Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH:10]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:23][O:25][CH2:26][CH3:27])[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC=C(c2c[nH]c3ncccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCCn1cc(C2=CCN(C(=O)OCC)CC2)c2cccnc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.30 g (4.76 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid ethyl ester were dissolved in 11 ml of DMF and, at room temperature, 0.25 g (5.6 mmol) of 60% sodium hydride were carefully added. This mixture was stirred for half an hour at room temperature. 0.75 ml (6.0 mmol) of 2-bromoethyl ethyl ether were dropwise added and the stirring was continued for 24 hours at 60° C. The reaction mixture was cooled to room temperature and poured over cold water. This aqueous phase was extracted twice with dichloromethane and the organic phase was washed with water and brine, dried with magnesium sulphate, filtered and evaporated to dryness. The 1.46 g (74% of yield) of crude material were pure enough for the next synthetic step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:23][N:24]=[C:25]=[S:26].CCOCC>C1COCC1>[CH3:23][NH:24][C:25]([NH:19][NH:18][C:16](=[S:17])[NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]1[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)=[S:26]
Reactant: CN=C=S
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNC(=S)NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reaction time: 8 h

Procedure:
1.62 g (5 mmol) of N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]hydrazine carbothioamide are dissolved in 30 ml of THF, 0.44 g (6 mmol) of methyl isothiocyanate are added, and the reaction mixture is left to stand overnight at room temperature. Ether is added to complete precipitation and the precipitate formed is suction filtered, washed with ether and recrystallised from ethanol. The analytical values are summarized in Table I.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.BrCCBr.[Cu](C#N)C#N.[Cl-].[Li+].B(F)(F)F.CCOCC.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:35]=1[CH:36]=[O:37]>C1COCC1.[Zn].O>[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:35]=1[CH:36]([OH:37])[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: N#C[Cu]C#N
Agent: FB(F)F
Agent: [Cl-]
Solvent: BrCCBr
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1ccc(CC(O)c2c(Cl)cccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A solution of methyl 4-(bromomethyl)benzoate (2.0 g, 8.7 mmol) in THF (4.4 ml) was added slowly to cut zinc foil (683 mg, 10.44 mmol) which had been activated with 1,2-dibromoethane (80 mg). After 3 h of stirring at room temperature 2 ml of the solution was referred to a solution of copper cyanide (396 mg, 4.4 mmol) and lithium chloride (356 mg, 8.4 mmol) in THF (4 ml) cooled to −78°. This solution was warmed to −20° and then cooled back to −78°. Boron trifluoride etherate (983 μl, 8 mmol) was then added followed by 2,6-dichlorobenzaldehyde (0.56 g, 3.2 mmol) in THF (1 ml). The reaction was stirred for 2 h and then allowed to warm slowly to room temperature. Water (20 ml) was then added and the reaction mixture extracted into EtOAc (3×25 ml) and the combined organics dried (Na2SO4) and evaporated. Purification by column chromatography (SiO2; hexane:EtOAc. 4:1) gave the title compound as a colourless oil (863 mg, 83%). δH (CDCl3) 7.95 (2H, m, ArH), 7.93-7.26 (4H, m, ArH), 7.17-7.12 (1H, m, ArH), 5.73-5.65 (1H, m, CH), 3.91 (3H, s, CO2Me), 3.43 (1H, dd, J 13.5, 8.4 Hz, CHAB4}L ) and 3.28 (1H, dd, J 13.5, 6.3Hz, CHAHB), m/z (ESI, 60V) 325(MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH2:42][CH:41]3[N:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:38]([CH2:39][CH2:40]3)[CH:37]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:36]2[CH2:37][CH:38]3[N:43]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH:41]([CH2:40][CH2:39]3)[CH:42]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C2C=C(B3OC(C)(C)C(C)(C)O3)CC1CC2
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C2C=C(c3cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n4nccc4n3)CC1CC2
Temperature: 100 °C

