Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.N1C=CC=CC=1.Cl[C:49]([O:51][CH3:52])=[O:50]>C(Cl)Cl>[C:17]1([C@H:15]([NH:14][C:12](=[O:13])[NH:11][C:9]2[N:8]=[CH:7][C:6]3[C:2]([NH:1][C:49](=[O:50])[O:51][CH3:52])=[N:3][N:4]([C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:5]=3[CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)Cl
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a 50 mL round bottom flask charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (380 mg, 0.705 mmol) in DCM (10 ml) was added pyridine (1 ml) followed by methyl chloroformate (65 μl, 0.847 mmol). The flask was capped and the contents stirred at room temperature for 16 h. An additional aliquot of methyl chloroformate (65 μL, 0.847 mmol) was added to push the reaction to completion. The volatiles were removed in vacuo, the resulting residue redissolved in DCM and washed with saturated copper sulfate solution (2×10 mL). The organics were separated using a phase separator cartridge and concentrated. The resulting residue was purified by flash column chromatography on silica gel (ISCO; 80 g prepacked) eluting with ethyl acetate/hexanes to give (R)-methyl (6-(3-(1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)carbamate (371 mg, 0.622 mmol, 88%) as a white solid. MS ESI calc'd. For C36H33N6O3 [M+H]+ 597. found 597.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[N:12][CH:13]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36](OB(O)O)=[CH:35][CH:34]=1>O1CCOCC1>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][CH2:16][N:17]3[C:25]4[C:20](=[CH:21][C:22]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:23][CH:24]=4)[CH:19]=[CH:18]3)=[N:12][CH:13]=2)=[CH:35][CH:34]=1
Reactant: Brc1ccc(C#CCn2ccc3cc(CN4CCCC4)ccc32)nc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Clc1ccc(-c2ccc(C#CCn3ccc4cc(CN5CCCC5)ccc43)nc2)cc1
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere 0.5 mL 2 M Na2CO3 solution and 10 mg (0.01 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 59 mg (0.15 mmol) 1-[3-(5-bromo-pyridin-2-yl)-prop-2-ynyl]-5-pyrrolidin-1-ylmethyl-1H-indole and 50 mg (0.32 mmol) 4-chlorophenyl-boric acid in 5 mL 1,4-dioxane and the reaction mixture is stirred for 2.5 h at 110° C. The mixture is evaporated down i. vac., the residue is combined with 3 mL water, extracted with 5 mL EtOAc, the organic phase is washed with saturated NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by HPLC.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([NH:19][O:20]C(OC)CCCC)=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.CO>C(Cl)Cl>[C:1]1([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:32])([S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([NH:19][OH:20])=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCC(OC)ONC(=O)C(C)(CCc1ccc(C2=CCCCCC2)cc1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCc1ccc(C2=CCCCCC2)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
4-(4-Cyclohept-1-en-1-ylphenyl)-N-[(1-methoxypentyl)oxy]-2-methyl-2-(methylsulfonyl)butanamide (205 mg, 0.36 mmol) was dissolved in methylene chloride (4 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 1.82 mL, 7.30 mmol) and the solution was stirred at rt for 20 minutes. Methanol (500 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography eluting with methylene chloride/methanol to afford 4-(4-cyclohept-1-en-1-ylphenyl)-N-hydroxy-2-methyl-2-(methylsulfonyl)butanamide as a solid. 91.5 mg. LCMS: (M+1) 366.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:26]=[CH:25][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2].[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]([CH3:30])[CH3:29])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:34][C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:43])[F:44])=[CH:39][CH:40]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:25][CH:26]=3)=[N:8][C:7]=2[CH:27]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(Cc5ccc(C(F)(F)F)cc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 14.4 %

