Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[NH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2].[C:17]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[C:1]([C:6]1[N:7]([CH3:17])[CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]=1[CH3:11])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1cn(C)c(C(=O)OCC)c1C
Yield: 91 %

Procedure:
A solution of 2,4-dicarbethoxy-3 methylpyrrole (25) (2.44 g, 10.9 mmol), K2CO3 (9.9 g), and iodomethane (55 ml) in 750 ml acetone was refluxed at 50° C. for 15 hours. The solution was concentrated in vacuo, partitioned between 450 ml of dichloromethane and 600 ml of water. The aqueous layer was extracted with CH2Cl2 (2×500 ml), dried (sodium sulfate), and concentrated in vacuo to yield a brown oil that solidified upon standing at room temperature for several minutes and was used without further purification. (2.37 g, 91% yield). TLC (benzene) Rf 0.3; 1H NMR (CD2Cl2) δ 7.31 (s, 1H), 4,23 (m, 4H), 3,84 (s, 3H), 2.54 (2, 3H), 1.33 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16](F)=[O:17])=[N:9]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:28]=1)[CH:7]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[N:8]1[C:12]([CH3:13])=[CH:11][C:10]([CH2:14][CH2:15][C:16]([NH:34][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[O:17])=[N:9]1
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(CCC(=O)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)NS(=O)(=O)C(F)(F)F)nn1C(OCc1ccc(Cl)cc1)c1cccc(Cl)c1
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of acid fluoride 9 (0.14 g, 0.33 mmol) and DMAP 0.161 g (1.3 mmol) in dry DCM, trifluoromethanesulfonamide 0.147 g (0.98 mmol) was added. The mixture was stirred under a nitrogen atmosphere for 16 hours before diluting with EtOAc. The organic phase was washed with 2M HCl, followed by brine, dried over MgSO4 and evaporated to dryness. The crude acyl sulphonamide 10 was purified on silica to yield 0.13 g as a white solid (72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@H:7]([CH2:16][CH2:17][OH:18])[NH:8]C(OC(C)(C)C)=O)([CH3:4])(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1.N(C(N(C)C)=O)=NC(N(C)C)=O.[ClH:59]>O1CCCC1.C(O)C>[ClH:59].[CH2:1]([O:5][C:6](=[O:19])[C@H:7]([CH2:16][CH2:17][O:18][C:43]1[CH:44]=[CH:45][C:40]([F:39])=[CH:41][CH:42]=1)[NH2:8])[CH3:4]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)[C@@H](N)CCOc1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of BOC-L-homoserine t-butyl ester (3.2 g, 11.6 mmol) in tetrahydrofuran is added triphenylphosphine (7.59 g, 29 mmol), p-fluorophenol (2.08 g, 18.6 mmol) and 1,1′-azobis(N,N-dimethylformamide) (3.2 g, 18.6 mmol). The mixture is stirred overnight, washed with brine, dried over MgSO4, and the solvent is removed to give an orange oil. The oil is purified by flash chromatography (SiO2, 85% hexane/15% ethyl acetate) to give a clear oil which is dissolved in ethanol (100 mL) and the solution is saturated with HCl gas, then stirred overnight. The mixture is concentrated to give O-(4-fluorophenyl)-L-homoserine ethyl ester hydrochloride as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]([CH3:26])=[C:23]([CH3:25])[CH:24]=1.FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:25][C:23]1[CH:24]=[C:19]([O:18][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH2:14][CH:15]([OH:36])[CH2:17][OH:16])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:21][C:22]=1[CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccn3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-5,6-dimethyl-[2,2′]bipyridine (compound 341) (95 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, the mixture was stirred at 0° C. for 30 min, and the mixture was then stirred at room temperature for 5 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, the mixture was extracted with chloroform, and the chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (63 mg, yield 64%).
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46]([CH2:48][C:49](O)=O)#[N:47].C(=O)([O-])O.[Na+]>C(#N)C>[C:46]([CH2:48][C:49]1[NH:45][C:44]2[CH:43]=[CH:42][CH:41]=[C:3]([C:4]([NH:6][C:7]3[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=4[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)=[O:28])=[O:12])=[CH:9][C:8]=3[O:39][CH3:40])=[O:5])[C:2]=2[N:1]=1)#[N:47]
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Reactant: N#CCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CC#N)nc12
Temperature: 100 °C
Yield: 30.9 %