Procedure:
To 5-chloro-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (11.1 g, 25.8 mmol) in DME (200 mL) was added tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (9.5 g, 28.4 mmol), PdCl2(dppf)2 (2.1 g, 2.6 mmol) and 2M Na2CO3 (100 ml). The reaction was heated at 100° C. for 16 hours, at which time LC/MS analysis confirmed full consumption of starting material. On cooling, H2O (80 ml) and EtOAc (200 ml) were added and the organics were extracted with EtOAc (2×250 ml), dried (Na2SO4) and concentrated in vacuo to give a crude product. Gradient column chromatography on silica eluting with 10% to 60% EtOAc/hexanes(0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl.C(OCC)C>[CH:24]([CH:21]1[CH2:22][CH2:23][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Oxalyl chloride (18.5 mL, 2M in DCM, 37.0 mmol) in DCM (230 mL) was cooled with a dry ice/acetone bath. DMSO (5.15 mL, 72.6 mmol) was added dropwise via addition funnel and the reaction was stirred for 10 min. N-Boc-4-piperidinemethanol in DCM (20 mL) was added dropwise via addition funnel and the reaction was stirred for 15 min. TEA (17.0 mL, 122 mmol) was then added dropwise via addition funnel and the reaction was warmed to rt. The reaction was diluted with diethyl ether, washed with H2O and brine, dried (MgSO4) and concentrated to provide the title compound (5.36 g, 25.1 mmol, 100%, approximately 96% pure, used without further purification). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29-1.34 (m, 3H), 1.37 (s, 9H), 1.75-1.83 (m, 2H), 2.87 (s, 2H), 3.78 (d, J=13.2 Hz, 2H), 9.56 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9][C@@H:8]2[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C@H:8]2[CH2:9][C:7]2([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=C(O)CC[C@H]1CC1(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CC[C@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
As in Example 111, (S)-2,2-diphenylcyclopropanepropanoic acid (6.38 g) and 4-nitrophenol (4 g) in dichloromethane (100 mL) was treated with 1,3-dicyclohexylcarbodiimide (4.95 g) and the mixture was stirred at 25° C. for 1 hour. The crude ester, isolated in the usual way, was crystallized from 2-propanol to give 4.8 g of (S)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester. The analytical sample was obtained from the same solvent, mp 76°-77° C.; [α]D25 -93.53° (c, 1.0, MeOH).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>CO>[NH:3]1[C:2]2[NH:1][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:6]=2[CH:5]=[N:4]1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cc[nH]n1
Solvent: CO
Product: CCOC(=O)c1cc2cn[nH]c2[nH]1
Yield: 110.4 %

Procedure:
3-Aminopyrazole (1.203 mmol, 0.1 g), ethyl bromopyruvate (1.504 mmol, 0.293 g) and methanol were added into a flask and refluxed for 1.5 h. The solvent was evaporated and the residue was dissolved in DCM and washed with Na2HCO3. The organic phase was dried, filtered and evaporated. 0.238 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.30 (t, 3H), 4.26 (q, 2H), 6.76 (d, 1H), 7.68 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([CH:20]=O)=[CH:17][CH:18]=2)[CH:13]=[N:12]1.N1CCCCC1>CCO>[NH:11]1[C:19]2[C:14](=[CH:15][C:16](/[CH:20]=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: O=Cc1ccc2[nH]ncc2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2/C1=C\c1ccc2[nH]ncc2c1
Temperature: 90 °C
Yield: 7.7 %

Procedure:
A scintillation vial was charged with indolin-2-one (67 mg, 0.500 mmol), 1H-indazole-5-carbaldehyde (73 mg, 0.550 mmol), piperidine (5.0 uL, 0.076 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed and the product purified by preparatory reverse-phase HPLC to give 10 mg, 7.6% of the title compound. 1H NMR (400 MHz, CD3OD) δ 8.20-8.18 (m, 2H), 7.89 (s, 1H), 7.76 (d, J=7.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.24 (t, J=7.4 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H); MS ESI 262.0 [M+H]+, calcd for [C16H11IN3O+H]+ 262.10.
Reaction SMILES: [C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[NH:14][CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](Cl)=[O:45].N1C=CC=CC=1.O>ClCCCl.C(OCC)(=O)C>[C:1]1([CH3:38])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:44](=[O:45])[C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)[CH2:13][CH:12]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=3)=[O:24])[C:11]2=[O:37])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CNc3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3cccs3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Yield: 91.1 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (500 mg) obtained from Step 1 of Example 93 was suspended in 1,2-dichloroethane (10 ml), 2-thienylcarbonyl chloride (157 mg) and pyridine (87 μl) were added, and the mixture was refluxed for 2 hours. Water (100 ml) and ethyl acetate (100 ml) were added, separated, the organic layer was washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was washed with diethyl ether, to thereby obtain 553 mg of the titled compound (Yield: 91.3%).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:34])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[C:30]([O:29][C:27]([NH:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:34])[C:12]=2[N:11]=[CH:1]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: CCOC(OCC)OCC
Reactant: CC(C)(C)OC(=O)NCCCNc1c(N)c(Cl)nc2ccccc12
Product: CC(C)(C)OC(=O)NCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 100 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
0.36 ml (2.14 mmol) of triethyl ortho-formate was added to 0.15 g (0.428 mmol) of 3-amino-4-[3-(tert-butoxycarbonylamino)-propylamino]-2-chloro-quinoline. The mixture was stirred at 100° C. for 2 hours and then at 80° C. for overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol 150:1 to 100:1 (v/v)) to obtain 0.14 g (0.388 mmol) of 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-1H-imidazo[4,5-c]quinoline shown below as white powder (mp: 155-156° C.). ##STR36## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3380, 1680, 1520.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[Cl-].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][Zn+])=[CH:18][CH:17]=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.C1COCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][CH:10]=[CH:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C[Zn+])cc1
Reactant: Ic1ccc(-c2ncco2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(Cc2ccc(-c3ncco3)cc2)cc1
Reaction time: 3 h
Yield: 81.5 %