Procedure:
To a solution of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)-N-(piperidin-4-ylmethyl)benzamide (25 mg, INTERMEDIATE 15) in tetrahydrofuran (5 ml) was added sodium hydride (5 mg of a 60% dispersion in oil). The reaction was allowed to stir at room temperature for five min, and then 1-(bromomethyl)-4-(trifluoromethyl)benzene was added. The reaction was stirred for 1 h and then was concentrated. The residue was purified by reverse-phase HPLC on a Biotage Parallex Flex, Kromasil C18 21×100 mm column, eluting at 15 ml/min with 90% water (0.1% TFA) to 95% acetonitrile (0.1% TFA) over 10 min, hold for 2 min, then back to 90% water over 0.5 min, hold for 0.5 min, to provide the title compound (5 mg, 14.4%). Mass spectrum (ESI) 561.2 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J=8.5 Hz, 2H), 7.92-7.94 (m, 3H), 7.55 (d, J=8 Hz, 2H), 7.50 (s, 1H), 7.42 (d, J=8 Hz, 2H), 6.37 (m, 1H), 3.54 (s, 2H), 3.44-3.51 (m, 2H), 3.40 (m, 2H), 2.89 (m, 2H), 1.98-2.03 (m, 2H), 1.83 (s, 1H) 1.74-1.77 (m, 2H), 1.67-1.71 (m, 1H), 1.45 (d, J=7 Hz, 6H), 1.36-1.40 (m, 2H), 1.25 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:26])/[CH:5]=[C:6](\[CH3:25])/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]#[C:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])C.[OH-].[Na+]>C1COCC1.CCO>[CH3:25]/[C:6](/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]#[C:15][C:16]1[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:24])=[CH:5]\[C:4]([OH:26])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(C#CC2=C(C)CCCC2(C)C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1=C(C#CC2=C(/C=C/C(C)=C/C(=O)O)CCC2)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
(2E,4E)-3-Methyl-5-[2-(2,6,6-trimethyl-cyclohex-1-enylethynyl)-cyclopent-1-enyl]-penta-2,4-dienoic acid ethyl ester (1. 47 g) was dissolved in 14 ml of THF/EtOH=1/1. 3N aqueous NaOH (7.0 ml) was added and the reaction flask kept in the dark. After stirring for 16 hours at ambient temperature, the mixture was poured onto crushed ice/HCl, extracted twice with EtOEt, washed with water, dried over Na2SO4, and evaporated to dryness. Crystallization from EtOEt/pentane afforded 1.31 g of (2E,4E)-3-Methyl-5-[2-(2,6,6-trimethyl-cyclohex-1-enylethynyl)-cyclopent-1-enyl] -penta-2,4-dienoic acid as yellow crystals of mp. 173-174° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:15]1([S:21]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
To a solution of indole (2.4 g, 20 mol) in dry THF (20 ml) under argon at −78° C. was added dropwise via syringe over 10 min n-butyllithium (1.6M in hexanes; 14 ml). The cooling bath was removed and the solution was stirred for 1 h while warming to 0° C. The resulting indole anion precipitated as a very fine white solid in a cloudy colorless solution. After the suspension was recooled to −78° C., benzenesulfonyl chloride (2.8 ml, 22 mmol) was added via syringe over 20 min, keeping the temperature below −60° C. The resulting colorless mixture was allowed to warm slowly to room temperature overnight, poured into 2% aqueous sodium bicarbonate (30 ml), and extracted with ethyl acetate (2×25 ml). The combined extracts were washed with 2% aqueous sodium bicarbonate(30 ml), water (2×25 ml), dried over anhydrous sodium sulphate, and evaporated to give a light amber oil which crystallized when triturated with 2:1 hexane/ether (15 ml). After standing in the cold (−20° C.) for several hours, the product was collected by filtration, washed with hexane, and dried in vacum to provide pure 1-phenylsulfonyl-indole (60) as white crystals (4.8 g, 90.6%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([O:22][CH2:23][CH:24]=[CH2:25])[CH:19]1[O:21][CH2:20]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[CH2:23]([O:22][CH2:18][CH:19]([OH:21])[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:20][CH:19]([OH:21])[CH2:18][O:22][CH2:23][CH:24]=[CH2:25])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH:24]=[CH2:25]
Reactant: C=CCOCC1CO1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: C=CCOCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COCC=C)cc2)cc1
Temperature: 110 °C

Procedure:
Bisphenol A (228 g; 1 mole), allyl glycidyl ether having an epoxide content of 8.64 equiv./kg (231.5 g; 2 equiv.), and benzyltrimethylammonium chloride (2 g) were stirred together and heated to 110° C., at which temperature an exothermic reaction commenced, the temperature rising spontaneously to 120° C. When the temperature began to fall, heating was resumed to keep the mixture at 120° C. After 11/2 hours at this temperature the mixture was heated at 150° C. for 3 hours. The residual mixture had an epoxide content of 0.20 equiv./kg, indicating that the reaction was essentially complete.
Reaction SMILES: Br[CH:2]([O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:3](=[O:11])[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6]Cl.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:2]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[C:3]2[C:4]([CH2:9][CH3:10])([CH3:8])[CH2:5][CH2:6][O:11]2)=[CH:14][CH:15]=1
Reactant: c1c[nH]cn1
Reactant: CCC(C)(CCCl)C(=O)C(Br)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(C)CCOC1=C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 14 %

