Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])[O:6][CH3:7])[CH3:2].C(N(CC)CC)C.[CH3:19][N:20]1[C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=[N:21]1>C1COCC1>[CH2:10]([O:9][CH:4]([O:3][CH2:1][CH3:2])/[C:5](=[N:8]/[C:25]([C:24]1[N:20]([CH3:19])[N:21]=[CH:22][CH:23]=1)=[O:26])/[O:6][CH3:7])[CH3:11]
Reactant: CCOC(OCC)C(=N)OC
Reactant: Cn1nccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(OCC)/C(=N/C(=O)c1ccnn1C)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.1 %

Procedure:
To a stirred solution of diethoxyacetonitrile (60 g, 0.465 mol) in absolute methanol (150 mL) under an atmosphere of argon was added a solution of sodium methylate (2.5 g; 0.047 mol) in absolute methanol (20 mL), and the reaction mixture was stirred at room temperature until the nitrile disappeared completely (70–75 h). The reaction was monitored by 1H NMR. The reaction mixture was treated, while stirring, with CO2 until the precipitate of sodium carbonate ceased to form. The latter was filtered off and washed with methanol (50 mL). The filtrate was evaporated under on a rotary evaporator at a bath temperature less than 30° C. The resulting liquid was dissolved in ether (250 mL), filtered to remove the remaining inorganic salts, and evaporated again to give the crude methyl 2,2-diethoxyethanimidoate (71.0 g, 95%). It was distilled under vacuum through a 15-cm Vigreux column, affording 56.2 g (75%) of methyl 2,2-diethoxyethanimidoate (bp. 77–78° C. at 20–22 mm Hg) with a purity of more than 95% by 1H NMR. To a solution of the methyl 2,2-diethoxyethanimidoate (52.1 g, 0.321 mol) and triethylamine (49 mL, 0.353 mol) in absolute THF (300 mL) was added a solution of 1-methyl-1H-pyrazole-5-carbonyl Chloride (46.5 g, 0.321 mol, from Step 1) in absolute THF (150 mL) dropwise under an atmosphere of argon at 0–5° C. over a period of 2 h. The reaction mixture was stirred overnight at a room temperature. The residue the formed was filtered off, and the filtrate was evaporated on a rotary evaporator to give methyl (1Z)-2,2-Diethoxy-N-[(1-methyl-1H-pyrazol-5-yl)carbonyl]ethanimidoate (90 g) as a yellow viscous mass, which was used at the next stage without additional purification. The 90 g of the crude product N-acylated imidate ester obtained at the previous stage was dissolved in absolute dichloromethane (450 mL), and treated with methylhydrazine (17.1 mL, 0.321 mol) with stirring over a period of 10 min. The reaction mixture was stirred at room temperature for 3 h, washed with water (3×300 mL), and dried with anhydrous sodium sulfate. The solvent was removed under vacuum on a rotary evaporator, and the residue (56.5 g) was purified chromatographically on silica gel using hexane/ethyl acetate (1:2) as the eluent. The solvent was evaporated to give 40.1 g (47% based on 1-methyl-1H-pyrazole-5-carbonyl chloride) of the pure title product.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([O:18]C)=O.Cl.[CH3:21][O:22][C:23](=[O:27])[C@H:24]([CH3:26])[NH2:25]>O1CCOCC1>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:14])[C:4](=[O:15])[C:3]=1[C:16]([NH:25][C@@H:24]([CH3:26])[C:23]([O:22][CH3:21])=[O:27])=[O:18]
Reactant: COC(=O)[C@H](C)N
Reactant: COC(=O)c1c(O)c2cccc(OC)c2n(C)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)NC(=O)c1c(O)c2cccc(OC)c2n(C)c1=O
Temperature: 120 °C
Reaction time: 18 h

Procedure:
In a 35 mL sealed vial under N2 was suspended methyl 4-hydroxy-8-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.50 g, 1.9 mmol) in 1,4-dioxane (15 mL). To this solution was added L-alanine methyl ester hydrochloride (0.29 g, 2.1 mmol) and the reaction mixture was stirred at 120° C. overnight (18 h). The solution was removed from the heat and filtered over a fine frit funnel to remove any undissolved starting material. The filtrate was concentrated in vacuo and the remaining precipitate was suspended in Et2O, filtered and washed with Et2O and dried to provide a light yellow solid. Yield=0.40 g, 63%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH:45]([CH2:47][CH3:48])[CH3:46])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH:45]([CH2:47][CH3:48])[CH3:46])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C(C)CC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C(C)CC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-butyl) imidazol-2-yl]methyl]sulfanyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (550 mg) in dichloromethane (1.5 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (299 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[[[1-(2-butyl)imidazol-2-yl]methyl]sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (350 mg) (Compound 352) as yellow amorphous.
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH2:29][CH2:28][NH:27][C:26]5=[O:30])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH2:29][CH2:28][N:27]([CH3:34])[C:26]5=[O:30])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N4CCNC4=O)ccc32)n1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(N4CCN(C)C4=O)ccc32)n1)c1ccccc1
Yield: 43.5 %