Procedure:
To a solution of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (240 mg) in acetonitrile (1 ml) was added cyanoacetic acid (662 mg). The solution was heated at 100° C. for 8 hours. After cooling, aqueous sodium hydrogen carbonate was added to the mixture and extracted with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (7% methanol in chloroform) and preparative thin-layer chromatography (ethyl acetate:methanol=1:1) to give 4-[[2-cyanomethyl-1H-benzimidazol-4-yl]carbonylamino]-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (80 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)[C:5]([Cl:22])=[CH:4][N:3]=1.[F:23][CH:24]([F:31])[N:25]1[CH:29]=[C:28]([NH2:30])[CH:27]=[N:26]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[Cl:22][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2([C:19]([NH2:21])=[O:20])[CH2:18][CH2:17]2)=[N:7][C:2]([NH:30][C:28]2[CH:27]=[N:26][N:25]([CH:24]([F:31])[F:23])[CH:29]=2)=[N:3][CH:4]=1
Reactant: NC(=O)C1(c2ccccc2CCc2nc(Cl)ncc2Cl)CC1
Reactant: Nc1cnn(C(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C(F)F)c3)ncc2Cl)CC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 5 %

Procedure:
A mixture of 1-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide A14 (0.076 g, 0.225 mmol), 1-(difluoromethyl)-1H-pyrazol-4-amine A28 (0.030 g, 0.23 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.023 mmol) in 1,4-dioxane (4.0 mL) was stirred in a microwave reactor at 120° C. for 2 hours. The volatiles were evaporated in vacuo and the residue was purified by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-5% MeOH in DCM). Fractions containing suspected product were combined and the solvent removed in vacuo to give a residue that was purified further by column chromatography (Biotage Isolera, 12 g SiO2 cartridge, 0-60% EtOAc in petroleum benzine 40-60° C.). Fractions containing suspected product were combined, the solvent was removed in vacuo and the resulting solid purified by prep-LCMS to give the title compound 34 as a white solid (0.005 g, 5%). LCMS-B: rt 3.41 min; m/z 433 [M+H]+.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].[H-].[Na+]>CN(C)C=O.O>[NH2:16][C:15]1[C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[S:8][C:1]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1Cl
Reactant: SCc1ccccc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(-c2ccccc2)sc2ccccc12
Yield: 93.4 %

Procedure:
from 10.5 g (84 mmol) of benzylmercaptan and the equimolar quantity of sodium methoxide the corresponding salt is prepared. A solution of sodium benzylthiolate is stirred for 1 hour at ambient temperature in 150 milliliters of absolute dimethyl formamide after the addition of 10.5 g (76 mmol) of 2-chloro-benzonitrile and 8.0 g of a disbursion of NaH at 50% (0.167 mol). The mixture is then poured into water and the product extracted with CH2Cl2. By evaporating the organic phase dried over Na2SO4 and re-crystallising the residue in cyclohexane, 16.0 g (93% of theory) of 3-amino-2-phenyl--benzo(b)thiophene are obtained, yellow plates, mp 110°-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([O-])([OH:12])=[O:11]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: COc1ccc(O)c([N+](=O)[O-])c1
Yield: 58 %

Procedure:
To a stirred solution of 124 mg of 4-methoxyphenol in dichloromethane were added 1 g of silica gel and 0.077 ml of concentrated nitric acid at room temperature. After the completion of the reaction was detected by thin layer chromatography, the reaction mixture was filtered using Cerite. The filtrate was evaporated, and the residue was purified by silica gel chromatography (dichloromethane) to give 98.5 mg (58%) of 4-methoxy-2-nitrophenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1.[Br:16]N1C(=O)CCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C@H:5]1[C:9]2[CH:10]=[C:11]([Br:16])[C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)C[C@@H]1COc2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 36 h
Yield: 99.9 %

Procedure:
To a mixture of methyl((3S)-6-hydroxy-2,3-dihydro-1-benzofuran-3-yl)acetate (10 g) in THF (dry) (192 mL) was added N-bromosuccinimide (8.55 g) at 0° C. The mixture was gradually warmed to room temperature and stirred at room temperature for 1.5 day. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (13.78 g).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[C:8]([C:49]#[N:50])=[CH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:50][CH2:49][C:8]1[C:9]([NH:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][CH:7]=1
Reactant: CCCCc1ncc(C#N)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCc1ncc(CN)c(NCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)n1

Procedure:
2-Butyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine-5-carbonitrile, the intermediate in Step 2 of Example 14, is reduced with excess lithium aluminum hydride to afford 5-aminomethyl-2-butyl-4-{N-[(2'-[N-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyrimidine. The triphenylmethyl group is removed, as described in Step 4 of Example 1, to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([OH:16])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27]>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH:13]([O:16][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])[CH2:14][CH3:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(Oc1ccccc1[N+](=O)[O-])C(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 2 h
Yield: 56.3 %

