Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Mg].[CH3:10][O:11][C:12]([C:14]12[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:21][CH2:20][C:19](=[O:29])[CH:18]1[CH2:17][N:16]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15]2)=[O:13].[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]([C:14]12[CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][C:19]([OH:29])([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[CH:18]1[CH2:17][N:16]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:15]2)=[O:13]
Reactant: Cc1ccc(Br)cc1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(O)(c1ccc(C)cc1)CCC2c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5.1 cm3 of 4-bromotoluene and 1 g of magnesium turnings in 100 cm3 of diethyl ether were heated at reflux for one hour. 100 cm3 of toluene were added and the mixture was heated to 60° C. under a stream of nitrogen. After cooling to a temperature in the region of 5° C., a solution of 10 g of methyl(3aRS,4SR,7aRS)-2-benzyl-7-oxo-4-phenyloctahydroisoindole-3a-carboxylate in 80 cm3 of toluene was added. The reaction mixture was stirred for one hour at a temperature in the region of 20° C. and then hydrolysed with 100 cm3 of a saturated aqueous ammonium chloride solution. The aqueous phase was separated by settling and extracted with two times 75 cm3 of ethyl acetate. The organic phases were combined, washed successively with 100 cm3 of distilled water and 100 cm3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. After purification by flash chromatography on silica gel (230-400 mesh), elution was carried out with a cyclohexane/ethyl acetate (80/20 by volume) mixture, 9 g of methyl(3aRS,4SR,7RS,7aRS)-2-benzyl-7-hydroxy-7-(4-methylphenyl)-4-phenyloctahydroisoindole-3a-carboxylate were obtained in the form of a white solid, the characteristics of which were as follows:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:41]=[CH:40][CH:39]=[CH:38][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[C:14]2([CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]2)[N:13]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[O:16]=[C:15]1[C:14]2([CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[N:13]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:12][N:11]1[CH2:10][C:9]1[CH:38]=[CH:39][CH:40]=[CH:41][C:8]=1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCNCC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To a solution of benzyl 3-(2-(tert-butoxycarbonyl)benzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.59 g, 1.06 mmol) in methanol (20 mL), was added 10 wt % palladium on carbon (0.1 g). After stirring under hydrogen at room temperature and atmospheric pressure for 2 hours, the reaction mixture was filtered, washed with methanol, concentrated in vacuo to obtain tert-butyl 2-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.4 g, 90%).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([OH:30])=O)[C:17]=3[C:16]=2[CH:15]=1.CNC.O>O1CCCC1>[F:13][C:14]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:37])[N:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:25]=[C:26]([CH2:27][C:28]([N:3]([CH3:4])[CH3:1])=[O:30])[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
A suspension of 1.7 g (10.5 mmol) of 1,1′-carbonylbis-1H-imidazole and of 3 g (8.9 mmol) of 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid in 300 ml of tetrahydrofuran is stirred at 40° C. for 3 h. The mixture is cooled to room temperature, 10 ml of liquefied dimethylamine are added and the mixture is stirred for 2 h. After standing overnight, 300 ml of water are added and the precipitate is collected by filtration and recrystallized from dimethylformamide. 0.8 g (2.2 mmol) of solid is obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenylphosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([F:13])[CH:3]=1.[CH:14]([C:16]([CH3:18])=O)=[CH2:15]>>[F:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]2[C:3]=1[C:16]([CH3:18])=[CH:14][CH:15]=[N:1]2
Reactant: COc1cc([N+](=O)[O-])c(N)cc1F
Reactant: C=CC(C)=O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1F
Yield: 32 %