Procedure:
C A Schlenk Flask was charged with tetrakis(triphenylphosphine)palladium(0) (0.42 g, 0.37 mmol), nitrogen, THF (20 ML), 2-(4-iodophenyl)oxazole (1 g, 3.7 mmol), and 4-methoxybenzyl zinc chloride (0.5 M in THF, 9.6 mL, 4.8 mmol). After 3 hours, the filtrate was concentrated. The resulting solid was treated with a mixture of ethyl acetate and a dilute aqueous ammonium chloride solution. The mixture was filtered and the organic layer was dried and concentrated. Purification on silica gel using a gradient of dichloromethane in hexane gave 0.8 g of 2-[4-[(4-methoxyphenyl)methyl]phenyl]oxazole, 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H), 7.68 (s, 1H), 7.27 (d, 2H), 7.22 (s, 1H), 7.13 (d, 2H), 6.82 (d, 2H), 3.96 (s, 2H), 3.78 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C([Mg:16][Br:17])(C)C>CCOCC>[F:8][C:7]1[C:2]([Mg:16][Br:17])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9]
Reactant: CC(C)[Mg]Br
Reactant: Fc1c(F)c(F)c(Cl)c(F)c1F
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F
Temperature: 60 °C

Procedure:
In a drybox, 31.45 g of chloropentafluorobenzene prepared as in Example 21 above (0.155 mole) and 64.42 g of a 2 molar ether solution of isopropylmagnesium bromide (iPrMgBr) (0.141 mole) are charged to a Fisher Porter reactor and heated to 60° C. for 4.5 hours. Pentafluorophenylmagnesium bromide is formed.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17]4[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[CH:20][C:18]=4[N:19]=3)=[CH:11][CH:10]=2)[S:3]1.[Mg].O.Cl>CO>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]4[CH:20]=[C:21]([Cl:25])[C:22]([Cl:24])=[CH:23][C:17]=4[N:16]=3)=[CH:11][CH:10]=2)[S:3]1
Reactant: O=C1NC(=O)C(=Cc2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc2)S1
Agent: Cl
Agent: [Mg]
Solvent: CO
Solvent: O
Product: O=C1NC(=O)C(Cc2ccc(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc2)S1
Temperature: 25 °C
Reaction time: 40 h
Yield: 19.9 %

Procedure:
A suspension of 2-[4-[(2,4-dioxothiazolidin-5-ylidene)methyl]phenyl]-5,6-dichlorobenzimidazole (100 mg, 0.256 mmol) and magnesium turnings (125 mg, 5.1 mmol) in methanol (20 mL) was stirred for 40 h at room temperature. Water and hydrochloric acid (1 mol/L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed washed with water and brine, dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (10:1 chloroform/methanol) and triturated with ethanol to give 2-[4-[(2,4-dioxothiazolidin-5-yl)methyl]phenyl]-5,6-dichlorobenzimidazole (20 mg, 20%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[O:9].[CH3:12][O:13]C(OC)N(C)C>C(O)(=O)C>[CH:12]([NH:10][C:8](=[O:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:11])=[O:13]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccccc1CC(N)=O
Solvent: CC(=O)O
Product: Cc1ccccc1CC(=O)NC=O
Temperature: 120 °C
Reaction time: 0.92 h