Procedure:
69.9 g (0.19 mole) of 1-bromo-1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone, 26.2 g (0.38 mole) of imidazole and 52.4 g (0.38 mole) of potassium carbonate in 500 ml of toluene are heated at 90° C. for 10 hours. The reaction mixture is then allowed to cool and is poured onto 500 ml of water. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated. The residue is purified by column chromatography (ethyl acetate/cyclohexane=3:1). 8.5 g (14% of theory) of (4-chlorophenoxy)-(imidazol-1-yl)-(3-ethyl-3-methyltetrahydrofuran-2-ylidene)-methane of refractive index nD20 1.5552 are obtained.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:37])=[CH:7][CH:6]=1)([OH:4])=O.[C:38]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])(=[O:41])[NH:39][NH2:40]>>[C:43]([O:42][C:38]([NH:39][NH:40][C:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:37])=[CH:9][CH:10]=1)=[O:4])=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)O)cc1
Agent: [Na]
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1-c1ccc(C(=O)NNC(=O)OC(C)(C)C)cc1

Procedure:
The compound obtained in Example 21 and tert-butyl carbazate are treated in the same manner as in Example 22 to give 2-[4-(tert-butoxycarbonylhydrazinocarbonyl)phenyl]-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][OH:13])=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromophenol (10 g, 58 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (9.6 g, 69 mmol) and potassium carbonate (13.6 g, 98 mmol). The mixture was stirred at room temperature for 12 h. LCMS showed the reaction was almost complete. The mixture was partitioned between water and ethyl acetate (20 mL×3), The combined organics were dried and concentrated to give the title compound that was used in the next step without further purification (14.7 g, quant). 1H NMR (400 MHz, CD3OD) δ 7.36 (d, 2 H), 6.84 (d, 2 H), 4.05 (t, 2 H), 3.72 (t, 2 H), 1.96 (m, 2 H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:18][C:19]1[CH:24]=[N:23][CH:22]=[C:21](I)[N:20]=1>O1CCCC1.CN(C)C=O.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>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:21]2[CH:22]=[N:23][CH:24]=[C:19]([I:18])[N:20]=2)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cncc(I)n1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccccc1
Temperature: 100 °C
Yield: 15.3 %

Procedure:
Part B. An oven-dried sealed tube was charged with 2-bromo-4-methyl-thiazole-5-carboxylic acid benzylamide (800 mg, 2.57 mmol, 1.0 equiv). The sealed tube was purged with nitrogen and Rieke zinc (10 mL, 10 g of zinc in 100 mL of tetrahydrofuran) was added. The reaction was heated in the microwave oven for 15 min. at 100° C. Stirring was stopped and the remaining zinc was allowed to settle. The supernatant containing the zinc reagent was transferred via syringe to a solution of 2,6-diiodopyrazine (680 mg, 2.1 mmol, 0.8 equiv), Pd(PPh3)4 (236 mg, 0.2 mmol, 7 mol %) in tetrahydrofuran (5 mL) and dimethyl formamide (0.2 mL). The reaction mixture was purged with nitrogen for 10 min, then stirred at 160° C. for 16 hr. After cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography [SiO2, ethyl acetate/heptane, 10:90 to 40:60, v/v] to afford 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid benzylamide (140 mg, 13%). MS (M+H)+=436, Rt=1.51 min.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[C:5]1[C:10]2[N:11]([CH3:15])[C:12](=[O:14])[NH:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.O>[Br:19][C:8]1[C:9]2[NH:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=2[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: CCCN(CCC)c1cccc2[nH]c(=O)n(C)c12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCN(CCC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Yield: 27.7 %

Procedure:
A mixture of 7-dipropylamino-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (200 mg, 0.809 mmol), N-bromosuccinimide (216 mg, 1.21 mmol) and catalytic amount of benzoylperoxide in carbon tetrachloride (20 ml) was refluxed for 60 h and diluted with water. The aqueous solution was extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 30% ethyl acetate/n-hexane to afford 73 mg (28%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)=[C:4]([Cl:23])[CH:3]=1.[CH3:24][C@H]1CN(CC2C=CC(NC)=CC=2)CCN1C(OC(C)(C)C)=O.[BH4-].[Na+]>>[Cl:23][C:4]1[CH:3]=[C:2]([NH:1][CH3:24])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[C@@H:11]([CH3:22])[CH2:10]1
Reactant: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)cc1
Reactant: C[C@H]1CN(Cc2ccc(N)cc2Cl)CCN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Product: CNc1ccc(CN2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c(Cl)c1
Temperature: 50 °C