Procedure:
7.05 g (30.2 mmol) 2-tert-Butoxycarbonylamino-3-hydroxy-pentanoic acid in 7 ml dimethylformamide were added at 0° C. to 2.80 g (64.1 mmol) sodium hydride (55%) in 56 ml dimethylformamide. The suspension was stirred for 2 hours and then 3.54 ml (33.2 mmol) 1-fluoro-2-nitrobenzene were added. After stirring for 2 days the mixture was poured on ice/water and extracted with diethylether. The pH was adjusted to 1 by adding aqueous hydrochloric acid. Extraction with ethylacetate and chromatography on silicagel with ethylacetate/heptane 1/1 yielded 6.03 g (56%) 2-tert-butoxycarbonylamino-3-(2-nitro-phenoxy)-pentanoic acid as orange oil, MS m/e (%): 353.4 (M−H, 100).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10](I)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]2[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]2)=[CH:20][C:19]=1[F:33])#[CH:17].C(N(C(C)C)C(C)C)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([C:18]1[CH:32]=[CH:31][C:21]([CH2:22][N:23]3[CH2:26][CH:25]([C:27]([O:29][CH3:30])=[O:28])[CH2:24]3)=[CH:20][C:19]=1[F:33])=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Reactant: Nc1ccc(Cc2ccccc2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(Cc5ccccc5)ccc4[nH]3)c(F)c2)C1
Reaction time: 3 h

Procedure:
To a sealed flask was added 4-benzyl-2-iodobenzenamine (0.20 g, 0.65 mmol) and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate (0.32 g, 1.3 mmol) in THF (15 mL). To this solution was added PdCl2(PPh3)2 (0.045 g, 0.065 mmol), CuI (0.025 g, 0.13 mmol), and ethyldiisopropylamine (0.90 mL, 5.2 mmol). The flask was flushed with Ar, sealed and placed in a preheated oil bath at 100° C. for 3 h. The mixture was concentrated under reduced pressure to afford a dark oil which was adsorbed onto silica and purified (30% EtOAc/hexanes to 100% EtOAc) to afford title compound as a yellow oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.1 (M++1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10](I)=[CH:9][N:8]([C:12]([CH3:22])([CH3:21])[CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:6]=2[N:7]=1.[Br:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([CH:35]=1)[C:29](N(OC)C)=[O:30]>>[Br:23][C:24]1[CH:35]=[C:28]([C:29]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[N:8]([C:12]([CH3:22])([CH3:21])[CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[CH:9]=2)=[O:30])[CH:27]=[N:26][CH:25]=1
Reactant: CC(C)(COC1CCCCO1)n1cc(I)c2cnc(Cl)nc21
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(Br)c2)c2cnc(Cl)nc21

Procedure:
The title compound was prepared according to the method described for Preparation 28 using 2-chloro-7-[1,1-dimethyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (see Preparation 45) and 5-bromo-N-methoxy-N-methylnicotinamide to afford the title compound as a yellow solid in 41% yield, 3.0 g.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].Br[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O1CCOCC1.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH3:19][C:13]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: CC1(Br)CCCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)/C(=N\OC1(C)CCCCC1)C(C)=O
Yield: 68.3 %

Procedure:
Ethyl (Z)-2-hydroxyimino-3-oxobutyrate (3.18 g, 20 mmol) and 1-bromo-1-methylcyclohexane (3.54 g, 20 mmol) in dry dioxane (15 ml) were stirred together in the dark and silver trifluoromethanesulphonate (5.13 g, 20 mmol) was added portionwise over 4 h. After a total of 100 h the mixture was filtered through Kieselguhr and the residue was washed well with dioxane. The filtrate was evaporated in vacuo, toluene was added and evaporated in vacuo and the residual oil was dissolved in ethyl acetate and washed with dilute aqueous NaHCO3, followed by water and brine. Ater drying (MgS4) the ethyl acetate was evaporated in vacuo and the residual oil was chromatographed on silica gel, to give the title compound as a yellow oil (3.49 g; 69%); νmax (CH2Cl2) 2945, 1740, 1685, 1370, 1320, 1235, 1070 and 1005 cm-1 ; δH (60 MHz, CDCl3) 1.35 (6H, s superimposed on t), 1.4-2.0 (10H, m), 2.37 (3H, s), 4.55 (2H, q, J 7 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[NH:36][N:35]=NN=3)[CH:14]=2)=[CH:4][N:3]=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:6][C:5]([C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][N:19]3[S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[C:15]([C:32]3[O:40][C:39]([CH2:38][Cl:37])=[N:35][N:36]=3)[CH:14]=2)=[CH:4][N:3]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnn[nH]4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2ncc3c(-c4nnc(CCl)o4)cc(-c4cnc(Cl)c(NS(C)(=O)=O)c4)cc32)cc1
Temperature: 105 °C
Yield: 23.5 %

