Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]([CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:52][OH:53]>CC(N(C)C)=O>[CH2:54]([C@H:51]([NH:50][C:26](=[O:28])[C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][N:16]=[CH:21][CH:20]=2)=[CH:30][CH:29]=1)[CH2:52][OH:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: N[C@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
In a microwave vial containing 3 eq. of PS-DCC, 4-(pyridin-4-yl)benzoic acid (20 mg, 0.1 mmol) was added dissolved in DMA (1.0 ml). Then a solution of HOBT (14 mg, 0.1 mmol) dissolved in DMA (0.3 ml) was added followed by the addition of DIEA (36 μl, 0.2 mmol) dissolved in DMA (0.3 ml) and the addition of (S)-2-amino-3-phenylpropan-1-ol (17 mg, 0.11 mmol) dissolved in DMA (0.6 ml). The mixture was heated in the microwave to 100° C. for 600 seconds. The reaction was filtered through Si-Carbonate, 6 ml-1 g supplied by Silicycle chemical Division and transferred to 20 ml vials. The reaction was checked by LC/MS and concentrated to dryness. The residues were dissolved in 1:1 DMSO/MeOH and purified by reverse phase HPLC (TFA method). Product was characterized by 1H NMR, MS and LC/MS.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:24])[C:5]1=[O:35].C(N(C(C)C)CC)(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)=[O:24])[C:5](=[O:35])[N:4]3[CH2:3][CH2:2][NH:1][S:46]([CH3:45])(=[O:48])=[O:47])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[3-(4-morpholinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.67 (s, 1 H), 1.99 (br. s., 2 H), 2.90 (s, 3 H), 3.07 (d, J=12.07 Hz, 2 H), 3.12-3.28 (m, 4 H), 3.39-3.51 (m, 4 H), 3.59-3.72 (m, 2 H), 3.92-4.04 (m, 1 H), 4.15 (s, 2 H), 4.35 (t, J=7.23 Hz, 2 H), 7.09-7.17 (m, 2 H), 7.29 (t, J=6.60 Hz, 1 H), 7.35-7.44 (m, 2 H), 8.13 (s, 1 H), 8.56 (d, J=1.40 Hz, 1 H), 9.80 (br. s., 1 H), 10.31 (t, J=5.83 Hz, 1 H); ES+ MS: 562 (M+H+).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5]([Cl:14])=[O:6]
Reactant: CON=C(C(C)=O)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CON=C(C(C)=O)C(=O)Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
2 drops of dimethylformamide are added to a solution, at 20° C., of 2-methoxyimino-3-oxo-butyric acid (syn isomer) (4.08 g) in diethyl ether (50 cc), and oxalyl chloride (2 cc) dissolved in ethyl ether (5 cc) is then added dropwise in the course of 15 minutes. The mixture is stirred for 1 hour at 20° C., a further drop of dimethylformamide is added, and the reaction is continued for 15 minutes. The mixture is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in petroleum ether (2×30 cc), the solvent being evaporated off, each time, at 20° C. under 20 mm Hg (2.7 kPa). The 2-methoxyimino-3-oxo-butanoyl chloride (syn isomer) thus obtained is dissolved in methylene chloride (50 cc), and a 5.4 N solution of hydrogen chloride in ether (0.2 cc), and bromine (1.14 cc) are added to this solution at 20° C. The mixture is stirred for 20 hours at 20° C. and is then concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa), and a brown oil consisting principally of 4-bromo-2-methoxyimino-3-oxo-butyryl chloride (syn isomer) (5.42 g) is obtained.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>O1CCOCC1>[Cl:20][C:21]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:22]=1[C:23]([NH:13][S:10]([C:8]([CH3:9])=[CH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:11])=[O:12])=[O:24]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CC(=Cc1ccccc1)S(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(=Cc1ccccc1)S(=O)(=O)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
Phenyl-propene-2-sulfonic acid amide is dissolved in dioxane followed by the addition of potassium carbonate and 2,4-dichlorobenzoyl chloride. The resulting solution is stirred in a sealed tube at 100° C. for 18.5 h, cooled to room temperature (RT) and partitioned between 1M HCl and ethyl acetate. The aqueous phase is separated and extracted with further portions of ethyl acetate. The organic fractions are combined, washed with brine, dried over MgSO4 and concentrated in vacuo. After flash column chromatography (dichloromethane) 1-phenyl-propene-2-sulfonic acid 2,4-dichlorobenzoylamide can be isolated as a colourless oil. Yield 55 mg (56%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[NH2:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][CH:44]=[CH:43]2>ClC(Cl)C>[NH:45]1[C:46]2[C:42](=[CH:41][C:40]([NH:39][C:5]3[C:4]4[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([I:1])[CH:3]=4)[N:8]=[CH:7][N:6]=3)=[CH:48][CH:47]=2)[CH:43]=[CH:44]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: COc1cc2nc[nH]c(=O)c2cc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2cc1I