Procedure:
To a solution of 2-[(S)-1-Phenylethylamino]-4-[5-(imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (Example 385) (0.025 mmol) in anhydrous DMF (0.2 ml) under nitrogen was added NaH (60%) in one portion. After stirring for ten minutes, iodomethane (0.028 mmol) was added dropwise. The reaction was stirred at room temperature for 2.5 h. and quenched with water. The mixture was extracted with methylene chloride. The organic extracts were combined, washed with brine and dried over MgSO4. Removal of the solvent and subsequent purification by preparative thin layer chromatography (acetone/hexane system) provided 4.5 mg of the title compound. Mass spectrum (ESI) 414.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[N:27](C(OC(C)(C)C)=O)[CH:26]=[CH:25]3)C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(OC(C)C)(OC(C)C)OC(C)C.[Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][CH:26]=[CH:25]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)CC1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc3[nH]ccc3c2)CC1
Yield: 62 %

Procedure:
In a similar manner to Step 2 of Reference Example 1, 5-[1-(tert-butoxycarbonyl)-4-piperidyl-N-(tert-butoxycarbonyl)amino]-1-(tert-butoxycarbonyl)indole (320 mg, 0.621 mmol) was dissolved in THF (5 mL), and the solution was treated with triisopropyl borate (0.215 mL, 0.932 mmol) and LDA-heptane/THF/ethylbenzene solution (2.0 mol/L, 0.776 mL, 1.55 mmol), followed by purification by slurry using hexane to obtain Compound BQ (177 mg, yield 62%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)[O:3]1.CC[N:21]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:21])=[O:14])=[CH:11][CH:10]=2)[O:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(C(N)=O)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (200 mg, 0.746 mmol), EDCI (214 mg, 1.12 mmol), HOBt (151 mg, 1.12 mmol) and Et3N (151 mg, 1.49 mmol) in DCM (20 mL) was bubbled ammonia until saturation. The mixture was stirred at room temperature for 3 h, then was filtered and the filtrate was concentrated to give residue which was purified by column chromatography (DCM:MeOH=50:1) to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (90 mg, 45%) as a yellow solid. LC-MS: 248 [M+H]+, tR=1.421 min.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[Cl:9][Sb-:10]([Cl:15])([Cl:14])([Cl:13])([Cl:12])[Cl:11].[CH3:16][O+](C)C>CCOCC>[Cl:9][Sb-:10]([Cl:15])([Cl:14])([Cl:13])([Cl:12])[Cl:11].[CH3:16][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: Clc1nsc(Cl)c1Cl
Reactant: C[O+](C)C
Agent: Cl[Sb-](Cl)(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: C[n+]1sc(Cl)c(Cl)c1Cl

Procedure:
Trichloroisothiazole (10 ml) and trimethyloxonium hexachloroantimonate (7.9 g, 0.02 mol) were heated at 90° for 30 min. After cooling ether (150 ml) was added and the solid collected to yield 7.8 g (73%) of product, mp >240. Spectral data (NMR & IR) were consistent with the assigned structure.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:13])[C:11]#[CH:12])=[CH:6][CH:5]=1)([O-])=O.C([Mg]Cl)#C.[N+](C1C=CC(C=O)=CC=1)([O-])=O.[Cl-].[NH4+]>CO.[Zn].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:13])[C:11]#[CH:12])=[CH:8][CH:9]=1
Reactant: C#CC(O)c1ccc([N+](=O)[O-])cc1
Agent: C#C[Mg]Cl
Agent: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: C#CC(O)c1ccc(N)cc1