Procedure:
N-{2-Chloro-5-[1-[(4-methylphenyl)sulfonyl]-4-(1H-tetrazol-5-yl)-1H-indazol-6-yl]-3-pyridinyl}methanesulfonamide (1.3 g, 2.385 mmol) and chloro acetylchloride (0.285 ml, 3.58 mmol) were placed in toluene (35 ml) and the mixture heated at 105° C. for 30 mins. The temperature was increased to 115° C. and the mixture heated for 1 h. The mixture was cooled to room temperature and the solvent removed in vacuo. This was purified by chromatography on a silica (100 g) cartridge eluting with 0-100% ethyl acetate in cyclohexane followed by 0-20% methanol in dichloromethane, to give the title compound as a yellow solid (0.332 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[Cl:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][N:27]2[CH3:30])=[CH:23][C:22]=1[NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:19])[CH2:12][CH:13]([CH3:18])[CH2:14][C:15]([NH:31][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][C:21]=2[Cl:20])[N:27]([CH3:30])[CH:26]=[CH:25]3)=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cn1ccc2cc(N)c(Cl)cc21
Reactant: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Product: CC(CC(=O)Nc1ccc(C#N)c(Cl)c1)CC(=O)Nc1cc2ccn(C)c2cc1Cl

Procedure:
Using 5-(3-chloro-4-cyanophenylamino)-3-methyl-5-oxopentanoic acid and 6-chloro-1-methyl-1H-indol-5-amine, and by the reaction and purification in the same manner as in the method described in Step 2 of Example 3, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][S:7]([NH2:10])(=[O:9])=[O:8].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[CH:5]=[CH:6][S:7]([NH:10][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:17]([O:16][CH3:15])[CH:18]=1)(=[O:8])=[O:9]
Reactant: NS(=O)(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(C(=O)NS(=O)(=O)C=Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 70 %

Procedure:
A mixture of 3,4-dichlorostyrylsulfonamide (12.6 g., 0.05 mole) and 3,4-dimethoxybenzoyl chloride (11.0 g., 0.055 mole) in 15 ml. of phosphorous oxychloride is heated at steam bath temperature for a period of 30 min. Excess phosphorous oxychloride is removed under reduced pressure and dry benzene added. The benzene is evaporated and the treatment repeated two times. Benzene (50 ml.) is added to the residue thus obtained and the insoluble solid collected providing 14.6 g. (70% yield) of N-(3,4-dichlorostyrylsulfonyl)-3,4-dimethoxybenzamide, m.p. 145°-147° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH:28]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCC1

Procedure:
The title compound, white solid (77 mg, 75%), MS (ISP) m/z=413.5 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: O.O.Cl[Sn]Cl.[Cl:6][C:7]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:8]=1[C:9]([N:11]1[CH2:17][CH2:16][CH:15]=[CH:14][C:13]2[S:18][CH:19]=[CH:20][C:12]1=2)=[O:10]>C(O)C>[Cl:6][C:7]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:8]=1[C:9]([N:11]1[CH2:17][CH2:16][CH:15]=[CH:14][C:13]2[S:18][CH:19]=[CH:20][C:12]1=2)=[O:10]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCC=Cc2sccc21
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(C(=O)N2CCC=Cc3sccc32)c(Cl)c1
Temperature: 75 °C

Procedure:
To a solution of 2.36 g of SnCl2.2H2O in 13 ml of ethanol is added 0.70 g of 4-(2-chloro-4-nitrobenzoyl)-5,6-dihydro-4H-thieno[3,2-b]azepine. The mixture is heated at 75° C. for one hour, cooled to room temperature and concentrated under vacuum to 10 ml. The mixture is chilled in an ice bath and 1M NaHCO3 added slowly. The mixture is extracted with 100 ml ethyl acetate and then with 80 ml of ethyl acetate. The extracts are combined, washed with brine and dried (Na2SO4). The extract is passed through a thin pad of hydrous magnesium silicate and the pad washed with ethyl acetate. The filtrate is concentrated to give a solid which is crystallized from ethyl acetate to give white crystals, m.p. 192°-200° C.