Procedure:
The title compound was prepared from 1,1-dimethylethyl (2S)-4-[(4-amino-2-chlorophenyl)methyl]-2-methyl-1-piperazinecarboxylate (D104) using a method similar to that described for D3 in Description 3A although the reaction was heated at 50° C. overnight prior to, and for 24 h after addition of sodium borohydride.(3 eq.). MS (ES): MH+ 354/356.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30](=O)[C:31]([CH3:34])(C)[CH3:32]>>[F:22][C:21]1[CH:32]=[C:31]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:34]=[CH:17][CH:18]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)cs2)C1

Procedure:
250 mg (about 0.211 mmol) of the compound from Example 53A and 154 mg (0.710 mmol) of 1-bromo-3,3-dimethylbutan-2-one were reacted according to the General Method 3. Yield: 88 mg (29% of theory).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.I[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([O:8][CH2:12][CH2:13][CH3:14])[CH:7]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc(Cl)ccc1CO
Temperature: 100 °C
Yield: 57.8 %

Procedure:
Charge 5-chloro-2-(hydroxymethyl)phenol (997 mg, 6.29 mmol, PREPARATION 7), iodopropane (1.17 g, 6.92 mmol), K2CO3 (1.74 g, 12.58 mmol) and DMF (6 mL) to a sealed tube. The reaction mixture was heated to 100° C. overnight. It was then poured into ice-water and extracted with ethyl acetate twice, washed the organic phase with water twice, brine and dried with Na2SO4, concentrated and purified by silica gel chromatograph to give the title compound (729 mg, 58%). 1H NMR (400 MHz, CDCl3): δ 1.05 (3H, t, J=7.2 Hz), 1.79-1.88 (2H, m), 3.96 (2H, t, J=6.4 Hz), 4.64 (2H, s), 6.85 (1H, d, J=1.2 Hz), 6.91 (1H, dd, J=1.6 Hz, 8.4 Hz), 7.20 (1H, d, J=8.0 Hz).
Reaction SMILES: P([O-])(O)(O)=O.[K+].N(S([O-])(=O)=O)(S([O-])(=O)=[O:10])[O].[K+].[K+].[OH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([O:30][CH:31]([CH3:35])[C:32]([OH:34])=[O:33])=[CH:22][CH:21]=1>O.C(O)C>[C:32]([CH:31]([O:30][C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:19])[C:21](=[O:10])[CH:22]=1)[CH3:35])([OH:34])=[O:33]
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: CC(Oc1ccc(O)c2ccccc12)C(=O)O
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(OC1=CC(=O)C(=O)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 38.0 g potassium dihydrogen phosphate in 7.5 liters of distilled water (pH 4.0) was added 89.4 g (0.33 mole) of potassium nitrosodisulfonate (Fremy's reagent). To this solution was added immediately a solution of 34.8 g (0.15 mole) of 2-(4-hydroxy-1-naphthoxy)propionic acid in 125 ml ethanol. The mixture was stirred for 2.5 hours under nitrogen at room temperature. The yellow-brown solid was collected, washed with a little water and dried (under nitrogen). The yield was 30.0 g (81 percent). The crude product melted at 182° to 184° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:44])[C@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:26])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1.[CH2:45]1[CH:47]([CH:48](O)C#N)[CH2:46]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:15]([NH:24][C:25]([C@@H:27]2[CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][N:28]2[C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])=[O:26])[C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[NH:1][CH2:48][CH:47]3[CH2:45][CH2:46]3)[CH2:9][CH2:10]2)=[O:44])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N)CC1
Reactant: N#CC(O)C1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2NCC2CC2)CC1
Yield: 85.6 %

Procedure:
To a 50 round-bottomed flask equipped with stirring was added tert-butyl 3-(N-{(1R)-2-[4-(2-aminophenyl)piperidyl]-1-[(4-chlorophenyl)methyl]-2-oxoethyl)carbamoyl)(3S)-1,2,3,4-tetrahydroisoquinoline-2-carboxylate (Example 20) (462 mg, 0.75 mmol) followed by 1,2-dichloroethane (20 mL) and cyclopropyl-carboxaldehyde (Aldrich) (58 mg, 0.83 mmol). The reaction mixture was stirred for 6 h, then treated with sodium triacetoxyborohydride (Aldrich) (176 mg, 0.83 mmol) at 0° C. After stirring for 12 h at RT, the reaction mixture was quenched with satd NaHCO3 (20 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (2×20 mL). The organic fractions were combined, washed with satd NaCl (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (1:10 MeOH:EtOAc) provided the title compound as a white foam (431 mg). MS (ESI, pos. ion) m/z: 671 (M+1); MS (ESI, neg. ion) m/z: 669 (M−1). Calcd for C39H47ClN4O4: 670.33.