Procedure:
The intermediate 4-amino-2-fluoro-5-nitroanisole and methyl vinyl ketone were subjected to a Skraup reaction. A 32% yield of crude 5-fluoro-6-methoxy-4-methyl-8-nitroquinoline resulted. It was obtained in pure form by recrystallization from ethyl acetate. The recovery was 73% of product which melted 142°-144°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1I.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:25]3[CH:26]=[CH:27][C:28]([C:30]([F:33])([F:32])[F:31])=[CH:29][C:24]=3[Cl:23])=[CH:16][CH:15]=2)[N:13]=1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(C(F)(F)F)cc2Cl)cc1
Yield: 25.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 2-chloro-1-iodo-4-(trifluoromethyl)benzene (0.147 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.51 (d, J=8.7 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.67-7.87 (m, 3H), 7.84 (t, J=8.4 Hz, 2H), 8.05 (d, J=8.4 Hz, 2H), 8.11 (s, 1H), 12.75 (br s, 1H). MS (m/z): 492.22 (M+).
Reaction SMILES: [F:1][C:2]1([F:16])[C:7](O)(O)[CH2:6][CH2:5][N:4](C(=O)C(F)(F)F)[CH2:3]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:24][CH:7]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1([F:1])[F:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N1CCC(O)(O)C(F)(F)C1)C(F)(F)F
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: FC1(F)CNCCC1NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In a 100 mL flask, 2.00 g (8.0 mmol) of 3,3-difluoro-4,4-dihydroxy-1-trifluoroacetylpiperidine 13 (J. Org. Chem. 2010, 75, 929-932) and 2.15 g (20.0 mmol; 2.5 equiv) of benzylamine were dissolved in 50 mL of toluene. The mixture was heated under reflux with a Dean Stark trap during 15 hours. After cooling to room temperature, the solvent was removed in vacuo. The resulting oil was dissolved in 25 mL of absolute methanol and 0.56 g (8.8 mmol; 1.1 equiv) of sodium cyanoborohydride and 0.48 g (8.0 mmol; 1 equiv) of acetic acid were slowly added at room temperature. The solution was stirred during 4 hours at room temperature. After removing the solvent under vacuum, the crude oil was redissolved in 50 mL of dichloromethane and poured in 50 mL of a saturated aqueous NaHCO3 solution and was subsequently extracted with dichloromethane (3×50 mL). The combined organic layers were washed with brine and dried over MgSO4. Filtration of the solids and evaporation of the solvent resulted in a crude oil which was purified via flash chromatography (EtOAc, Rf=0.03) yielding 1.32 g (5.8 mmol; 73% yield) of benzyl-(3,3-difluoro-piperidin-4-yl)amine 14 as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]2)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@:25]([OH:40])([C@H:32]([S:34][CH:35]([CH2:38][OH:39])[CH2:36][OH:37])[CH3:33])[CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:40])([CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)[C@H:32]([S:34][C@@H:35]1[CH2:36][O:37][C@@H:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:6]3)[O:39][CH2:38]1)[CH3:33]
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)c1ccc2cc(C=O)ccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2cc([C@H]3OC[C@H](S[C@H](C)[C@](O)(Cn4cncn4)c4ccc(F)cc4F)CO3)ccc2c1
Temperature: 0 °C

Procedure:
A solution of methyl 6-formyl-2-naphthalenecarboxylate (227 mg, 1.06 mmol) obtained in example 3 (2), (2R,3R)-2-(2,4-difluorophenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol (381 mg, 1.06 mmol) and p-toluenesulfonic acid monohydrate (363 mg, 1.91 mmol) in anhydrous tetrahydrofuran (50 ml) was concentrated at room temperature using a rotary evaporator under reduced pressure and then using a vacuum pump. A solution of the residue in anhydrous tetrahydrofuran (40 ml) was concentrated according to the procedure described above. The same procedure was repeated twice. A solution of the resulting residue in tetrahydrofuran (50 ml) was poured into a saturated aqueous sodium hydrogencarbonate solution cooled to 0° C. with stirring. The mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:2) as the eluant to afford methyl 6-[trans-5-[((1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (trans isomer, 331 mg, yield 56%) as a white solid, and then using ethyl acetate-hexane (3:1) as the eluant to afford methyl 6-[cis-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]-2-naphthalenecarboxylate (cis isomer, 77 mg, yield 14%) as a colorless oil. The trans isomer was recrystallized from ethyl acetate-hexane to give white fluffy crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH2:57])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7].CCN(C(C)C)C(C)C.[O:69]1[CH2:72][CH:71]([O:73][C:74](=O)[O:75]C2C=CC([N+]([O-])=O)=CC=2)[CH2:70]1>C(#N)C>[CH3:1][O:2][C:3](=[O:59])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:20][C:19]2[C:21]3[C:26]([CH:27]=[CH:28][C:18]=2[N:17]=1)=[CH:25][C:24]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]4[NH:40][C:41]([CH:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49](=[O:58])[CH:50]([NH:57][C:74]([O:73][CH:71]5[CH2:72][O:69][CH2:70]5)=[O:75])[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)=[N:42][CH:43]=4)[CH:35]=2)[CH:30]=1)=[CH:23][CH:22]=3)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(N)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc3cc(-c4ccc5cc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC7COC7)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 3 h
Yield: 311.9 %

