C:2]1=2
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](OC3CCCCO3)c3cc4ccccc4s3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: OC1C[C@@H]2[C@@H](/C=C/[C@@H](OC3CCCCO3)c3cc4ccccc4s3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 10 °C
Reaction time: 2 h
Yield: 111.5 %

Procedure:
To a cold (−65 to −75° C.) solution consisting of (3aR,4R,5R,6aS)-4-((3R,E)-3-(benzo[b]thiophen-2-yl)-3-(tetrahydro-2H-pyran-2-yloxy)prop-1-enyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one (intermediate 30, 0.369 mg, 0.740 mmol) in toluene (8 mL) was added a solution consisting of DIBAL-H in toluene (1 M, 1.11 mL) over the course of ten seconds. The reaction mixture was stirred for two hours and was complete as judged by TLC. The reaction mixture was warmed to 10° C. and was subsequently quenched with a 7:1 mixture of THF-water (8 mL). The reaction mixture was allowed to stir overnight (18 hours). After stirring overnight a white solid had formed. The reaction mixture was decanted away and the solid was washed with 50% brine in water (3×30 mL). The organic layer was separated, dried over sodium sulfate, filtered, and the filtrate was evaporated to afford the title intermediate 31 (413 mg, 112% crude) as a yellow-green oil; MS (+cAPCI) m/z 523 (m+Na+); 1H NMR (CDCl3), δ 7.70-8.00 (m, 2H), 7.20-7.40 (m, 3H), 5.40-5.50 (m, 3H), 4.55-4.95 (m, 5H), 1.20-2.60 (m, 20H).
Reaction SMILES: C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C#C)C=CC=CC=1.[C:28]([O:36][CH:37]([CH2:41][CH:42]=[CH2:43])[CH2:38]C=C)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[C:28]([O:36][CH:37]1[CH2:38][CH:43]=[CH:42][CH2:41]1)(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=CCC(CC=C)OC(=O)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: O=C(OC1CC=CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 22 h
Yield: 69.4 %

Procedure:
A 100 ml flask was charged with 0.53 g (1.9 mmol) of tricyclohexylphosphine, 0.62 g (1.0 mmol) of di-μ-chlorobis((p-cymene)chlororuthenium), 50 ml of toluene, 0.22 ml (2 mmol) of phenylacetylene and 8.28 g (38.3 mmol) of 1,6-heptadiene-4-yl benzoate and the mixture was stirred at 80° C. for 22 hours in a nitrogen stream. The reaction solution was washed with an aqueous 1% sodium hydroxide solution and saturated brine in this order, followed by drying using magnesium sulfate anhydride. A solvent was distilled and the residue was subjected to vacuum distillation (73-74° C./5 mmHg) to obtain 5.00 g of an object material in a yield of 69.4%.
Reaction SMILES: Br[C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]([CH2:11][CH3:12])[N:3]=1.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:11]([N:4]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[C:2]([C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[N:3]1)[CH3:12]
Reactant: CCn1nc(Br)c2ncccc21
Reactant: COc1ccc(B(O)O)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccc(OC)nc2)c2ncccc21
Yield: 88.9 %

Procedure:
To a mixture of 3-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (120 mg), 6-methoxypyridin-3-ylboronic acid (122 mg), Pd(OAc)2 (11.92 mg) and Xphos (50.6 mg) in THF (3 mL) was added a solution of Cs2CO3 (346 mg) in H2O (1 mL). The mixture was exposed to microwave irradiation at 100° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (120 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([S:13][CH2:14][CH2:15][CH2:16]Cl)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>>[C:7]1([S:13][CH2:14][CH2:15][CH2:16][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CNCCN1
Reactant: ClCCCSc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(SCCCN2CCNCC2)cc1