Temperature: 50 °C
Yield: 27.1 %

Procedure:
In a round bottom flask 6-Iodo-7-methoxy-3H-quinazolin-4-one (500 mg, 1.65 mmol), triphenyl phosphine polymer (2.75 gm, 3 mmol/gm) and carbon tetrachloride (2.53 gm, 16.5 mmol) were combined in 3 mL of dichloroethane and heated at reflux for 5 hours. 5-Aminoindole (686 mg, 1.65 mmol) was added to the mixture and heated at 50° C. overnight. Reaction mixture was concentrated in vacuo and the residue was chromatographed on silica gel 20% MeOH/1% ammonium hydroxide (NH4OH)/CHCl3 to provide 186 mg (28%) of product as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C1(C)C=CC=CC=1>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (6.51 g), 1-Boc-piperazine (6.71 g) and potassium carbonate (9.95 g) were added dimethylformamide (15 mL) and toluene (30 mL), and the mixture was stirred at 100° C. for 2 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (9.42 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH:11][C:10]1[C:9](=[O:19])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:20]([Cu])#[N:21]>CN1C(=O)CCC1.O>[O:19]=[C:9]1[C:10]2[NH:11][C:12]3[C:4](=[CH:3][C:2]([C:20]#[N:21])=[CH:14][C:13]=3[C:15]([F:18])([F:17])[F:16])[C:5]=2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1CCCc2c1[nH]c1c(C(F)(F)F)cc(Br)cc21
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CCCC3=O
Temperature: 210 °C
Reaction time: 15 h
Yield: 79.9 %

Procedure:
6-Bromo-8-(trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one (600 mg, 1.8 mmol) and CuCN (480 mg, 5.4 mmol) were mixed together in NMP (6 mL) and stirred at 210° C. under N2 atmosphere for 15 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and filtered through a pad of Celite®. The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to obtain the crude material which was purified by washing with 10% EtOAc-hexane to afford the title compound as a pale brown solid (400 mg, 80%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.26 (bs, 1H), 8.22 (s, 1H), 7.86-7.90 (m, 1H), 3.09 (t, J=12.0 Hz, 2H), 2.77-2.70 (m, 2H), 2.40-2.31 (m, 2H). IR cm−1 2240 (CN)
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH2:11]([N:13]1[C:17]([CH:18]=[O:19])=[C:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35])=[CH:23][CH:22]=2)[C:15]([CH2:41][CH2:42][CH3:43])=[N:14]1)[CH3:12].CC(=CC)C>O.C(O)(C)(C)C.C1COCC1>[CH2:11]([N:13]1[C:17]([C:18]([OH:6])=[O:19])=[C:16]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][S:34]([C:37]([F:38])([F:40])[F:39])(=[O:35])=[O:36])=[CH:25][CH:26]=2)[C:15]([CH2:41][CH2:42][CH3:43])=[N:14]1)[CH3:12]
Reactant: O=P([O-])(O)O
Reactant: CCCc1nn(CC)c(C=O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCCc1nn(CC)c(C(=O)O)c1Cc1ccc(-c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 3 h
Yield: 56.3 %

Procedure:
A solution of sodium chlorite (0.4 g) and sodium dihydrogen orthophosphate (2.56 g) in water (5 ml) was added to a solution of the product of Example 88 (430 mg) and 2-methyl-2-butene (4.5 ml, 2M solution in THF) in t-butanol (5 ml) and THF (10 ml) and the resulting mixture stirred for 3 h. Solvent was removed in vacuo, the residue taken up in dichloromethane (10 ml) and washed with water (10 ml). 2N Sodium hydroxide (10 ml) was added to the organic solution and the organic layer removed. 2N Hydrochloric acid (~11 ml) was added to the aqueous phase which was then extracted with ethyl acetate (2×15 ml). The dried organic extracts were evaporated in vacuo to give a yellow gummy solid which was recrystaltised from System D (1:1) to give the title compound as a white solid (250 mg) m.p. 68°-72° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:28]([O:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:43](Cl)=[O:44])=[CH:38][CH:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH2:42][C:43]([NH:21][C:18]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:44])=[CH:40][CH:41]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-phenylpyrazin-2-amine (7a) (504 mg, 1.33 mmol) and 4-(dimethylamino)pyridine (16.3 mg, 133 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 18 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (100 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=4/1) to give Compound 11a (630 mg, 1.01 mmol, 75.4%) as a yellow foamy solid. Rf=0.33 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.18 (s, 6H), 0.23 (s, 6H), 0.94 (s, 9H), 0.96 (s, 9H), 3.47 (s, 2H), 6.72-6.79 (AA′BB′, 2H), 6.96-7.02 (AA′BB′, 2H), 7.03-7.09 (AA′BB′, 2H), 7.29-7.39 (m, 3H), 7.66-7.74 (m, 2H), 8.05-8.12 (AA′BB′, 2H), 8.98 (s, 1H), 10.54 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.9, 18.0, 25.50 (3C), 25.54 (3C), 41.7, 119.5 (2C), 120.3 (2C), 127.8 (2C), 127.9, 128.0 (2C), 128.2 (2C), 128.5, 128.9, 130.3 (2C), 130.5, 137.6, 142.8, 147.6, 148.0, 153.8, 156.7, 169.3; IR (KBr, cm−1) 523, 694, 781, 804, 839, 914, 1020, 1070, 1086, 1105, 1169, 1263, 1371, 1416, 1510, 1605, 1672, 2857, 2886, 2930, 2955, 3040, 3059, 3233; HRMS (ESI+) m/z 648.3043 ([M+Na]+, C36H47N3NaO3Si2+ requires 648.3048).