Procedure:
A mixture of 2-o-tolylacetamide (Lee, Dong-Ung; Mayer, Klaus K.; Wiegrebe, Wolfgang; Lauber, Rolf; Schlunegger, Urs P.; Arch. Pharm. 1988, 321; 265-272) (320 mg, 2.15 mmol) and N,N,-dimethylformamide dimethylacetal (1.1 mL, 8.59 mmol) was stirred under N2 for 55 min at 120° C. The excess of N,N,-dimethylformamide dimethylacetal was eliminated under reduced pressure. The residue was dissolved in 3 mL of 70% aqueous acetic acid and stirred at 0° C. for 30 min. The precipitate was filtered, washed with water and dried to afford the title compound as a white solid. MS (DCI/NH3) m/z 195 (M+NH4)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:10]=1[CH2:11][NH:12][C:13]1[N:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>O1CCCC1>[NH2:16][CH2:15][C:14]1[C:13]([N:12]=[CH:11][C:10]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:9]=2[O:8][CH3:7])=[N:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CNc2ncccc2C#N)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=Nc2ncccc2CN)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.5 %

Procedure:
Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was added slowly to a solution of 2-[(2,4-dimethoxybenzyl)amino]nicotinonitrile (2.80 g, 10.4 mmol) in tetrahydrofuran (35 mL) at 0° C. The reaction was allowed to warm to room temperature and stir for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.92 g). MS 274.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:15]3)=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:12][N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[CH2:15]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C(N1CCCC(COc2cccnc2)C1)C1(c2ccc(Cl)cc2)CCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Clc1ccc(C2(CN3CCCC(COc4cccnc4)C3)CCC2)cc1
Yield: 41 %

Procedure:
Compound 87 was synthesized from compound 85 (0.50 g, 1.25 mmol) and lithium aluminum hydride (0.10 g), using the method described for the synthesis of compound 83 to give 0.19 g of the desired product 87. C22H27ClN2O, LRMS (m/z)=371 (MH+).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32]N[CH2:30]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:33][CH2:34][CH:29]([CH3:30])[CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCCNC1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Solvent: CN(C)C=O
Product: CC1CCCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 86.9 %

Procedure:
To a solution of 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.50 g, 1.2 mmol, from Example S1-A) in DMF (5 mL) was added 3-methylpiperidine (0.47 g, 4.7 mmol). The reaction was reacted at 120° C. for 5 hours, cooled, and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel using hexane/ethyl acetate (5:1) to give 0.50 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27].[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42](Cl)(=[O:44])=[O:43].O1CCCC1.Cl>N1C=CC=CC=1>[CH3:28][O:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][C:34]=1[S:42]([NH:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]([CH3:26])=[CH:5][C:4]=1[OH:27])(=[O:44])=[O:43]
Reactant: CCCCCCCCCCCCCCCCOc1cc(N)c(O)cc1C
Reactant: COCCOc1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20 g of 2-amino-4-hexadecyloxy-5-methylphenol hydrochloride and 18 g of 4-(2-methoxyethoxy)nitrobenzene-3-sulfonyl chloride prepared as described in Step (a) above were added to a mixture of 100 ml of tetrahydrofuran and 10 ml of pyridine and the mixture was stirred at room temperature for 3 hours. The reaction mixture was added to a mixture of 300 ml of ice water and 50 ml of concentrated hydrochloric acid with stirring. The crystals thus-precipitated were recovered with filtration, washed with water, air-dried and recrystallized from 100 ml of acetonitrile. Yield: 35 g. Melting Point: 85.5° to 86° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:9]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:11][CH:12]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:10]2[NH:11][CH:12]=[C:8]([CH2:7][CH2:6][CH2:4][OH:3])[C:9]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Yield: 91 %

Procedure:
In a similar manner to that described in Example 1(vi) above, 4-(2-ethoxycarbonylethyl)-2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step 23(ii) above] was reduced using lithium aluminum hydride to afford the title compound (yield 91%) as a pale brown powder.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([C:23]1[O:24][C:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>C(Cl)(Cl)Cl>[CH2:28]([C:25]1[O:24][C:23]([CH:5]([C:4]([OH:35])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:27][CH:26]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cc2ccccc2)o1
Solvent: ClC(Cl)Cl
Product: O=C(NC(C(=O)O)c1ccc(Cc2ccccc2)o1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[(5-benzyl)furan-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 43) by the procedure described in Example 24. vmax (CHCl3) 3430, 3294, 1727, 1662 cm-1. δ (CD3SOCD3) 1.70-1.80 (2H, m), 2.40-2.74 (5H, m), 3.90 and 3.94 (2H, two s's), 5.30-5.35 (1H, m), 5.99-6.02 (1H, m), 6.22 and 6.26 (1H, two d's, J 4.10 Hz), 7.09-7.32 (10H, m), 8.48 (1H, d, J 6.98 Hz), m/z 423 (M+). [Found (HRMS): 423.1503. Calc for C24H25NO4S; 423.1504].