Procedure:
1-(4-Nitro-phenyl)-2-propyn-1-ol (4.89 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-nitrobenzaldehyde (Aldrich) according to method A above) was added to 10% H2O in methanol (150 mL) and to this mixture was added zinc dust (44.01 mmol) and ammonium chloride (10.67 mmol). The reaction was heated at reflux for 3 h, at which time the reaction was cooled and the solid was filtered off. The solids were washed extensively with ethyl acetate, and the ethyl acetate and methanol were evaporated in vacuo. The resulting precipitate was filtered off, dried and recrystallized from ethyl acetate/hexane to yield 1-(4-amino-phenyl)-2-propyn-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:11]([Cl:10])(=[O:13])=[O:12])[CH:5]=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A stirred solution of 2-chloroanisole (8.90 mL, 70.1 mmol) in chloroform (100 mL) was cooled to 0° C., and treated drop-wise with chlorosulfonic acid (9.3 mL, 140 mmol). After stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water (250 mL) and the separated, aqueous phase extracted with chloroform (2×50 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a viscous oil which crystallized upon standing (8.58 g, 52%), m.p. 78° C.;
Reaction SMILES: NN.[Cl:3][C:4]1[C:5]([OH:31])=[C:6]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:7][N:8]1[CH2:13][CH2:12][C:11]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)([F:14])[CH2:10][CH2:9]1>C(O)C>[NH2:16][CH2:15][C:11]1([F:14])[CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:27]=[C:28]([Cl:30])[CH:29]=[C:4]([Cl:3])[C:5]=2[OH:31])[CH2:9][CH2:10]1
Reactant: O=C1c2ccccc2C(=O)N1CC1(F)CCN(Cc2cc(Cl)cc(Cl)c2O)CC1
Agent: NN
Solvent: CCO
Product: NCC1(F)CCN(Cc2cc(Cl)cc(Cl)c2O)CC1
Reaction time: 5 h

Procedure:
Hydrazine (10 ml) was added to a solution of 2-[1-(3,5-dichloro-2-hydroxy-benzyl)-4-fluoro-piperidin-4-ylmethyl]-isoindole-1,3-dione (20.7 g) in ethanol (600 ml). The obtained solution was stirred for 5 hours while heating to reflux, and then subjected to heated filtration. The filtrate was concentrated, water was added to the residue, and then extraction with dichloromethane was followed by concentration. The obtained residue was recrystallized from isopropyl ether-pentane to obtain 2-(4-aminomethyl-4-fluoro-piperidin-1-ylmethyl)-4,6-dichlorophenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[Cl:20][C:21]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:22]=1[CH2:23]Cl.CCN(CC)CC>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:13][C:14]1[N:18]=[CH:17][N:16]([CH2:23][C:22]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:21]=2[Cl:20])[CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)[C@H](Cc1cn(Cc2ccc(Cl)cc2Cl)cn1)NC(=O)OC(C)(C)C

Procedure:
N-(tert-butoxycarbonyl)-L-histidine methyl ester (1.0 g) was added to a solution of 2,4-dichlorobenzyl chloride (0.73 g) and Et3N (0.27 g) in benzene (10 ml) and the mixture was heated under reflux for 1 hr. The mixture was cooled and the precipitate was removed by filtration. The filtrate was washed with H2O, dried over Na2SO4, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (eluent; 95:5, CHCl3/MeOH) to give N-(tert-butoxycarbonyl)-1-[(2,4-dichlorophenyl)methyl]-L-histidine methyl ester. The obtained compound was treated in a similar manner as described in R. Example 4 to give 1-[(2,4-Dichlorophenyl)methyl]-L-histidine methyl ester, dihydrochloride salt.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:18])=[O:17])[C:8]=1[CH3:27]>C1COCC1.CO>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:28])=[O:4])=[C:8]2[CH3:27])(=[O:17])=[O:18])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 18 h

Procedure:
1M Aqueous NaOH (1.5 mL) is added to a solution of [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (218 mg, 0.53 mmol) in 1:1 THF/MeOH (6 mL). After 18 hours, the reaction is evaporated and the residue dissolved in water. The aqueous solution is acidified to pH 1, and the resulting precipitate is collected by filtration to afford [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid; MH+=399.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])(=[O:10])=[O:9])=[C:4]([F:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:29][CH3:30])=[C:24](B(O)O)[CH:25]=1>>[F:18][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[C:20]([F:19])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])(=[O:10])=[O:9]
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccc(Br)cc1F)c1ccccc1Cl
Product: COc1ccc(F)cc1-c1ccc(S(=O)(=O)c2ccccc2Cl)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of step (ii) and 5-fluoro-2-methoxybenzene boronic acid which was used directly in step (iv) without further characterisation.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C@@H:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:13]([Cl:31])[CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[Cl:17][C:15]1[CH:16]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH:12]=[C:13]([Cl:31])[C:14]=1[CH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:20]1=[O:30]
Reactant: COC(=O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2cc(Cl)c(C[C@@H]3CCN(C4CCOCC4)C3=O)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
Treat a solution of 3′,5′-dichloro-4′-[(R)-2-oxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid methyl ester (2.56 g, 5.5 mmol) in methanol (25 mL) with 5N aqueous sodium hydroxide (5.5 mL). Heat the reaction to 60° C. and stir for 1 hr. Cool to room temperature, quench with 1N hydrochloric acid and extract the aqueous with ethyl acetate. Wash the organic layer with brine, dry over magnesium sulfate, and filter. Remove the solvent under vacuum to afford 2.48 g (100%) of desired product: MS (m/z): 448 (M+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O>[CH3:19][NH:12][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(C)c1ccc(C(C)N)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNC(C)c1ccc(C(C)C)cc1
Yield: 69.4 %