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CS(Cl)(=O)=O.[CH:36]([N:39](CC)C(C)C)(C)C.CN.C1COCC1>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:23]5[CH:28]=[CH:27][C:26]([CH2:29][NH:39][CH3:36])=[CH:25][CH:24]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CO)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4′-(hydroxymethyl)-6-methylbiphenyl-3-yl)cyclopropanecarboxamide (610 mg, 1.52 mmol), methanesulfonyl chloride (0.13 mL, 1.7 mmol), and N,N-diisopropylethylamine (0.79 mL, 4.6 mmol) were dissolved in dichloromethane (10 mL) at 25° C. The reaction was stirred for 10 minutes before a 2.0 M solution of MeNH2 in THF (15 mL, 30 mmol) was added. The mixture was stirred for 30 minutes at ambient temperature before it was extracted with 1N HCl (20 mL×2) and saturated NaHCO3 (20 mL×2). The organic extracts were dried over Na2SO4 and evaporated. The crude product was purified by chromatography on silica gel (eluting with 0-20% methanol in dichloromethane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-((methylamino)methyl)biphenyl-3-yl)cyclopropanecarboxamide (379 mg, 60%). ESI-MS m/z calc. 414.5. found 415.5 (M+1)+; retention time 2.44 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH3:14])[C:5]=2[NH:4][N:3]=1.[CH3:15]OS(OC)(=O)=O>[OH-].[Na+].O>[CH3:15][N:3]1[C:2]([CH3:1])=[C:10]2[C:5]([N:6]([CH3:14])[C:7](=[O:13])[N:8]([CH3:12])[C:9]2=[O:11])=[N:4]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1n[nH]c2c1c(=O)n(C)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1c2c(=O)n(C)c(=O)n(C)c2nn1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of Step 4 intermediate (5.2 g, 26.77 mmol) in 1 N sodium hydroxide (52 ml) was added dimethylsulphate (5.2 ml) and stirred at room temperature for 1 h. The reaction mixture was diluted with water and the solid precipitated out was filtered, washed with water and dried to give 3.85 g of the product as off white solid; 1H NMR (300 MHz, CDCl3): δ 2.59 (s, 3H), 3.36 (s, 3H), 3.48 (s, 3H), 3.79 (s, 3H).
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1C#N.Cl.[OH-].[Na+].[CH2:19]([O:21]CC)C>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:19]([NH:7][C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:9]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOCC
Reactant: N#Cc1ccccc1N
Reactant: BrC1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopentyl bromide (2M in diethyl ether, 317 m].) was added dropwise a solution of 2-amino benzonitrile (25.0 g) in dry diethyl ether (400 ml) at 5°-10° C. under stirring for 2 hours. After completion of the addition, the mixture was allowed to warm to room temperature and then stirred at ambient temperature overnight. The reaction mixture was treated with 5N aqueous hydrochloric acid (150 ml) at 10°-20° C. and then stirred at room temperature for additional 30 minutes. To the mixture was added dropwise 5N sodium hydroxide aqueous solution. The resultant mixture was filtered by suction to remove an insoluble inorganic material. The organic layer was separated from the filtrate. The aqueous layer was extracted with ethyl acetate (2×200 ml). The organic layer and the extracts were combined and washed with a brine (100 ml). Dryness over sodium sulfate and evaporation under reduced pressure gave a crude product. The product was subjected by column chromatography on silica gel with a mixture of n-hexane and ethyl acetate (10:1) as an eluent to give |-cyclopentylcarbonylaniline (37.4 g) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([N:12]1[CH2:17][CH2:16][CH:15]([O:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH2:5]([N:12]1[CH2:13][CH2:14][CH:15]([O:18][CH2:19][C:20]([O:3][CH2:1][CH3:2])=[O:21])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: OCCOC1CCN(Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)COC1CCN(Cc2ccccc2)CC1
Reaction time: 48 h
Yield: 65.8 %

Procedure:
15.6 g (0.2 mole) of acetyl chloride were added dropwise while cooling at 20° C with an ice bath to a solution of 47 g (0.2 mole) of 2-(1-benzyl-4-piperidyloxy)-ethanol, prepared according to the step B of Example I, and 20.2 g (0.2 mole) of triethylamine in 300 ml of benzene and after standing for 48 hours at room temperature, the precipitate was removed by vacuum filtration. The benzene filtrate was washed with aqueous sodium bicarbonate solution, then water, dried and the benzene distilled off. The residue was distilled to obtain 36.5 g (66% yield) of ethyl 2-(1-benzyl-4-piperidyloxy)-acetate as a clear oil boiling at 160°-170° C at 0.1 mm Hg and having a refractive index nD20 = 1.512.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[C:6]([NH2:16])[C:5]=1[NH2:17].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].O.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:17]=[C:33]([C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[C:30]([F:29])([F:39])[F:40])[NH:16][C:6]=2[CH:7]=[C:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:9]=1)=[O:18]
Reactant: COC(=O)c1cc(N2CCOCC2)cc(N)c1N
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N2CCOCC2)cc2[nH]c(-c3ccccc3C(F)(F)F)nc12
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a mixture of 2,3-diamino-5-morpholin-4-yl-benzoic acid methyl ester (73; 600 mg, 2.39 mmol) in EtOH (60 ml) was added sodium metabisulfite (373 mg, 1.96 mmol), H2O (2 ml) and 2-trifluoromethylbenzaldehyde (74; 990 mg, 5.69 mmol). The resulting reaction mixture was stirred under reflux for 3 h. It was then cooled to room temperature and concentrated under reduced pressure. Purification by chromatography afforded 6-morpholin-4-yl-2-(2-trifluoromethyl-phenyl)-1H-benzoimidazole-4-carboxylic acid methyl ester 75 (670 mg, 69.2%) as a yellow solid.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2C([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[CH:4][C:5]([Br:16])=[CH:6]3)[CH:2]=1)=O.[OH-].[Na+]>O.C(O)(=O)C.[Hg]=O>[Br:16][C:5]1[CH:6]=[C:7]([C:14]([OH:15])=[O:13])[C:8]2[C:3]([CH:4]=1)=[CH:2][CH:1]=[CH:10][CH:9]=2
Reactant: O=C1OC(=O)c2cc(Br)cc3cccc1c23
Agent: O=[Hg]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)cc2ccccc12
Temperature: 25 °C

Procedure:
To a mixture of 3-bromo-1,8-naphthalic anhydride (compound 74, 22.8 g, 82.4 mmol) and sodium hydroxide (13.2 g, 330 mmol) in water (500 mL) was added a solution of mercury(II) oxide (23.2 g, 107 mmol) in water (70 mL) and glacial acetic acid (24 mL). The reaction mixture was heated at reflux for 4 days and then cooled to room temperature. The resulting solid was filtered and dried in vacuo.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][O:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:15][O:14][CH2:13][CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: OB(O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
A mixture of 4-mercaptophenylboronic acid (1.0 g, 90%, 5.84 mmol), 1-bromo-2-methoxyethane (1.8 g, 13 mmol) and K2CO3 (2.70 g, 19.5 mmol) in CH3CN (20 mL) was stirred at ambient temperature overnight. After CH3CN was removed, water was added to the residue, and the solid was collected via filtration and washed with water to give 0.9 g of the crude (4-{[2-(methoxy)ethyl]thio}phenyl)boronic acid (75% pure by LC-MS). The crude boronic acid was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11]Br)[N:8]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:28][C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)[N:8]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:7]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)c1cc(CBr)n(-c2c(Cl)cccc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(COc2ccc(Br)cc2)n(-c2c(Cl)cccc2Cl)n1

Procedure:
Into a 500 mL flask was weighed 19.3 g (53 mmol) of 5-bromomethyl-1-(2,6-dichloro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester, 13.7 g (79 mmol) of 4-bromophenol, 10.9 mg (79 mmol) of potassium carbonate, and 100 mL of ACN. The reaction mixture was heated to reflux for 4 h. After cooling, the crude reaction mixture was washed into a separatory funnel with ethyl acetate and water. The organic layer was separated, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography on silica eluting with DCM-methanol (100:0 to 98:2) to afford 5-(4-bromophenoxymethyl)-1-(2,6-dichlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester as an off white solid (25.3 g, 100%); 1H NMR (400 MHz, CDCl3): δ 7.45 (m, 6H), 7.06 (s, 1H), 6.67 (d J=8.8 Hz 2H), 4.88 (s, 2H), 4.43 (q, J=7.07 Hz 2H), 1.41 (t, J=7.07 Hz 3H), MS (ES): 491 [M+Na]+.