Procedure:
To 1 liter 50% aqueous alcohol are added 3 moles piperazine, 1 mole 3-phenylthio-1-chloropropane, 1 mole 10N sodium hydroxide. The mixture is refluxed for 24 hours, with stirring. The methanol is then evaporated off, and the resulting material is extracted with methylene chloride. The organic phase is thoroughly washed with water, and is then concentrated and distilled, to give 1-(3-phenylthiopropyl)piperazine, bp0.5 mm =140°-142° C.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[NH:6][C:5]1=O.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>CN(C)C=O>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][C:26]([NH:29]/[CH:3]=[C:4]3\[CH2:5][N:6]=[CH:7][C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)=[CH:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\CN=Cc4ccccc43)cc2)CC1
Temperature: 110 °C
Yield: 98.1 %

Procedure:
A mixture of 4-methoxymethylene-4H-isoquinoline-1,3-dione (101.5 mg, 0.5 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (95.6 mg, 0.5 mmol) in 1 mL of N,N-dimethylformamide is heated at 110° C. for 1 h. After cooling in the refrigerator, the precipitate is collected, and washed with ether to give 163 mg (90%) of yellow solid mp 245-246° C.; MS (ESI) m/z 363.19 (M+1); Analysis for C21H22N4O2: Calcd: C, 69.59; H, 6.12; N, 15.46. Found: C, 69.49; H, 6.10; N, 15.36.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:15][C@@H:16]([OH:45])[C@@H:17]([NH:33][C:34](=[O:44])[O:35][C@@H:36]3[C@H:43]4[C@H:39]([O:40][CH2:41][CH2:42]4)[O:38][CH2:37]3)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]CC4C=CC=CC=4)=[CH:21][CH:20]=3)(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CO[C:52](OC)([CH3:54])[CH3:53].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([N:14]([CH2:15][C@H:16]3[O:45][C:52]([CH3:54])([CH3:53])[N:33]([C:34]([O:35][C@@H:36]4[C@H:43]5[C@H:39]([O:40][CH2:41][CH2:42]5)[O:38][CH2:37]4)=[O:44])[C@H:17]3[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[CH2:46][CH:47]([CH3:48])[CH3:49])(=[O:12])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCCO2
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc2c(c1)OCCO2

Procedure:
250 mg of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-(4-benzyloxybenzyl)propylcarbamate, 2 mL of 2,2-dimethoxypropane, 0.5 g of p-toluenesulfonic acid in 50 mL of dichloromethane were refluxed for 3 h and then extracted with sodium bicarbonate solution. Chromatography on silica gel (1:1 ethylacetate/hexanes) gave 220 mg of the desired compound as an oil which was dissolved in methanol and hydrogenated (at 50 psi) over 5% palladium on carbon. Filtration and evaporation of the volatiles gave the desired title compound as an oil
Reaction SMILES: [ClH:1].[ClH:2].[CH2:3]([NH2:9])[CH:4]1O[CH2:7][CH2:6][CH2:5]1>>[ClH:1].[Cl:1][CH:4]([CH2:5][CH2:6][CH2:7][Cl:2])[CH2:3][NH2:9]
Reactant: NCC1CCCO1
Agent: Cl
Product: NCC(Cl)CCCCl
Temperature: 130 °C

Procedure:
1,500 parts of hydrochloric acid (chemically pure) are added to 137.5 parts of tetrahydrofurfurylamine hydrochloride at room temperature. The reaction solution is then heated to 130° C. in a pressure apparatus. This raises the pressure up to 8 bar. After a reaction time of 24 hours, the mixture is cooled to a temperature of 25° C. The dark brown solution is treated with activated carbon and filtered until it is clear, and the mother liquor is concentrated in a rotary evaporator. Recrystallization from 1,200 parts of ethanol gives 130 parts of an analytically pure product, 2,5-dichloropentylamine hydrochloride, having the following formula ##STR35##
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][C:3]=1[CH2:17][N:18]1[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]1.[OH-].[Na+].O>C(O)C.O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)=[N:4][C:3]=1[CH2:17][N:18]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a mixed solution of the compound (31 mg, 0.078 mmol) obtained in Example 71c in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (0.31 mL, 0.62 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (21 mg, 72%) as colorless crystals.