Procedure:
(1-{2-[7-(6-{2-[1-(2-Amino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.200 g, 0.22 mmol) was dissolved in acetonitrile (2.2 mL). DIPEA (0.155 mL, 0.8905 mmol) and Carbonic acid 4-nitro-phenyl ester oxetan-3-yl ester (0.059 g, 0.244 mmol) was added, and the solution was allowed to stir for about three hours. Upon completion, the crude product was purified by reverse phase HPLC (10-50% acetonitrile:water; 0.1% formic acid modifier), and lyophilized giving [2-Methyl-1-(2-{7-[6-(2-{1-[2-(oxetan-3-yloxycarbonylamino)-2-phenyl-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-naphthalen-2-yl]-1H-naphtho[1,2-d]imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (0.61 g, 31% yield). LCMS-ESI+: calc'd for C51H52N8O7: 888.40 (M+); Found: 889.86 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Yield: 75 %

Procedure:
According to the general procedure as outlined above for the synthesis of intermediate 43, f 5-chloroisatin, compound VIII, (10.0 g, 55.07 mmol) was reacted with potassium carbonate (9.89 g, 5.03 mmol) and tert-butyl bromoacetate (8.95 ml, 60.58 mmol) in N,N-dimethylformamide (100 ml) to give the title compound (12.14 g, 75%) as orange solid (HPLC purity: 99%) after precipitation from water. MS (ESI−): 294.2
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([OH:12])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]([CH2:24]Cl)=[CH2:23]>CC(C)=O>[CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:13])[C:8]([O:12][CH2:24][C:22]([Cl:21])=[CH2:23])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1
Reactant: C=C(Cl)CCl
Reactant: Cc1cc(=O)oc2c(C)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(Cl)COc1ccc2c(C)cc(=O)oc2c1C
Yield: 77 %

Procedure:
A mixture of 4,8-dimethyl-7-hydroxycoumarin (8.00 g., 42.1 m mole); anhydrous potassium carbonate (18.1 g., 130 m mole); 2,3-dichloropropene (33.6 g., 302 m mole); and acetone (600 ml.) was stirred and heated under reflux for twenty-four hours. The reaction mixture was concentrated to ca. 200 ml., filtered, and the inorganic salts were washed with acetone. Evaporation of the combined filtrate and washing under reduced pressure left a tan-colored residue (11.30 g.). Recrystallization from aqueous methanol gave a 77% yield of 4,8-dimethyl-7-(2'-chloroallyloxy)coumarin as small, off-white needles (8.55 g., m.p. 117.5°-120° C.). Another recrystallization did not change the m.p. but gave an analytical sample.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20]>>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([F:19])=[CH:15][C:14]=1[F:20]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Fuming nitric acid 90% (8.5 mL, 0.19 mol) was added with gentle stirring to concentrated sulfuric acid 98% (125 mL) in a 1 L beaker. After stirring for 10 minutes at room temperature, 2,4-difluorobenzoic acid methyl ester (21.9 g, 0.127 mol) was added dropwise. After the addition, the reaction mixture was allowed to stir gently for 40 minutes at room temperature. The reaction mixture was then poured into ice-H2O (1 L) and stirred for 10 minutes. The mixture was extracted with EtOAc. The layers were separated, and the organic layer was washed sequentially with 1N NaCl, saturated NaHCO3, H2O and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow residue. This residue was washed with 10% EtOAc/hexane, filtered, and dried to yield a pale yellow solid, 29.0 g (0.133 mol, 82%). mp 78-80° C. Analysis for C8H5F2NO4: Calcd: C, 44.25; H, 2.32; N, 6.45. Found: C, 44.18; H, 2.39; N, 6.14.
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].C(OCC)C.P(Br)(Br)[Br:17]>N1C=CC=CC=1>[Br:17][CH2:2][CH2:3][S:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: BrP(Br)Br
Reactant: COC(=O)CCSCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CCSCCBr
Temperature: 25 °C
Reaction time: 5 h

