Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[O:6]1)(=O)C.[P:22]([O:29]CC)([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:24]([O:23][P:22]([O:26][CH2:27][CH3:28])([CH:5]1[CH2:9][CH2:8][CH:7]([CH2:10][O:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:14])[O:6]1)=[O:29])[CH3:25]
Reactant: CC(=O)OC1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: CCOP(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of (±)-2-acetoxy-5-(p-toluenesulfonoxymethyl)-tetrahydrofuran (example 59) (1.63 g, 5.19 mmol) and triethyl phosphite (1.16 mL, 6.75 mmol) in methylene chloride (75 mL) at -35° C. was added titanium (IV) chloride (0.57 mL, 5.19 mmol) dropwise. The yellow solution was then stirred at -35° C. for 30 min and then at 0° C. for 30 min. Saturated NaHCO3 (75 mL) was then added to the reaction mixture and the suspension was then filtered through Celite. The mixture was then partitioned followed by extraction of the aqueous phase with methylene chloride (2×50 mL). The combined extracts were then washed with brine (100 mL), dried (MgSO4) and concentrated. The residue was then purified by chromatography eluting with 75% EtAc/hexanes→EtAc giving the title compound as 1:1 mixture of cis and trans isomers (1.42 g, 78%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]2[N:10]([C:14]3[CH:19]=[C:18]([O:20][CH2:21][C:22]4[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=4[F:31])[C:17]([O:32][CH2:33][CH2:34][OH:35])=[CH:16][C:15]=3[Cl:36])[C:11](=[O:13])[NH:12][C:7]2=[CH:6][CH:5]=1)(O)=[O:2].B.O1CCCC1.O.[Cl-].[NH4+]>O1CCCC1>[Cl:36][C:15]1[CH:16]=[C:17]([O:32][CH2:33][CH2:34][OH:35])[C:18]([O:20][CH2:21][C:22]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]([F:30])[C:23]=2[F:31])=[CH:19][C:14]=1[N:10]1[C:8]2=[N:9][C:4]([CH2:1][OH:2])=[CH:5][CH:6]=[C:7]2[NH:12][C:11]1=[O:13]
Reactant: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3ccc(C(=O)O)nc32)c(Cl)cc1OCCO
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1COc1cc(-n2c(=O)[nH]c3ccc(CO)nc32)c(Cl)cc1OCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 5-carboxy-3-[2-chloro-5-(2,3-difluoro-6-methoxybenzyl-oxy)-4-(2-hydroxyethoxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (28 mg) in tetrahydrofuran (3 mL) was added borane-tetrahydrofuran complex (1.2 mol/L tetrahydrofuran solution, 0.21 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture were added water and a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 5 minutes. The mixture was extracted with ethyl acetate twice, and the extracts were dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate−ethyl acetate/methanol=10/1) to give the title compound (6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[NH4+].[Cl-]>C(O)C.[Fe]>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-nitrobenzoate (17 g, 62.0 mmol) in ethanol (85 mL) had NH4Cl solution (17 g in 85 mL water, 317.8 mmol) followed by Fe powder (27.8 g, 498.1 mmol) added. The resulting reaction mixture was stirred at 90° C. for 1 h. On completion, the reaction mixture was filtered and the filtrate was concentrated till dry. The resulting solid was dissolved in sat. sodium bicarbonate solution and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford solid methyl 3-amino-5-bromo-2-methylbenzoate (15 g, 99.1%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc2[nH]ccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C)cccc32)cc1
Reaction time: 0.08 h
Yield: 90.7 %

Procedure:
To a solution of 4-methyl-1H-indole (2.53 g) in N,N-dimethylformamide (20 mL) was added 55% sodium hydride (0.88 g) under ice-cooling, and the mixture was stirred at the same temperature for 5 minutes. To this mixture was added p-toluenesulfonyl chloride (4.04 g) at the same temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give 4-methyl-1-(toluene-4-sulfonyl)-1H-indole (4.99 g). This material was dissolved in dichloromethane (100 mL). To the solution was added bromine (26% dichloromethane solution, 12.62 g) in a dropwise manner under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1). The purified material was crystallized from n-hexane-diethyl ether, and the crystals were collected by filtration. The crystals were washed with n-hexane and dried under reduced pressure to give the title compound (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4](O)=[O:5].C1(N=C=NC2CCCCC2)CCCCC1.[CH3:38][S:39]([CH3:42])(=[NH:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([N:41]=[S:39]([CH3:42])([CH3:38])=[O:40])=[O:5]
Reactant: CS(C)(=N)=O
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CS(C)(=O)=NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl

Procedure:
A solution of 2.46 g of 2-chloro-5-(o-chloro-p-trifluoromethyl-phenoxy)-benzoic acid in 20 ml of methylene chloride is added dropwise at room temperature while stirring to a solution of 1.3 g of dicyclohexylcarbodiimide and 0.6 g of dimethyl sulphoximine in 5 ml of methylene chloride, a slight exothermic reaction occurring. After a reaction time of 15 minutes the solvent is removed by evaporation under reduced pressure and the residue is purified by chromatography on silica gel with n-hexane/ethyl acetate (9:1). The white crystalline product is then recrystallized from methylene chloride/n-hexane. There is obtained N-[2-chloro-5-(o-chloro-p-trifluoromethyl-phenoxy)-benzoyl]-S,S-dimethyl-sulphoximine, m.p. 128°-131° C.; mass spectrum: m/e 425/427; 1H-NMR (CDCl3): 7.8-6.9 (m,6H), 3.4 (s,6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[NH2:21])[CH:10]=[CH:11][CH:12]=1.N1C=CC=C[C:23]=1C1C=C(NC2C=CC(I)=CC=2[N+]([O-])=O)C=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([N:13]2[C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[N:21]=[CH:23]2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1Nc1cccc(-c2ccccn2)c1
Reactant: Nc1cc(I)ccc1Nc1cccc(-c2ccccn2)c1
Product: Ic1ccc2c(c1)ncn2-c1cccc(-c2ccccn2)c1
Yield: 53 %

Procedure:
1-(3-(2-Pyridyl)phenyl)-5-iodobenzimidazole (11f) was prepared analogously from 10f (Example 13). Yield: 53% (from 6f). Mp 157-158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH:28]1([N:31]([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)(=[O:34])=[O:33])[CH2:30][CH2:29]1>CCOC(C)=O.O.CCC(C)=O>[CH:28]1([N:31]([CH:45]2[CH2:50][CH2:49][N:48]([CH2:11][CH2:10][O:9][CH:8]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:47][CH2:46]2)[S:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:42])[F:43])[CH:36]=2)(=[O:33])=[O:34])[CH2:30][CH2:29]1
Reactant: Fc1ccc(C(OCCCl)c2ccc(F)cc2)cc1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 80 °C

Procedure:
A mixture of 1-[bis(4-fluorophenyl)methoxy]-2-chloroethane (3.0 g, 10.7 mmol), sodium iodide (4.3 g, 28.9 mmol), and MEK (20 mL) was heated at 80° C. for 24 hours. After allowing the reaction to return to ambient temperature it was filtered. To an aliquat of the filtrate (0.78 mmol) was added potassium carbonate (294 mg, 2.13 mmol) and N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide (0.71 mmol). The mixture was heated at 80° C. for 16 hours. After TLC indicated the reaction to be complete, water and EtOAc were added to the reaction mixture. The phases were separated, and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were washed with water, washed with brine, dried with sodium sulfate, and concentrated. Purification was then carried out using silica gel chromatography as described in Example 22.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(Cl)CCl.[CH:40]1[CH:41]=[CH:42]C2N(O)N=[N:46][C:44]=2[CH:45]=1.N1CCCCC1>C(Cl)Cl>[C:10]([O:14][C:15](=[O:16])[NH:17][CH:18]1[CH2:19][CH2:20][N:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([N:46]3[CH2:42][CH2:41][CH2:40][CH2:45][CH2:44]3)=[O:33])=[CH:34][CH:35]=2)(=[O:25])=[O:26])[CH2:22][CH2:23]1)([CH3:12])([CH3:13])[CH3:11]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)N3CCCCC3)cc2)CC1
Reaction time: 24 h
Yield: 72.4 %