Procedure:
A suspension of 1-(4-isopropylphenyl) ethylamine (81 g) was stirred vigorously in a solution of sodium hydroxide (50 g) in water (250 ml) at room temperature. Dimethyl sulphate (64 g) was added dropwise to the stirred suspension over a period of 1 hour. The suspension was stored in a refrigerator overnight and three layers were formed. The top layer of organic material was extracted with ether and the ether solution was separated and dried over anhydrous magnesium sulphate. The ether was evaporated under reduced pressure to give a yellow oil which was distilled at a water pump to give N-methyl-1-(4-isopropylphenyl) ethylamine (61 g, 69%) colourless oil, boiling point 112° to 114° C./20 mm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:13])=[O:12])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([N:34]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)=[O:4].C1COCC1.Cl>Cl.CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[S:18][C:17]3[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:16]=3[CH:15]=2)(=[O:12])=[O:13])[CH2:8][C:7](=[O:24])[N:6]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([NH2:34])[CH:27]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Yield: 101.2 %

Procedure:
Concentrated HCl (12M, one drop) is added at 0° C. to a mixture containing (±)-1-[3-(benzhydrylidene-amino)-4-cyano-benzyl]-4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-6-oxo-piperazine-2-carboxylic acid methyl ester (60 mg, 0.08 mmol) in MeOH (5 mL). Added THF (2 mL) followed by a second drop of 12M HCl and warmed reaction mixture to ambient temperature. The reaction is quenched by pouring the reaction mixture onto a 1:1 mixture of CH2Cl2/aqueous NaHCO3 and the layers are separated. The aqueous phase is washed with CH2Cl2 and then the combined organic phase is washed with brine, dried over anhydrous MgSO4, filtered and concentrated. The crude residue is chromatographed on silica gel (CH2Cl2 to 4% MeOH/CH2Cl2) to provide 42 mg (93%) of the title compound. 1H NMR (300 MHz, CDCl3) δ2.98 (dd, J=12.5, 3.5 Hz, 1H), 3.60 (d, J=16.8 Hz, 1H), 3.69 (d, J=15.3 Hz, 1H), 3.79 (s, 3H), 3.98 (m, 1H), 4.21-4.31 (m, 2H), 4.44 (br s, 2H), 5.36 (d, J=15.3 Hz, 1H), 6.47 (dd, J=8.0, 1.4 Hz, 1H), 6.54 (s, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.45 (dd, J=8.5, 1.8 Hz, 1H), 7.80-7.86 (m, 3H) ppm; MS (ISP loop): m/z 519 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]3[C:14]4[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17][C:15]=4[N:16]=[C:10]3[C@H:9]2[CH:29]([CH3:31])[CH3:30])=[N:6][CH:7]=1.[C:36]([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH:29]([C@H:9]1[N:8]([C:5]2[N:4]=[C:3]([C:32]([F:35])([F:33])[F:34])[C:2]([CH3:36])=[CH:7][N:6]=2)[CH2:13][CH2:12][N:11]2[C:14]3[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[C:18]([C:25]([O:27][CH3:28])=[O:26])=[CH:17][C:15]=3[N:16]=[C:10]12)([CH3:31])[CH3:30]
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(Br)c(C(F)(F)F)n1)[C@@H]3C(C)C
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1ncc(C)c(C(F)(F)F)n1)[C@@H]3C(C)C
Temperature: 120 °C
Yield: 56 %

Procedure:
A mixture of (R)-methyl 2-(5-bromo-4-(trifluoromethyl)pyrimidin-2-yl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (7 mg, 0.012 mmol), Pd(PPh3)4 (1 mg, cat. Amount), 2M aq. K2CO3 solution (100 μL, excess), and dry 1,4-Dioxane (700 μL) was degassed and refilled with nitrogen gas for 3 times. A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (5 mg, excess) in dry 1,4-Dioxane (100 μL) was added. The mixture was heated in a microwave oven for 30 minutes at 120° C. After concentration, the residue was filtered and purified by Gilson to afford 3.5 mg (R)-methyl 1-isopropyl-2-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate (56% yield). LC-MS: m/z 512.3 [M+H]+.