Procedure:
8.2 g. of this ester are dissolved in 27 ml. anhydrous diethyl ether, 0.8 ml. pyridine is added thereto and then 1.9 ml. phosphorus tribromide is added dropwise, while cooling with ice. The reaction mixture is subsequently stirred for 5 hours at ambient temperature. Ice water is then added thereto, followed by extraction with diethyl ether. The extract is washed with water, dried and evaporated to give 10.1 g. of an oil which is chromatographed with 480 g. of silica gel, using ligroin-diethyl ether (2:1 v/v) as elution agent, 7.1 g. methyl 3-(2-bromoethylthio)-propionate being obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=2)[C:3]=1[C:18]([NH2:20])=[O:19].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1>CCO.N1CCCCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:4]2[C:3]([C:18]([NH2:20])=[O:19])=[C:2]([N:1]=[CH:26][C:25]3[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=3)[NH:6][N:5]=2)=[CH:13][CH:12]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(Nc2n[nH]c(N)c2C(N)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)c1ccc(Nc2n[nH]c(N=Cc3ccc(O)cc3)c2C(N)=O)cc1

Procedure:
5-amino-3-((4-(tert-butyl)phenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (325 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-(tert-butyl)phenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][NH:6][C:7]([NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:12](C)[CH:11]=1)=[O:8])C>Cl>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:21])=[O:3])=[CH:11][CH:12]=1
Reactant: CCOC(=O)CNC(=O)Nc1cc(C)nc2ccccc12
Agent: Cl
Product: O=C(O)CNC(=O)Nc1ccnc2ccccc12
Temperature: 80 °C

Procedure:
[3-(2-Methyl-quinolin-4-yl)-ureido]-acetic acid ethyl ester (7.2 g, 25 mmol) is suspended in 6N aqueous HCl (250 mL), and the mixture is heated at 80° C. for 15 h. The mixture is cooled, filtered from the resulting precipitate and the solid dried to provide the title compound as hydrochloride salt.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH2:19]([NH:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[CH3:20]>>[CH:22]1([N:21]([CH2:19][CH3:20])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCNC1CCCCC1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Product: CCN(c1cc(C(=O)Nc2ccc(O)cc2C)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and N-ethylcyclohexylamine (Aldrich), the title compound was obtained as a yellow solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[I:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]2)[CH:10]=1.[BH4-].[Na+].[OH-].[Na+]>CCO>[I:5][C:6]1[CH:7]=[N:8][N:9]([CH:11]2[CH2:16][CH2:15][CH:14]([NH:1][CH2:2][CH2:3][OH:4])[CH2:13][CH2:12]2)[CH:10]=1
Reactant: O=C1CCC(n2cc(I)cn2)CC1
Reactant: NCCO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCCNC1CCC(n2cc(I)cn2)CC1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
2-Amino-ethanol (0.30 mL; 4.96 mmol; 1.4 eq.) was added in one portion to a solution of 4-(4-Iodo-pyrazol-1-yl)-cyclohexanone (intermediate 20; 1.00 g; 3.45 mmol; 1.0 eq.) in EtOH. After 1 h the reaction solution was cooled to 0° C. and NaBH4 (290 mg; 7.67 mmol; 2.2 eq.) added portionwise over 1 min. After a further 1 h the reaction suspension was poured into 1 N NaOH solution and extracted with DCM. Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification using a SCX-2 cartridge afforded the title compound as a white solid (1.00 g; 84%). 1H NMR (300 MHz, DMSO) δ 7.94 (s, 1H), 7.49 (s, 1H), 4.47 (brs, 1H), 4.12 (m, 1H), 3.45 (m, 2H), 2.60 (t, J=5.8 Hz, 2H), 2.41 (m, 1H), 2.95 (m, 4H), 1.72 (m, 2H), 1.13 (m, 2H).