Procedure:
Diisopropylethylamine (0.36 ml, 2.1 mmol) was added in one portion to a stirred solution of 4-(4-tert-butoxycarbonylamino-piperidine-1-sulfonyl)-benzoic acid (0.2 g, 0.52 mmol), EDC (0.2 g, 1.04 mmol) and HOBT (0.16 g, 1.04 mmol) in DCM (5 ml) at room temperature. The mixture was stirred at room temperature for 10 minutes before piperidine (0.07 ml, 0.78 mmol) was added in one portion and stirring continued for 24 hours. After this time the mixture was diluted with DCM (50 ml), washed sequentially with saturated sodium bicarbonate (20 ml), water (20 ml) and brine (20 ml). The organic layer was separated, dired (MgSO4), filtered and concentrated. The resulting residue was purified by flash column chromatography (elution: 0 to 2% MeOH in DCM) to give the title compound (0.17 g, 74% yield) as a white powder. δH (250 MHz, MeOD) 7.89-8.06 (m, 2 H) 7.67-7.82 (m, 2 H) 3.68-3.93 (m, 4 H) 2.54-2.75 (m, 2 H) 2.02 (dd, J=12.94, 3.35 Hz, 2 H) 1.76-1.91 (m, 4 H) 1.56-1.75 (m, 4 H) 1.53 (s, 9 H). Tr=1.94 min m/z (ES+) (M+Na+) 474.
Reaction SMILES: [K].[NH2-].[K+].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][N:5]=1.C([N:19](CC)CCN(CC)CC)C.[NH4+].[K+].C1C2C(=CC=C(C([O-])=O)C=2)C=CN=1.Cl>O.C1OCCOCCOCCOCCOCCOC1.C(O)(=O)C.C1(C)C=CC=CC=1>[NH2:19][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: O=C(O)c1ccc2ccncc2c1
Reactant: CCN(CC)CCN(CC)CC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])c1ccc2ccncc2c1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Nc1nccc2ccc(C(=O)O)cc12
Temperature: 87 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 1 L flask was equipped with magnetic stirring bar, cooling bath (liquid nitrogen), stopcock connected to an ammonia cylinder and a vacuum system. The flask was charged with FeCl3 (0.1 g) and evacuated. Ammonium gas was condensed to give liquid ammonium (600 ml). Potassium (19.50 g 0.50 mole) was added in small pieces (each about 0.5 g) under an argon atmosphere. The solution initially became blue but became a grey suspension after heating at reflux for 30 min. Into the potassium amide/liquid ammonia suspension was added in small portions isoquinoline-7-carboxylic acid {ref F. T. Tyson, JACS, 1939,61,183} (17.0 g 0.10 mole). The free acid initially dissolved but the formed potassium salt soon precipitated as fine particles to give a suspension which was heated at reflux for 6 h. After careful addition of tetraethylethylene diamine (TEEDA) (86 g 0.50 mole), toluene (170 ml) and 18-crown-6 (1 g) the ammonia was allowed to evaporate slowly over 40 h to give a new suspension of the isoquinoline-7-carboxylic acid potassium salt. The reaction mixture was heated to 87° C. for 48 h. A sample was removed and analysed by nmr which indicated that there was still some unreacted starting material present. Ammonia was bubbled through the reaction mixture for 2 h and nmr analysis then revealed that no starting material remained. The reaction was then cooled to −16° C., ice (200 g) was added to destroy excess potassium amide and all solvents evaporated at 76° C. and 7 mmHg and then at 65° C. and 0.7 mmHg to give a powder which was dissolved in water (1.2 L) and filtered through Celite to give a clear solution. This was acidified to pH 7 by addition of acetic acid (34 g) and allowed to stand overnight. The precipitate was collected by filtration, washed with water (50 ml×2) and dried by azeotroping with ethanol (50 ml×2) at 50° C. and 7 mmHg then at 50° C. and 0.7 mmHg to give the crude product (17.6 g 94%) as an off-white powder. The crude product (17.6 g) was dissolved in water (4 L), and concentrated HCl was added to give a pH of 1.30. The solution was stirred for 1 h, and filtered through Celite to give a clear solution to which was added concentration ammonia solution to give a pH of 5.07. After stirring for 2 h and standing overnight the precipitate was filtered, washed with water (50 ml×2) and dried by azeotroping with ethanol (50 ml×2) at 50° C. and 7 mmHg, and then at 50° C. and 0.7 mmHg to give title compound (15.5 g 88%) as a pale brown solid.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:14]=[C:13]([Br:15])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1>CO>[Br:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: C[O-]
Reactant: Clc1ccc2c(Br)cc(Br)nc2c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c2ccc(Cl)cc2n1
Temperature: 25 °C

Procedure:
Sodium methoxide (0.5 M in MeOH, 2.0 mL, 1.0 mmol) was added to a solution of 2,4-dibromo-7-chloroquinoline (341 mg, 1.06 mmol) in MeOH (7 mL). The mixture was refluxed for one hour then cooled to room temperature. The resulting precipitate was collected by filtration to afford the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.8 Hz, 1H); 7.85 (d, J=2.1 Hz, 1H); 7.40 (dd, J=8.8, 2.1 Hz, 1H); 7.22 (s, 1H); 4.04 (s, 3H); LC4 2.45 min. (M+H)=274.
Reaction SMILES: [C:1]1([S:7]([C:10]2([CH2:15][CH2:16][CH2:17]O)[CH2:14][CH:13]=[CH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:31][C:32]1[CH2:33][NH:34][CH2:35][CH2:36][C:37]=1[CH3:38].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:1]1([S:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:34]3[CH2:33][C:32]([CH3:31])=[C:37]([CH3:38])[CH2:36][CH2:35]3)[CH2:14][CH:13]=[CH:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)C1(CCCO)CC=CC1
Reactant: CC1=C(C)CNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1=C(C)CN(CCCC2(S(=O)(=O)c3ccccc3)CC=CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1-benzenesulphonylcyclopent-3-enyl)propan-1-ol (56 mg, 0.21 mmol) and triethylamine (41 μL, 0.29 mmol) in dichloromethane (5 ml) was cooled to 0° C. and treated with methanesulphonyl chloride (21 μL, 0.27 mmol). The mixture was allowed to warm to room temperature and stirred for 30 minutes, then diluted with water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile (5 ml), treated with 3,4-dimethyl-1,2,5,6-tetrahydropyridine (397 mg, 0.32 mmol) and potassium carbonate (58 mg, 0.42 mmol) and heated at 60° C. for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with 5% methanol/dichloromethane, to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11].Cl[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=1>>[Cl:2][C:3]1[C:7]([Cl:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:20]2[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[C:22]([O:30][CH3:31])[N:21]=2)[CH2:15][CH2:14]1)=[O:11]
Reactant: COC(=O)c1cc(OC)nc(Cl)n1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Agent: Cl
Product: COC(=O)c1cc(OC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 6 starting from 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1) and methyl 2-chloro-6-methoxypyrimidine-4-carboxylate (Intermediate 88).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (2.09 mL, 11.7 mmol) was added at 0° C. to a stirred solution of piperidine (0.40 g, 4.7 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-benzenesulfonyl chloride (1.20 g, 4.7 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1-(4-bromobenzenesulfonyl)-piperidine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO2S [M+] 304, obsd. 304.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2].CC(C)([O-])C.[K+].I[C:18]1[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.C(OCC)C.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>[C:1]([CH:3]([C:18]1[N:22]([CH3:23])[N:21]=[CH:20][CH:19]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])#[N:2]
Reactant: Cn1nccc1I
Reactant: CC(C)(C)OC(=O)CC#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1nccc1C(C#N)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of tert-butyl cyanoacetate (340 μL, 2.40 mmol) in 1,4-dioxane (5 mL) was added potassium t-butoxide (1M in tetrahydrofuran, 5 mL, 5.0 mmol) at room temperature. After 10 min, a solution of 5-iodo-1-methyl-1H-pyrazole (500 mg, 2.40 mmol) in 1,4-dioxane (5 mL) and tetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol) were added. The reaction mixture was stirred for 16 h at 70° C. The mixture was cooled and then was diluted with diethyl ether (50 mL) and a 10% aqueous solution of citric acid. The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×10 mL). The combined organics were washed with brine (15 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Gradient: 30% to 40% ethyl acetate in heptane) to afford tert-butyl 2-cyano-2-(1-methyl-1H-pyrazol-5-yl)acetate (132.8 mg) as a pale brown oil. MS (ES+) (M+H) 222.0, LCMS retention time: 2.74 min (Method L); 1H NMR (500 MHz, CDCl3) δ 1.50 (s, 9H), 3.93 (s, 3H), 4.80 (s, 1H), 6.39 (d, 1H), 7.48 (d 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1>[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:1][N:2]=[C:3]2[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CCC(=NO)CC1
Solvent: c1ccncc1
Product: CCOC(=O)C1CCC(=NOS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Yield: 74.9 %

Procedure:
To a solution of ethyl 4-(hydroxyimino)cyclohexanecarboxylate (1.85 g) in pyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (2.28 g) over 5-10 min at −20° C. The reaction mixture was stirred for several hours while allowing to gradually warm to 0° C. The reaction mixture was added to ice water, and the precipitate was collected by filtration, and washed with ice water to give the title compound (2.54 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:8]2[C:9]3[CH:15]=[C:14]([CH3:16])[NH:13][C:10]=3[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:13]2[C:10]3[CH:11]=[CH:12][C:7]4[N:8]([C:4]([CH3:3])=[N:5][N:6]=4)[C:9]=3[CH:15]=[C:14]2[CH3:16])=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(C)cc3c2ccc2nnc(C)n23)cc1
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
Sodium hydride (0.032 g, 0.81 mmol, 60% in mineral oil) was added to a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (50.0 mg, 0.268 mmol, Example 2, Step 5) in DMF (4 mL). After 10 minutes, p-methoxybenzyl chloride (0.036 mL, 0.27 mmol, Aldrich) was added. The reaction was stirred for 45 minutes, then was quenched with water, diluted with MeCN, filtered and purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) to afford product as a white solid (49 mg, 60%).